No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Lyonization Effects of the t(X;16) Translocation on the Phenotypic Expression in a Rare Female With Menkes Disease
Abstract
Menkes disease (MD) is a rare and severe X-linked recessive disorder of copper metabolism. The MD gene, ATP7A (ATPase Cu++ transporting alpha polypeptide), encodes an ATP-dependent copper-binding membrane protein. In this report, we describe a girl with typical clinical features of MD, carrying a balanced translocation between the chromosomes X and 16 producing the disruption of one copy of ATP7A gene and the silencing of the other copy because of the chromosome X inactivation. Fluorescence in situ hybridization experiments with bacterial derived artificial chromosome probes revealed that the breakpoints were located within Xq13.3 and 16p11.2. Replication pattern analysis demonstrated that the normal X chromosome was late replicating and consequently inactivated, whereas the der(X)t(X;16), bearing the disrupted ATP7A gene, was active. An innovative approach, based on FMR1 (fragile X mental retardation 1) gene polymorphism, has been used to disclose the paternal origin of the rearrangement providing a new diagnostic tool for determining the parental origin of defects involving the X chromosome and clarifying the mechanism leading to the cytogenetic rearrangement that occurred in our patient.
... MD variant phenotypes have been reported in some females [Barton et al., 1983;Favier et al., 1983;Gerdes et al., 1990;Moller et al., 2012], mostly associated with X-autosome translocations disrupting the ATP7A locus [Abusaad et al., 1999;Beck et al, 1994;Kapur et al., 1987;Sirleto et al., 2009;Sugio et al., 1998]. Heterozygous females were previously thought to be asymptomatic; however, half of obligate carrier females show regions of pili torti [Moore and Howell, 1985]. ...
... In a study by Kaler et al. [2010] only 12.5% of 24 male patients with classic MD, diagnosed and treated prior to 6 weeks of age, manifested clinical seizures, whereas 46% of them had at least one abnormal EEG tracing. The authors proposed that early identification and treatment of classic MD "improves brain electrical activity and decreases seizure occurrence in classic MD", Barton al., 1983 x x x x 2.5 Y/ death Favier et al., 1983 x x x x 34 Y Kapur et al., 1987 x x x x unknown Gerdes et al., 1990 x Beck et al., 1994 x x x unknown Sugio et al., 1998 x x x x unknown Abusaad et al., 1999 x x x x 18 M/ death Sirleto et al., 2009 x x x 26 M Moller et al., 2012 x Barton et al., 1983 unknown Mosaic TS Unknown Favier et al., 1983Unknown Kapur et al., 1987 x 46,X, t(X;2) (q13;q32.2) Unknown Gerdes et al., 1990 x Unknown Beck et al., 1994 x 46,X, t(X;1) (q13;q12) Unknown Sugio et al., 1998 x 46,X, t(X;21) (q13.3;p11.1) Unknown Abusaad et al., 1999 x 46,X, t(X;13) (q13.3;q14.3) ...
... Unknown Abusaad et al., 1999 x 46,X, t(X;13) (q13.3;q14.3) Unknown Sirleto et al., 2009 x 46,X, t(X;16) (q13.3;p11.2) Unknown Moller et al., 1998 x exon 6 deletion exon 6-9 deletion intronic missense Unknown c.2179G>A Unknown c.2383C>A x exon 1 deletion c.532G>T Present report ...
Menkes disease (MD; OMIM 309400) is an X-linked, neurodegenerative disorder resulting from deficient activity of copper-dependent enzymes and caused by alterations in the APT7A gene. In its classic form, it manifests in boys with hypotonia, seizures, skin and joint laxity, hair twisting (pili torti), cerebrovascular tortuosity, and bladder diverticulae. Menkes disease phenotypes have been reported in females with X; autosome translocations- disrupting ATP7A gene function- or ATP7A gene alterations. Those females manifest variable clinical findings, some of which, such as pili torti, seizure presence and/or age of onset, cerebrovascular tortuosity, degree of intellectual disability, and bladder divericulae are largely under-reported and under-studied. Here, we report on three females with Menkes disease and variant phenotypes, sharing characteristic features, one with classic Menkes disease and two with Menkes disease variants. We conclude that Menkes disease in females manifests with a variable spectrum of clinical findings but a few are uniformly present such as neurodevelopmental disability, hypotonia, and connective tissue findings. Others, such as seizures, cerebral atrophy, and cerebrovascular tortuosity may be present but are under-reported and under- studied. We propose that the diagnosis of Menkes disease or variants in females with suspicious clinical findings is an important one to consider as early treatment with parenteral copper may be considered. The effect of this treatment on the disease course in females with MD is unknown and remains to be seen. © 2014 Wiley Periodicals, Inc.
© 2014 Wiley Periodicals, Inc.
... Classical MD is characterized by mental retardation, hypothermia, seizures, cutis laxa, hypo-pigmentation, abnormal hair (kinky hair or pili torti), and decreased serum ceruloplasmin levels [3]. The majority of Menkes patients are males and, to our knowledge, only 9 affected females have been described so far45678910. Five of these patients had X-autosomal translocations5679,10] one had 45X/46XX mosaicism [4], one had an unknown karyotype [8], and two patients had normal karyotypes [4] . ...
... The majority of Menkes patients are males and, to our knowledge, only 9 affected females have been described so far45678910. Five of these patients had X-autosomal translocations5679,10] one had 45X/46XX mosaicism [4], one had an unknown karyotype [8], and two patients had normal karyotypes [4] . Skewed X-inactivation has been reported previously in unaffected female carriers [11], but to our knowledge, X-inactivation has not previously been investigated in females who are affected with MD, but have a normal karyotype. ...
... Five female cases of MD carrying X-autosome translocations have been described previously. Although the clinical symptoms of these females are generally more severe than the symptoms of the affected females with normal karyotypes described here, the clinical features were, at least also for the majority of these female patients, milder than those of the affected boys [9,10]. Studies of late replicating X performed in three of the five patients with X-autosome translocations revealed that the normal X-chromosome was inactive, at least in the majority of the analyzed cells [7,9,10]. ...
Menkes Disease (MD) is a rare X-linked recessive fatal neurodegenerative disorder caused by mutations in the ATP7A gene, and most patients are males. Female carriers are mosaics of wild-type and mutant cells due to the random X inactivation, and they are rarely affected. In the largest cohort of MD patients reported so far which consists of 517 families we identified 9 neurologically affected carriers with normal karyotypes.
We investigated at-risk females for mutations in the ATP7A gene by sequencing or by multiplex ligation-dependent probe amplification (MLPA). We analyzed the X-inactivation pattern in affected female carriers, unaffected female carriers and non-carrier females as controls, using the human androgen-receptor gene methylation assay (HUMAR).
The clinical symptoms of affected females are generally milder than those of affected boys with the same mutations. While a skewed inactivation of the X-chromosome which harbours the mutation was observed in 94% of 49 investigated unaffected carriers, a more varied pattern was observed in the affected carriers. Of 9 investigated affected females, preferential silencing of the normal X-chromosome was observed in 4, preferential X-inactivation of the mutant X chromosome in 2, an even X-inactivation pattern in 1, and an inconclusive pattern in 2. The X-inactivation pattern correlates with the degree of mental retardation in the affected females. Eighty-one percent of 32 investigated females in the control group had moderately skewed or an even X-inactivation pattern.
The X- inactivation pattern alone cannot be used to predict the phenotypic outcome in female carriers, as even those with skewed X-inactivation of the X-chromosome harbouring the mutation might have neurological symptoms.
... However, at least 22 female patients have been reported to date (Supplementary Table 3). Some of them were due to X-autosomal translocation [22][23][24][25][26] , mosaic of Turner syndrome 27 , and microdeletion of Xq28 4 , and 13 patients had a normal karyotype 4,10,27,28 . Skewed XCI (ratio < 24:76) toward the normal X chromosome was demonstrated in 4 patients, and among them, 3 patients had family members with skewed XCI toward the opposite mutated allele 10 . ...
Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene, and female carriers are usually asymptomatic. We describe a 7-month-old female patient with severe intellectual disability, epilepsy, and low levels of serum copper and ceruloplasmin. While heterozygous deletion of exons 16 and 17 of the ATP7A gene was detected in the proband, her mother, and her grandmother, only the proband suffered from Menkes disease clinically. Intriguingly, X chromosome inactivation (XCI) analysis demonstrated that the grandmother and the mother showed skewing of XCI toward the allele with the ATP7A deletion and that the proband had extremely skewed XCI toward the normal allele, resulting in exclusive expression of the pathogenic ATP7A mRNA transcripts. Expression bias analysis and recombination mapping of the X chromosome by the combination of whole genome and RNA sequencing demonstrated that meiotic recombination occurred at Xp21-p22 and Xq26-q28. Assuming that a genetic factor on the X chromosome enhanced or suppressed XCI of its allele, the factor must be on either of the two distal regions derived from her grandfather. Although we were unable to fully uncover the molecular mechanism, we concluded that unfavorable switching of skewed XCI caused Menkes disease in the proband.
... 221,222 Other female carriers present milder symptoms due to exon deletions or base-pair substitutions. 220,223,224 For patients with less severe phenotypes, Cu supplementation therapies result in improved survival rates; however, the response depends on the severity of the ATP7A mutation and the function of the resultant protein. Cu excretion via the biliary tract is also impaired, resulting in accumulation of Cu in the liver. ...
Copper (Cu) is an essential micronutrient required for the activity of redox‐active enzymes involved in critical metabolic reactions, signaling pathways, and biological functions. Transporters and chaperones control Cu ion levels and bioavailability to ensure proper subcellular and systemic Cu distribution. Intensive research has focused on understanding how mammalian cells maintain Cu homeostasis, and how molecular signals coordinate Cu acquisition and storage within organs. In humans, mutations of genes that regulate Cu homeostasis or facilitate interactions with Cu ions lead to numerous pathologic conditions. Malfunctions of the Cu⁺‐transporting ATPases ATP7A and ATP7B cause Menkes disease and Wilson disease, respectively. Additionally, defects in the mitochondrial and cellular distributions and homeostasis of Cu lead to severe neurodegenerative conditions, mitochondrial myopathies, and metabolic diseases. Cu has a dual nature in carcinogenesis as a promotor of tumor growth and an inducer of redox stress in cancer cells. Cu also plays role in cancer treatment as a component of drugs and a regulator of drug sensitivity and uptake. In this review, we provide an overview of the current knowledge of Cu metabolism and transport and its relation to various human pathologies.
... However, there have been five reports of Menkes disease affecting female patients with translocations that damaged ATP7A [43]. The disease in these cases is probably caused by inactivation of the X chromosome skewed towards leaving the derived chromosome X functional (the opposite scenario leads to partial monosomy of the autosome involved in the BCTs which induces cell death [44]). We conclude that it is highly probable that the identified translocation is responsible for the phenotype of the patient. ...
De novo balanced chromosomal aberrations (BCAs), such as reciprocal translocations and inversions, are genomic aberrations that, in approximately 25% of cases, affect the human phenotype. Delineation of the exact structure of BCAs may provide a precise diagnosis and/or point to new disease loci. We report on six patients with de novo balanced chromosomal translocations (BCTs) and one patient with a de novo inversion, in whom we mapped breakpoints to a resolution of 1 bp, using shallow whole-genome mate pair sequencing. In all seven cases, a disruption of at least one gene was found. In two patients, the phenotypic impact of the disrupted genes is well known (NFIA, ATP7A). In five patients, the aberration damaged genes: PARD3, EPHA6, KLF13, STK24, UBR3, MLLT10 and TLE3, whose influence on the human phenotype is poorly understood. In particular, our results suggest novel candidate genes for retinal degeneration with anophthalmia (EPHA6), developmental delay with speech impairment (KLF13), and developmental delay with brain dysembryoplastic neuroepithelial tumor (UBR3). In conclusion, identification of the exact structure of symptomatic BCTs using next generation sequencing is a viable method for both diagnosis and finding novel disease candidate genes in humans.
... Females may manifest the disease in cases of Turner syndrome, X-Autosome translocation, and unfavorably skewed X inactivation. [6][7][8][9] First case of our series had balanced X-autosome translocation 46,X,t(X;13)(q21;p11)[20] manifesting with classical MD. As expected by usual patterns of X inactivation observed in the majority of X-autosome balanced translocations, the X homolog involved in the X-autosome translocation which has an intact XIC at Xq13 (X-inactivation center) remains active, and the normal X chromosome gets inactivated. ...
Background:
Menkes disease (MD) is an X-linked recessive neurodegenerative disorder caused by mutations in ATP7A gene. Depending on the residual ATP7A activity, manifestation may be classical MD, occipital horn syndrome, or distal motor neuropathy. Neurological sparing is expected in female carriers. However, on rare occasions, females may manifest with classical clinical phenotype due to skewed X-chromosome inactivation, X-autosome translocation, and XO genotype. Here, we describe a small series of probands with MD and their response to copper histidine therapy. This series also includes a female with X-13 translocation manifesting neurological symptoms.
Methods:
The clinical profile, laboratory and radiological data, and follow-up of four children with MD were collected from the hospital database and are being presented.
Results:
All the four children in our series had developmental delay, recurrent respiratory tract infections, hair and skeletal changes, axial hypotonia, tortuous vessels on imaging, low serum copper, ceruloplasmin, and elevated lactate. Fetal hypokinesia and fetal growth retardation were present in two cases. Failure to thrive was present in three children and only one child had epilepsy. Subcutaneous copper histidine was administered to all children. The average time lapse in the initiation of treatment was 20.3 months, and average duration of follow-up was 14.3 months.
Conclusion:
We conclude that copper histidine therapy is beneficial in reversing the skin and hair changes, improving appendicular tone, socio-cognitive milestones, and improving weight gain, and immunity. Early diagnosis and management of MD are essential to have a better clinical outcome. More research is needed to explore and devise new strategies in the management of patients with MD.
... 4,11 In addition, there are few reports of females with milder symptoms who carry exon deletions (exon 6, 6-9, 1) or base-pair substitutions. [12][13][14] ...
Rahul Ojha,1 Asuri N Prasad1–4 1Department of Pediatrics, 2Section of Pediatric Neurology, 3Division of Clinical Neurological Sciences, 4Child Health Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada Abstract: Disorders of copper homeostasis are currently recognized across the life span. Their recognition and links to human disease have spanned several decades, beginning with the recognition of a degenerative disorder in the offspring of sheep grazing in copper-deficient pastures, through to the description of infants suffering from a progressive neurodegenerative disorder characterized by epileptic seizures, developmental regression, failure to thrive, and an unusual hair quality (giving the condition its distinctive label of “kinky hair disease”). In this review, we trace the historical background and describe the biochemistry and physiology of copper metabolism and transport, inheritance patterns, molecular genetics, and genotype–phenotype correlations based on current understanding of the disorder. It is clear from the clinical presentations and variants that disorders of copper homeostasis include phenotypes ranging from mild occipital horn syndrome to intermediate and severe forms of classical Menkes disease. The symptoms involve multiple organ systems such as brain, lung, gastrointestinal tract, urinary tract, connective tissue, and skin. A multisystem disorder needs a multidisciplinary approach to care, as treatment interventions permit longer survival for some individuals. Animal models have been developed to help screen treatment options and provide a better understanding of these disorders in the laboratory. Finally, we propose a multidisciplinary approach to promote continued research (both basic and clinical) to improve survival, quality of life, and care for these conditions. Keywords: Menkes disease, kinky hair, ceruloplasmin, neurodegenerative, copper homeostasis
... Menkes disease (MD), first described in 1962 by Menkes et al., is an X-linked recessive neurodegenerative disorder of copper metabolism (Desai et al., 2011;Menkes et al., 1962;Horn and Morton, 1986;Sirleto et al., 2009;Tümer and Møller, 2010), caused by mutations in a coppertransporting P-type adenosine triphosphatase (ATPase), type A (ATP7A) which plays a critical role in the development of the central nervous system. Absence or severe reduction in ATP7A activity compromises the intestinal uptake of copper and its consecutive transport into the developing brain (Kaler, 2013;, and results in a significant reduction of normal copper levels in the blood, liver, and brain (Danks et al., 1973). ...
... To date, only a few patients with the mild form have been reported [6]. A few female MNK patients were diagnosed having X chromosome abnormalities [7]. ...
... CS Alive, 4 years 8 months dn Sugio et al. (1998) 259 46,X,t(X;13)(q13.3;q14.3) CS 18 months dn Abusaad et al. (1999) 260 46,X,t(X;16)(q13.3;p11.2) CS Alive, 2 years 2 months dn Sirleto et al. (2009) ...
Menkes disease (MD) is a lethal multisystemic disorder of copper metabolism. Progressive neurodegeneration and connective tissue disturbances, together with the peculiar "kinky" hair are the main manifestations. MD is inherited as an X-linked recessive trait, and as expected the vast majority of patients are males. MD occurs due to mutations in the ATP7A gene and the vast majority of ATP7A mutations are intragenic mutations or partial gene deletions. ATP7A is an energy dependent transmembrane protein, which is involved in the delivery of copper to the secreted copper enzymes and in the export of surplus copper from cells. Severely affected MD patients die usually before the third year of life. A cure for the disease does not exist, but very early copper-histidine treatment may correct some of the neurological symptoms. This study reviews 274 published and 18 novel disease causing mutations identified in 370 unrelated MD patients, non-pathogenic variants of ATP7A, functional studies of the ATP7A mutations and animal models of MD.
... To date, only a few patients with the mild form have been reported [6]. A few female MNK patients were diagnosed having X chromosome abnormalities [7]. ...
Menkes disease (MNK) is an X-linked recessive disorder. Incidence of live-born infants with MNK is 2.8 per million live births in Japan. The aim of this study was to observe congenital malformations (CMs) in MNK patients. Subjects comprised 35 Japanese male patients with classical MNK who received copper histidine treatment. Patient clinical data were obtained anonymously from medical records or medical record summaries by pediatrician's retrospective review through a survey. We observed 21 different CMs in 14 patients. Eight of these had a single CM, while six had multiple CMs. The most frequent CM was higher arched palate with other CMs found in five patients. There was no relationship between CMs and mutations in the ATP7A gene. Using Mann-Whitney U tests, age at death was also significantly lower in MNK patients with CMs (P<0.05), compared to those without CMs, even though there was no significant difference of age onset, age at diagnosis and age at start of treatment with copper histidine between both groups of patients. Sudden death occurred in three MNK patients with CMs only: two with congenital heart disease, and one with microphallus.
... The skin and joint laxity of P5CSD is most likely the manifestation of alterations in the proline-rich connective tissue proteins collagen and elastin, as reflected in the morphological findings in the skin biopsy of the patient. Also arguing in favor of the involvement of collagen and elastin is the observation of changes in brain vasculature that replicate the kinky vessels found in Menkes disease (Sirleto et al. 2009), a disease in which a secondary defect in lysyl oxydation (and thus in collagen and elastin crosslinking; Robins 2007;Wagenseil and Mecham 2007) has been clearly documented (Royce and Steinmann 1990). Further support for a central role of collagen/elastin alterations is provided by the similarities with the arterial tortuosity syndrome (ATS; MIM208050) (Coucke et al. 2006), which also exhibits skin and joint laxity and which is due to loss-of-function mutations in the dehydroascorbate transporter GLUT10 (Lee et al. 2010;Segade 2010). ...
Δ(1)-Pyrroline-5-carboxylate synthetase (P5CS) catalyzes the first two steps of ornithine/proline biosynthesis. P5CS deficiency has been reported in three families, with patients presenting with cutis/joint laxity, cataracts, and neurodevelopmental delay. Only one family exhibited metabolic changes consistent with P5CS deficiency (low proline/ornithine/citrulline/arginine; fasting hyperammonemia). Here we report a new P5CS-deficient patient presenting the complete clinical/metabolic phenotype and carrying p.G93R and p.T299I substitutions in the γ-glutamyl kinase (γGK) component of P5CS. The effects of these substitutions are (1) tested in mutagenesis/functional studies with E.coli γGK, (2) rationalized by structural modelling, and (3) reflected in decreased P5CS protein in patient fibroblasts (shown by immunofluorescence). Using optical/electron microscopy on skin biopsy, we show collagen/elastin fiber alterations that may contribute to connective tissue laxity and are compatible with our angio-MRI finding of kinky brain vessels in the patient. MR spectroscopy revealed decreased brain creatine, which normalized after sustained arginine supplementation, with improvement of neurodevelopmental and metabolic parameters, suggesting a pathogenic role of brain creatine decrease and the value of arginine therapy. Morphological and functional studies of fibroblast mitochondria show that P5CS deficiency is not associated with the mitochondrial alterations observed in Δ(1)-pyrroline-5-carboxylate reductase deficiency (another proline biosynthesis defect presenting cutis laxa and neurological alterations).
... Cases of MD in females have been reported, but are rare. In a recent study, Sirleto et al. described 8 females who reportedly had MD, and showed that 5 of them carried X-linked chromosomal abnormalities [42]. ...
Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellular damage. Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, occipital horn syndrome, and Wilson’s disease.
Menkes disease and occipital horn syndrome are characterized by copper deficiency. Typical features of Menkes disease result from low copper-dependent enzyme activity. Standard treatment involves parenteral administration of copper-histidine. If treatment is initiated before 2 months of age, neurodegeneration can be prevented, while delayed treatment is utterly ineffective. Thus, neonatal mass screening should be implemented. Meanwhile, connective tissue disorders cannot be improved by copper-histidine treatment. Combination therapy with copper-histidine injections and oral administration of disulfiram is being investigated. Occipital horn syndrome characterized by connective tissue abnormalities is the mildest form of Menkes disease. Treatment has not been conducted for this syndrome.
Wilson’s disease is characterized by copper toxicity that typically affects the hepatic and nervous systems severely. Various other symptoms are observed as well, yet its early diagnosis is sometimes difficult. Chelating agents and zinc are effective treatments, but are inefficient in most patients with fulminant hepatic failure. In addition, some patients with neurological Wilson’s disease worsen or show poor response to chelating agents. Since early treatment is critical, a screening system for Wilson’s disease should be implemented in infants. Patients with Wilson’s disease may be at risk of developing hepatocellular carcinoma. Understanding the link between Wilson’s disease and hepatocellular carcinoma will be beneficial for disease treatment and prevention.
... A total of 10 females affected with Menkes disease have been reported (22,23), among whom one was mosaic for Turner (XO) syndrome and five had X-autosome translocations interrupting the ATP7A gene. As predicted for the latter circumstance (24), the normal X chromosomes in these five patients were preferentially inactivated, avoiding haploinsufficiency of the autosomal genes involved but resulting in the expression of Menkes disease. ...
Desai V, Donsante A, Swoboda KJ, Martensen M, Thompson J, Kaler SG. Favorably skewed X-inactivation accounts for neurological sparing in female carriers of Menkes disease.
Classical Menkes disease is an X-linked recessive neurodegenerative disorder caused by mutations in ATP7A, which is located at Xq13.1-q21. ATP7A encodes a copper-transporting P-type ATPase and plays a critical role in development of the central nervous system. With rare exceptions involving sex chromosome aneuploidy or X-autosome translocations, female carriers of ATP7A mutations are asymptomatic except for subtle hair and skin abnormalities, although the mechanism for this neurological sparing has not been reported. We studied a three-generation family in which a severe ATP7A mutation, a 5.5-kb genomic deletion spanning exons 13 and 14, segregated. The deletion junction fragment was amplified from the proband by long-range polymerase chain reaction and sequenced to characterize the breakpoints. We screened at-risk females in the family for this junction fragment and analyzed their X-inactivation patterns using the human androgen-receptor (HUMARA) gene methylation assay. We detected the junction fragment in the proband, two obligate heterozygotes, and four of six at-risk females. Skewed inactivation of the X chromosome harboring the deletion was noted in all female carriers of the deletion (n = 6), whereas random X-inactivation was observed in all non-carriers (n = 2). Our results formally document one mechanism for neurological sparing in female carriers of ATP7A mutations. Based on review of X-inactivation patterns in female carriers of other X-linked recessive diseases, our findings imply that substantial expression of a mutant ATP7A at the expense of the normal allele could be associated with neurologic symptoms in female carriers of Menkes disease and its allelic variants, occipital horn syndrome, and ATP7A-related distal motor neuropathy.
... Chromosome abnormalities affecting ATP7A were detected in eight patients, one male 33 and seven female patients. One of the female patients was mosaic for the Turner karyotype and the rest had X;autosome translocations (reviewed by Sirleto et al 34 ). Approximately 25% of the ATP7A mutations (n¼50) are gross deletions ranging in size from a single exon to deletion of the whole gene except for the first two exons. ...
Menkes disease (MD) is a lethal multisystemic disorder of copper metabolism. Progressive neurodegeneration and connective tissue disturbances, together with the peculiar 'kinky' hair are the main manifestations. MD is inherited as an X-linked recessive trait, and as expected the vast majority of patients are males. MD occurs due to mutations in the ATP7A gene and the vast majority of ATP7A mutations are intragenic mutations or partial gene deletions. ATP7A is an energy dependent transmembrane protein, which is involved in the delivery of copper to the secreted copper enzymes and in the export of surplus copper from cells. Severely affected MD patients die usually before the third year of life. A cure for the disease does not exist, but very early copper-histidine treatment may correct some of the neurological symptoms.
Trace elements are chemical elements needed in minute amounts for normal physiology. Some of the physiologically relevant trace elements include iodine, copper, iron, manganese, zinc, selenium, cobalt and molybdenum. Of these, some are metals, and in particular, transition metals. The different electron shells of an atom carry different energy levels, with those closest to the nucleus being lowest in energy. The number of electrons in the outermost shell determines the reactivity of such an atom. The electron shells are divided in sub-shells, and in particular the third shell has s, p and d sub-shells. Transition metals are strictly defined as elements whose atom has an incomplete d sub-shell. This incomplete d sub-shell makes them prone to chemical reactions, particularly redox reactions. Transition metals of biologic importance include copper, iron, manganese, cobalt and molybdenum. Zinc is not a transition metal, since it has a complete d sub-shell. Selenium, on the other hand, is strictly speaking a nonmetal, although given its chemical properties between those of metals and nonmetals, it is sometimes considered a metalloid. In this review, we summarize the current knowledge on the inborn errors of metal and metalloid metabolism.
Menkes and colleagues described Menkes disease in 1962 that reported five male infants in a family affected with a distinctive syndrome of neurologic degeneration, peculiar hair, and failure to thrive. Menkes disease is also called “kinky or steely hair disease.” The incidence of MK was originally estimated to be 1/35,000 (Danks et al. 1972), but more recent estimates have shown it to be a very rare disorder with 1/300,000 live-born babies affected (Tönnesen et al. 1991, 1992).
Menkes and colleagues described Menkes disease in 1962 that reported five male infants in a family affected with a distinctive syndrome of neurologic degeneration, peculiar hair, and failure to thrive. Menkes disease is also called “kinky or steely hair disease.” The incidence of MK was originally estimated to be 1/35,000 (Danks et al. 1972), but more recent estimates have shown it to be a very rare disorder with 1/300,000 live-born babies affected (Tönnesen et al. 1991, 1992).
In this chapter, we describe genetic movement disorders arising from endogenous dysregulation of calcium, copper, and manganese homeostasis. In general, dysregulation of metal homeostasis may lead to regional brain metal accumulation, systemic metal accumulation affecting the whole brain and other organs, or brain metal deficiency.
Primary familial brain calcification leading to regional brain calcium deposits is caused by mutations in inorganic phosphate transporter 2 (PiT2), platelet-derived growth factor (PDGFβ), or platelet-derived growth factor receptor-β (PDGFRβ). Mutations in these three genes explain 50 % of cases and further causative genes are likely involved.
Systemic accumulation of copper is the hallmark of Wilson disease and MEDNIK syndrome caused by mutations in ATP7B and AP1S1 genes, respectively. Menkes disease, caused by mutations in ATP7A, is an example of disorder of systemic copper deficiency.
Systemic accumulation of manganese has been described in manganese transporter deficiency caused by SLC30A10 mutations. The brain and liver are the most affected organs in these systemic disorders. Kufor-Rakeb syndrome, caused by mutations in ATP13A2, is likely also related to manganese toxicity.
Menkes disease is a lethal multisystemic disorder of copper metabolism characterized by connective tissue abnormalities, progressive neurodegeneration and peculiar "kinky hair." Epilepsy is one of the main clinical features of this disease but it has been described in detail by only a few authors. Most patients develop seizures from 2 to 3 months of age, accompanied by a neurodevelopmental regression. The history of epilepsy is usually characterized by 3 stages: an early stage with focal clonic seizures and status epilepticus, an intermediate stage with infantile spasms, and a late stage with multifocal, myoclonic, and tonic seizures. At the onset, epilepsy can be controlled with anticonvulsant therapy, whereas with the progression of disease, it becomes extremely resistant to all antiepileptic drugs. In this article, we analyze clinical and electroencephalographic (EEG) characteristics of epilepsy in patients with this syndrome.
The European Journal of Human Genetics is the official Journal of the European Society of Human Genetics, publishing high-quality, original research papers, short reports, News and Commentary articles and reviews in the rapidly expanding field of human genetics and genomics.
Moizard M-P, Ronce N, Blesson S, Bieth E, Burglen L, Mignot C, Mortemousque I, Marmin N, Dessay B, Danesino C, Feillet F, Castelnau P, Toutain A, Moraine C, Raynaud M. Twenty-five novel mutations including duplications in the ATP7A gene.
Menkes disease (MD) and occipital horn syndrome (OHS) are allelic X-linked recessive copper deficiency disorders resulting from ATP7A gene mutations. MD is a severe condition leading to progressive neurological degeneration and death in early childhood, whereas OHS has a milder phenotype with mainly connective tissue abnormalities. Until now, molecular analyses have revealed only deletions and point mutations in both diseases. This study reports new molecular data in a series of 40 patients referred for either MD or OHS. We describe 23 point mutations (9 missense mutations, 7 splice site variants, 4 nonsense mutations, and 3 small insertions or deletions) and 7 intragenic deletions. Of these, 18 point mutations and 3 deletions are novel. Furthermore, our finding of four whole exon duplications enlarges the mutation spectrum in the ATP7A gene. ATP7A alterations were found in 85% of cases. Of these alterations, two thirds were point mutations and the remaining one third consisted of large rearrangements. We found that 66.6% of point mutations resulted in impaired ATP7A transcript splicing, a phenomenon more frequent than expected. This finding enabled us to confirm the pathogenic role of ATP7A mutations, particularly in missense and splice site variants.
We have calculated the incidence of Menkes disease for Denmark, France, The Netherlands, the United Kingdom and West Germany, based on known Menkes patients born during the time period 1976-87. Considering live-born Menkes patients, the combined incidence for these five countries is 1 Menkes patient per 298,000 live-born babies. If the number of affected aborted fetuses are taken into account, the incidence is 1 Menkes per 254,000 live-born babies. This incidence, which is 2-4 times lower than earlier published incidence figures, places Menkes disease as an extremely rare disease. The mutation rate for Menkes disease is estimated to be 1.96 x 10(-6), based on the number of isolated Menkes cases born during the time period 1976-87 and the total number of newborn males during this time.
Three female patients with Menkes syndrome are described. Clinically, they have typical Menkes syndrome. Biochemically, they have significantly increased 64Cu-uptake in cultured fibroblasts. The chromosomal analysis was normal for two of the patients and abnormal for one patient (45X/46XX mosaicism).
We present data on corporal punishment (CP) by a nationally representative sample of 991 American parents interviewed in 1995. Six types of CP were examined: slaps on the hand or leg, spanking on the buttocks, pinching, shaking, hitting on the buttocks with a belt or paddle, and slapping in the face. The overall prevalence rate (the percentage of parents using any of these types of CP during the previous year) was 35% for infants and reached a peak of 94% at ages 3 and 4. Despite rapid decline after age 5, just over half of American parents hit children at age 12, a third at age 14, and 13% at age 17. Analysis of chronicity found that parents who hit teenage children did so an average of about six times during the year. Severity, as measured by hitting the child with a belt or paddle, was greatest for children age 5-12 (28% of such children). CP was more prevalent among African American and low socioeconomic status parents, in the South, for boys, and by mothers. The pervasiveness of CP reported in this article, and the harmful side effects of CP shown by recent longitudinal research, indicates a need for psychology and sociology textbooks to reverse the current tendency to almost ignore CP and instead treat it as a major aspect of the socialization experience of American children; and for developmental psychologists to be cognizant of the likelihood that parents are using CP far more often than even advocates of CP recommend, and to inform parents about the risks involved.
Sotos syndrome (SoS) is characterized by pre- and postnatal overgrowth with advanced bone age; a dysmorphic face with macrocephaly and pointed chin; large hands and feet; mental retardation; and possible susceptibility to tumors. It has been shown that the major cause of SoS is haploinsufficiency of the NSD1 gene at 5q35, because the majority of patients had either a common microdeletion including NSD1 or a truncated type of point mutation in NSD1. In the present study, we traced the parental origin of the microdeletions in 26 patients with SoS by the use of 16 microsatellite markers at or flanking the commonly deleted region. Deletions in 18 of the 20 informative cases occurred in the paternally derived chromosome 5, whereas those in the maternally derived chromosome were found in only two cases. Haplotyping analysis of the marker loci revealed that the paternal deletion in five of seven informative cases and the maternal deletion in one case arose through an intrachromosomal rearrangement, and two other cases of the paternal deletion involved an interchromosomal event, suggesting that the common microdeletion observed in SoS did not occur through a uniform mechanism but preferentially arose prezygotically.
To describe the systematic analysis of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes, characterise the structural chromosome rearrangements, map the translocation breakpoints, and report detectable genomic imbalances.
DNA microarrays were used with a resolution of 1 Mb for the detailed genome-wide analysis of the patients. Array CGH was used to screen for genomic imbalance and array painting to map chromosome breakpoints rapidly. These two methods facilitate rapid analysis of translocation breakpoints and screening for cryptic chromosome imbalance. Breakpoints of rearrangements were further refined (to the level of spanning clones) using fluorescence in situ hybridisation where appropriate.
Unexpected additional complexity or genome imbalance was found in six of 10 patients studied. The patients could be grouped according to the general nature of the karyotype rearrangement as follows: (A) three cases with complex multiple rearrangements including deletions, inversions, and insertions at or near one or both breakpoints; (B) three cases in which, while the translocations appeared to be balanced, microarray analysis identified previously unrecognised imbalance on chromosomes unrelated to the translocation; (C) four cases in which the translocation breakpoints appeared simple and balanced at the resolution used.
This high level of unexpected rearrangement complexity, if generally confirmed in the study of further patients, will have an impact on current diagnostic investigations of this type and provides an argument for the more widespread adoption of microarray analysis or other high resolution genome-wide screens for chromosome imbalance and rearrangement.
Using array comparative genome hybridisation (CGH) 41 de novo reciprocal translocations and 18 de novo complex chromosome rearrangements (CCRs) were screened. All cases had been interpreted as "balanced" by conventional cytogenetics. In all, 27 cases of reciprocal translocations were detected in patients with an abnormal phenotype, and after array CGH analysis, 11 were found to be unbalanced. Thus 40% (11 of 27) of patients with a "chromosomal phenotype" and an apparently balanced translocation were in fact unbalanced, and 18% (5 of 27) of the reciprocal translocations were instead complex rearrangements with >3 breakpoints. Fourteen fetuses with de novo, apparently balanced translocations, all but two with normal ultrasound findings, were also analysed and all were found to be normal using array CGH. Thirteen CCRs were detected in patients with abnormal phenotypes, two in women who had experienced repeated spontaneous abortions and three in fetuses. Sixteen patients were found to have unbalanced mutations, with up to 4 deletions. These results suggest that genome-wide array CGH may be advisable in all carriers of "balanced" CCRs. The parental origin of the deletions was investigated in 5 reciprocal translocations and 11 CCRs; all were found to be paternal. Using customized platforms in seven cases of CCRs, the deletion breakpoints were narrowed down to regions of a few hundred base pairs in length. No susceptibility motifs were associated with the imbalances. These results show that the phenotypic abnormalities of apparently balanced de novo CCRs are mainly due to cryptic deletions and that spermatogenesis is more prone to generate multiple chaotic chromosome imbalances and reciprocal translocations than oogenesis.
We report on a girl with Menkes syndrome (M.S.) and X-2 reciprocal translocation. We conclude that the probable locus for M.S. gene is at band Xql3. This case and other previous case reports of X-linked disorders in females suggest that chromosome analysis is indicated in all females who present with manifestations of a known X-linked lethal condition in order to detect a possible associated balanced X-autosome translocation.
Mammalian X-chromosome inactivation results in dosage compensation for X-linked genes. More than 30 years after its discovery, the molecular bases of this inactivation are being revealed. Multiple mechanisms are responsible for the initiation of this developmental event and the maintenance of the inactive state. Somatic cellular mosaicism, which is the genetic consequence of X-chromosome inactivation, has a profound influence on the phenotype of mammalian females.
Studies tracing parental origins of human mutations by means of cytogenetic polymorphisms and RFLPs show that most trisomics arise out of maternal errors of segregation at the first meiotic division in oocytes. Temporal disturbance of meiotic progression seems likely to underly aneuploidy production in the female mouse, and this could equally be true in women, most especially as they approach the menopause when irregular cyclicity sets in. For human monosomy X, a high proportion of cases show loss of the paternal sex chromosome, and from experimental data giving similar findings in the mouse, it seems likely that the error could arise at the pronuclear stage after sperm entry into the egg, rather than at meiosis in the male. For human point mutations and structural rearrangements, a bias exists towards paternal origins. Errors arising during spermatogonial proliferation in men could contribute point mutations, these accumulating over a lifetime to give paternal age effects. For structural rearrangements, the hypersensitive stage is likely to be the post-meiotic differentiating spermatid, a stage not subject to germinal selection, and one which in Drosophila has been shown to combine high breakability with enhanced repair. Lack of a comparable cell type to the condensing spermatid of the male might be a reason why balanced structural rearrangements are produced rather rarely in females, at least in the mouse.
We reviewed 122 cases of balanced X-autosome translocations in females, with respect to the X inactivation pattern, the position of the X break point and the resulting phenotype.
In 77% of the patients the translocated X chromosome was early replicating in all cells analysed. The break points in these cases were distributed all along the X chromosome. Most of these patients were either phenotypically normal or had gonadal dysgenesis, some had single gene disorders, and less than 9% had multiple congenital anomalies and/or mental retardation.
In the remaining 23% of the cases the translocated X chromosome was late replicating in a proportion of cells. In these cells only one of the translocation products was reported to replicate late, while the remaining portion of the X chromosome showed the same replication pattern as the homologous part of the active, structurally normal X chromosome. The analysis of DNA methylation in one of these cases confirmed noninactivation of the translocated segment. Consequently, these cells were functionally disomic for a part of the X chromosome. The presence of disomic cells was highly prevalent in translocations with break points at Xp22 and Xq28, even though spreading of X inactivation onto the adjacent autosomal segment was noted in most of these cases. This suggests that selection against cells with a late replicating translocated X is driven predominantly by a functional disomy X, and that the efficiency of this process depends primarily on the position of the X break point, and hence the size of the noninactivated region. Since the persistence of cells with a late replicating translocated X was usually associated with mental retardation and other abnormalities, it is concluded that the outcome of the selection process against the functional disomy X is the major determinant of the clinical status in most patients with balanced X-autosome translocations.
Cosmid clones containing human DNA inserts have been mapped on chromosome 11 by fluorescence in situ hybridization under conditions that suppress signal from repetitive DNA sequences. Thirteen known genes, one chromosome 11-specific DNA repeat, and 36 random clones were analyzed. High-resolution mapping was facilitated by using digital imaging microscopy and by analyzing extended (prometaphase) chromosomes. The map coordinates established by in situ hybridization showed a one to one correspondence with those determined by Southern (DNA) blot analysis of hybrid cell lines containing fragments of chromosome 11. Furthermore, by hybridizing three or more cosmids simultaneously, gene order on the chromosome could be established unequivocally. These results demonstrate the feasibility of rapidly producing high-resolution maps of human chromosomes by in situ hybridization.
The mitochondrial copper concentrations and cytochrome C oxidase activity of the fibroblasts from the patients with Menkes syndrome were investigated. Both the mitochondrial copper concentrations and cytochrome C oxidase activity of fibroblasts from patients with Menkes syndrome were lower than those of the control fibroblasts. These data indicate that the mitochondria of fibroblasts from patients with Menkes syndrome are in a state of copper deficiency. The activity decline of cytochrome C oxidase, a mitochondrial cuproenzyme, seems to be caused by copper deficiency in the mitochondria.
DNA replication patterns of X chromosomes in complete hydatidiform moles were studied using cultured fibroblasts from three 46,XX moles resulting from duplication of a haploid sperm, and from a 46,XY mole originating from dispermy. Control cultures included skin fibroblasts from an adult woman and a female fetus as well as PB lymphocytes from an adult woman. Cultures were treated with 5-bromo-deoxyuridine for the last 2-4 h of the S phase, and the chromosome slides prepared were stained by the Hoechst 33258-Giemsa procedure. Each of the three XX moles studied revealed one early-replicating and one late-replicating X chromosomes, while the XY mole revealed one early-replicating X chromosomes. DNA replication patterns of molar X chromosomes were similar to those of adult and fetal fibroblasts, but different from those in adult lymphocytes. These findings indicate that DNA replication kinetics of molar fibroblasts are tissue-specific rather than origin- or developmental-stage specific.
Menkes disease is an X-linked recessive disorder of copper metabolism, characterized by progressive neurological degeneration, abnormal hair and connective tissue manifestations. We present a female Menkes patient, with classical Menkes features, carrying a de novo balanced translocation 46,X,t(X;1)(q13;q12). The breakpoint on the X chromosome was narrowed down to Xq13.3 within a 1 Mb YAC contig containing the Menkes gene, using fluorescence in situ hybridization. The translocated X chromosome was of paternal origin and non-randomly active leading to the expression of the disease. This was additional evidence for paternal origin of de novo chromosome rearrangements, including all the X; autosomal translocations examined so far.
In the 25 y since copper deficiency was first delineated in persons with Menkes syndrome, advances in our understanding of the clinical, biochemical, and molecular aspects of this rare disorder have surpassed progress in the design of effective therapies. In contrast with purely nutritional copper deficiency, in which copper replacement can be curative, the nature of the basic defect in Menkes syndrome suggests that corrective efforts are likely to be more complicated, a point supported by the cumulative literature on this topic as well as by emerging molecular data. In this paper, certain clinical, biochemical, and molecular aspects of copper histidine treatment in 25 Menkes syndrome patients at the National Institutes of Health are reviewed. The delineation of a distinctive neurochemical pattern in plasma and cerebrospinal fluid, reflecting deficiency of the copper enzyme dopamine beta-monooxygenase, is arguably the most important finding in the study of Menkes syndrome. This abnormal pattern has proven extremely reliable as a rapid diagnostic test, enabling early identification of affected infants--a fundamental requirement for improving clinical outcomes. Of 11 patients identified by prenatal or prompt postnatal testing and treated within the first 10 d of age, one walked at 14 mo of age and has normal neurodevelopment at age 3 y and another infant's early progress appears promising. However, five patients died in infancy and neurodevelopmental outcome was suboptimal in four others. Consideration of additional therapeutic strategies seems necessary, therefore, for most patients and families facing this troublesome form of copper deficiency.
A girl with a 46,X,t(X;21) (q13.3;p11.1) karyotype presented with skin redundancy, especially in the neck, prominent occiput and micrognathia, and later developed hypotonia, hypopigmentation, sparse scalp hair, and profound mental retardation characteristic of Menkes disease. Her serum copper (14 microg/dl) and ceruloplasmin (9 mg/dl) levels were extremely low. Fluorescent in situ hybridization analysis with a 100-kb P1-derived artificial chromosome probe containing the Menkes disease gene demonstrated three twin-signals, one on the normal X chromosome and one each on derivative chromosomes X and 21, indicating that the Xq13.3 breakpoint was located within the gene. Replication pattern analysis showed that the normal X chromosome was late replicating, whereas the derivative X chromosome was selectively early replicating. These results indicated that Menkes disease in our patient resulted from a de novo translocation that disrupts the disease gene.
Menkes disease is a rare X-linked recessive disorder of copper metabolism, characterised by progressive neurological degeneration, abnormal hair and connective tissue manifestations. We report on a girl with classic Menkes disease, carrying a de novo balanced translocation 46,X,t(X;13)(q13.3; q14.3). The translocation breakpoints at Xq13.3 and 13q14.3 coincide with the Menkes disease and Wilson disease loci, respectively.
Menkes disease (MD; McKusick 309400) is an X-linked neurodegenerative disorder secondary to extrahepatic copper accumulation, caused by mutations of the gene encoding for the intracellular copper transporter ATPase alpha polypeptide (ATP7A). The clinical picture is characterized by severe psychomotor retardation, seizures, skin hypopigmentation and abnormal hair. Biochemically, MD patients have reduced serum levels of copper and ceruloplasmin. In some cases, early supplementation with parenteral copper histidinate reduced seizure activity and improved muscle tone and motor activity. Some of the clinical findings of MD have been proposed to be secondary to reduced activities of copper-dependent enzymes (i.e. cytochrome-c-oxidase, lysyl oxidase and dopamine β-hydroxylase). To study oxidative status and effects of copper histidinate therapy, we serially evaluated urinary organic acids in MD patients. We also evaluated respiratory chain enzymes activities in muscle and/or fibroblasts.
The transport and cellular metabolism of Cu depends on a series of membrane proteins and smaller soluble peptides that comprise a functionally integrated system for maintaining cellular Cu homeostasis. Inward transport across the plasma membrane appears to be a function of integral membrane proteins that form the channels that select Cu ions for passage. Two membrane-bound Cu-transporting ATPase enzymes, ATP7A and ATP7B, the products of the Menkes and Wilson disease genes, respectively, catalyze an ATP-dependent transfer of Cu to intracellular compartments or expel Cu from the cell. ATP7A and ATP7B work in concert with a series of smaller peptides, the copper chaperones, that exchange Cu at the ATPase sites or incorporate the Cu directly into the structure of Cu-dependent enzymes such as cytochrome c oxidase and Cu, Zn superoxide dismutase. These mechanisms come into play in response to a high influx of Cu or during the course of normal Cu metabolism.
In mammals, fertilization typically involves the ovulation of one or a few eggs at one end of the female reproductive tract
and the entry of millions of sperm at the other. Given this disparity in numbers, it might be expected that the more precious
commodity—eggs—would be subject to more stringent quality-control mechanisms. However, information from engineered mutations
of meiotic genes suggests just the opposite. Specifically, the available mutants demonstrate striking sexual dimorphism in
response to meiotic disruption; for example, faced with adversity, male meiosis grinds to a halt, whereas female meiosis soldiers
on. This female “robustness” comes with a cost, however, because aneuploidy appears to be increased in the resultant oocytes.
We report four cases of subjects with phenotypic abnormalities and mental retardation associated with apparently balanced translocations, two inherited and two de novo, which showed, by molecular analysis, a hidden complexity. All the cases have been analyzed with different molecular techniques, including array-CGH, and in two of them the translocation breakpoints have been defined at the level of base pairs via studies in somatic hybrids containing single derivative chromosomes. We demonstrated that all the translocations were in fact complex rearrangements and that an imbalance was present in three of them, thus accounting for the phenotypic abnormalities. In one case, a Prader-Willi subject, we were not able to determine the molecular cause of his phenotype. This study, while confirming previous data showing unexpected complexity in translocations, further underscores the need for molecular investigations before taking for granted an apparently simple cytogenetic interpretation.
We report the parental origin, and where possible the chromosomal origin of 115 de novo unbalanced structural chromosome abnormalities detectable by light microscopy. These consisted of 39 terminal deletions, 35 interstitial deletions, 8 rings, 12 duplications and 21 unbalanced translocations. In all categories the majority of abnormalities were of paternal origin, although the proportions varied from a high of 84% in the interstitial deletions and rings to a low of 58% in the duplications. Among the interstitial deletions and duplications, there were approximately equal numbers of intra- and interchromosomal abnormalities, while the majority of unbalanced translocations were isodisomic for the duplicated chromosome. The examination of the parental ages in the four main classes of abnormality showed terminal deletions of maternal origin to be associated with a significantly reduced maternal age. Thus, there is a clear propensity for structural chromosome abnormalities to occur in male germ cells, although the chromosomal origin seems similar irrespective of the parental origin.
Although balanced translocations are among the most common human chromosomal aberrations, the constitutional t(11;22)(q23;q11) is the only known recurrent non-Robertsonian translocation. Evidence indicates that de novo formation of the t(11;22) occurs during meiosis. To test the hypothesis that spatial proximity of chromosomes 11 and 22 in meiotic prophase oocytes and spermatocytes plays a role in the rearrangement, the positions of the 11q23 and 22q11 translocation breakpoints were examined. Fluorescence in situ hybridization with use of DNA probes for these sites demonstrates that 11q23 is closer to 22q11 in meiosis than to a control at 6q26. Although chromosome 21p11, another control, often lies as close to 11q23 as does 22q11 during meiosis, chromosome 21 rarely rearranges with 11q23, and the DNA sequence of chromosome 21 appears to be less susceptible than 22q11 to double-strand breaks (DSBs). It has been suggested that the rearrangement recurs as a result of the palindromic AT-rich repeats at both 11q23 and 22q11, which extrude hairpin structures that are susceptible to DSBs. To determine whether the DSBs at these sites coincide with normal hotspots of meiotic recombination, immunocytochemical mapping of MLH1, a protein involved in crossing over, was employed. The results indicate that the translocation breakpoints do not coincide with recombination hotspots and therefore are unlikely to be the result of meiotic programmed DSBs, although MRE11 is likely to be involved. Previous analysis indicated that the DSBs appear to be repaired by a mechanism similar to nonhomologous end joining (NHEJ), although NHEJ is normally suppressed during meiosis. Taken together, these studies support the hypothesis that physical proximity between 11q23 and 22q11--but not typical meiotic recombinational activity in meiotic prophase--plays an important role in the generation of the constitutional t(11;22) rearrangement.
Docherty Z 1999 Clinical expression of Menkes disease in a girl with X;13 translocation
- Mohammed I Abusaad
- Sn
- Cm Ogilvie
- J Ritchie
- Pohl
Abusaad I, Mohammed SN, Ogilvie CM, Ritchie J, Pohl KR, Docherty Z 1999 Clinical expression of Menkes disease in a girl with X;13 translocation. Am J Med Genet 87:354 –359
- T Strachan
- Ap Read
Strachan T, Read AP 1999 Genetica Umana Molecolare 2. Wiley, New York, pp
52–55
- Abusaad I