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Z Assouline,
M Jambou,
M Rio,
C Bole-Feysot,
P de Lonlay,
C Barnerias,
I Desguerre,
C Bonnemains,
C Guillermet,
J Steffann,
A Munnich,
J P Bonnefont,
A Rötig, A S Lebre
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ABSTRACT: Isolated complex I deficiency is a frequent cause of respiratory chain defects in childhood. In this study, we report our systematic approach with blue native PAGE (BN-PAGE) to study mitochondrial respiratory chain assembly in skin fibroblasts from patients with Leigh syndrome and CI deficiency. We describe five new NDUFS4 patients with a similar and constant abnormal BN-PAGE profile and present a meta-analysis of the literature. All NDUFS4 mutations that have been tested with BN-PAGE result in a constant and similar abnormal assembly profile with a complete loss of the fully assembled complex I usually due to a truncated protein and the loss of its canonical cAMP dependent protein kinase phosphorylation consensus site. We also report the association of abnormal brain MRI images with this characteristic BN-PAGE profile as the hallmarks of NDUFS4 mutations and the first founder NDUFS4 mutations in the North-African population.
Biochimica et Biophysica Acta 02/2012; 1822(6):1062-9. · 4.66 Impact Factor
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A S Lebre,
M Rio,
L Faivre d'Arcier,
D Vernerey,
P Landrieu,
A Slama,
C Jardel,
P Laforêt,
D Rodriguez,
N Dorison, [......],
B Funalot,
N Villeneuve,
V Valayannopoulos,
P de Lonlay,
I Desguerre,
F Brunelle,
J P Bonnefont,
A Rötig,
A Munnich,
N Boddaert
[show abstract]
[hide abstract]
ABSTRACT: To identify a consistent pattern of brain MRI imaging in primary complex I deficiency. Complex I deficiency, a major cause of respiratory chain dysfunction, accounts for various clinical presentations, including Leigh syndrome. Human complex I comprises seven core subunits encoded by mitochondrial DNA (mtDNA) and 38 core subunits encoded by nuclear DNA (nDNA). Moreover, its assembly requires six known and many unknown assembly factors. To date, no correlation between genotypes and brain MRI phenotypes has been found in complex I deficiencies.
The brain MRIs of 30 patients carrying known mutation(s) in genes involved in complex I were retrospectively collected and compared with the brain MRIs of 11 patients carrying known mutations in genes involved in the pyruvate dehydrogenase (PDH) complex as well as 10 patients with MT-TL1 mutations.
All complex I deficient patients showed bilateral brainstem lesions (30/30) and 77% (23/30) showed anomalies of the putamen. Supratentorial stroke-like lesions were only observed in complex I deficient patients carrying mtDNA mutations (8/19) and necrotising leucoencephalopathy in patients with nDNA mutations (4/5). Conversely, the isolated stroke-like images observed in patients with MT-TL1 mutations, or the corpus callosum malformations observed in PDH deficient patients, were never observed in complex I deficient patients.
A common pattern of brain MRI imaging was identified with abnormal signal intensities in brainstem and subtentorial nuclei with lactate peak as a clue of complex I deficiency. Combining clinico-biochemical data with brain imaging may therefore help orient genetic studies in complex I deficiency.
Journal of Medical Genetics 10/2010; 48(1):16-23. · 6.36 Impact Factor
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L Galmiche,
F Jaubert,
F Sauvat,
S Sarnacki,
O Goulet,
Z Assouline,
V Vedrenne, A-S Lebre,
N Boddaert,
N Brousse,
D Chrétien,
A Munnich,
A Rötig
[show abstract]
[hide abstract]
ABSTRACT: Chronic intestinal pseudo-obstruction (CIPO) is a severe disease of the digestive tract motility. In pediatric population, CIPO remains of unknown origin for most patients. Chronic intestinal pseudo-obstruction is also a common feature in the course of mitochondrial oxidative phosphorylation disorders related for some patients to mutations in TYMP, POLG1, mtDNA tRNA(leu(UUR)) or tRNA(lys) genes. We hypothesized that CIPOs could be the presenting symptom of respiratory chain enzyme deficiency and thus we investigated oxidative phosphorylation in small bowel and/or colon smooth muscle of primary CIPO children.
We studied eight children with CIPO and 12 pediatric controls. We collected clinical, radiological and pathological data and measured respiratory chain enzymatic activity in isolated smooth muscle of the small bowel and/or the colon. We also sequenced TYMP, POLG, mtDNA tRNA(leu(UUR)) and tRNA(lys) genes.
Neither pathological nor radiological data were in favor of a mitochondrial dysfunction. No respiratory chain enzyme deficiency was detected in CIPO children. In myogenic CIPO, respiratory enzymes and citrate synthase activities were increased in small bowel and/or colon whereas no abnormality was noted in neurogenic and unclassified CIPO. Levels of enzyme activities were higher in control small bowel than in control colon muscle. Sequencing of TYMP, POLG, mtDNA tRNA(leu(UUR)) and tRNA(lys) genes and POLG gene did not reveal mutation for any of the patients.
The normal enzymatic activities as the lack of radiological and genetic abnormalities indicate that, at variance with adult patients, oxidative phosphorylation deficiency is not a common cause of childhood CIPO.
Neurogastroenterology and Motility 09/2010; 23(1):24-9, e1. · 3.41 Impact Factor
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M Rio, A S Lebre,
P de Lonlay,
V Valayannopoulos,
I Desguerre,
J-L Dufier,
D Grévent,
M Zilbovicius,
C Tréguier,
F Brunelle,
C de Baracé,
J Kaplan,
M A Espinase-Berrod,
C Sainte-Rose,
S Puget,
A Rotig,
A Munnich,
N Boddaert
Neurology 07/2010; 75(1):93. · 8.31 Impact Factor
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N Boddaert,
I Desguerre,
N Bahi-Buisson,
S Romano,
V Valayannopoulos,
Y Saillour,
D Seidenwurm,
D Grevent,
L Berteloot, A-S Lebre,
M Zilbovicius,
S Puget,
R Salomon,
T Attie-Bitach,
A Munnich,
F Brunelle,
P de Lonlay
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIFS: To propose a MRI cerebellar algorithm that may be applied to guide genetic/malformative or biochemical investigations for patients with cerebellar ataxia.
Cerebral MRI of 158 patients with cerebellar ataxia and no supratentorial abnormality were examined according to a new categorization system based on posterior fossa imaging. The clinical and radiological findings were confronted to biochemical and/or genetic results using the MR cerebellar algorithm. Seven groups of cerebellar MRI pattern were described: vermian dysgenesis (n=27), cerebellar hypoplasia (n=15), hemispheric cerebellar dysgenesis (n=6), unilateral hemispheric atrophy (n=5), global cerebellar atrophy (n=84), signal abnormalities (n=11) and normal MRI (n=10). Cerebellar hypoplasia, vermian dysgenesis and hemispheric cerebellar dysgenesis groups were classified as malformative disorders. Global atrophy and signal abnormality groups were classified as metabolic disorders.
In the vermian dysgenesis group, a specific genetic diagnosis was obtained in eight children (8/27) and all of the mutated genes (AHI1 (JBS3), CEP290 (JBS5), TMEM67 (JBS6), and RPGRIP1L (JBS7)) are involved in primary cilia function. In the group of pontocerebellar hypoplasia specific genetic diagnosis was obtained in one patient (PCH2) (1/15). Thus, nine of 42 children classified as malformative disorder had a molecular diagnosis. Global atrophy and signal abnormality groups were classified as metabolic disorders, specific biochemical was obtained in 46/95 children. In global atrophy group, respiratory chain deficiency was diagnosed in 18 children (18/84). In 21 children a congenital disorders of glycosylation type 1a (CDG Ia) was diagnosed (21/84) and infantile neuroaxonale dystrophy (INAD) was diagnosed in one child. In signal abnormalities group, specific biochemical diagnosis was obtained in six out of 11 children, five children with respiratory chain deficiency and one child with sulphite oxidase deficiency. In hemispheric cerebellar dysgenesis and normal MRI groups, no biological diagnosis was found for any of the patients. In the group of unilateral hemispheric atrophy, we hypothesized a clastic prenatal injury.
The proposed MR cerebellar algorithm was useful to guide genetic/malformative or biochemical investigations, allowing an etiological diagnosis in 55 children.
Journal of Neuroradiology 04/2010; 37(4):220-30. · 1.21 Impact Factor
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A-S Lebre
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ABSTRACT: Mitochondrial diseases (MD) are the most frequent metabolic disorders. They have in common a respiratory chain deficiency. Clinical presentation of MD is very heterogeneous and the major physiological functions may be affected. Diagnosis is complex due to the potential involvement of two genomes (nuclear or mitochondrial DNA), the large number of candidate genes to screen and the small number of patients reported for each type of MD. Clinical presentation, trait of inheritance, cerebral imaging (MRI and CT-Scan) and specialized biochemical investigations are good indicators, but identification of causing mutation(s) is the clue to confirm diagnosis. Task is huge and progress in diagnosis of MD should come from genotype-phenotype correlations studies and from major technical improvements in molecular diagnosis. Exhaustive study of mitochondrial DNA is the first necessary step that is now possible with methods like Surveyor and Affymetrix resequencing chip. Combination of data including clinical informations, cerebral imaging, respiratory chain deficiency and/or assembly profile of respiratory chain complexes (BN-PAGE profile) may contribute for orientation for nuclear DNA studies. Elucidation of the genetic bases of MD is important for patients: identification of causing mutation(s) allows offering genetic counselling and possibility of prenatal diagnosis.
Pathologie Biologie 11/2009; 58(5):353-6. · 1.53 Impact Factor
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V Valayannopoulos,
L Hubert,
J F Benoist,
S Romano,
J B Arnoux,
D Chrétien,
J Kaplan,
F Fakhouri,
D Rabier,
A Rötig, A S Lebre,
A Munnich,
Y de Keyzer,
P de Lonlay
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ABSTRACT: An adult patient with methylmalonic aciduria due to defective cobalamin synthesis (CblA) responsive to vitamin B(12) presented suddenly with severe visual impairment ascribed to optic atrophy followed by a fatal multiorgan failure and lactic acidosis but low methylmalonic acid in plasma and urine. Multiple deficiency of oxidative phosphorylation was found in the patient's liver. We suggest that patients with B(12)-sensitive methylmalonic aciduria who have a milder clinical course should be carefully monitored for long-term complications.
Journal of Inherited Metabolic Disease 05/2009; 32(2):159-62. · 3.58 Impact Factor
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N. Brahimi,
M. Jambou,
E. Sarzi,
V. Serre,
N. Boddaert,
S. Romano,
P. de Lonlay,
A. Slama,
A. Munnich,
A. Rötig,
J.P. Bonnefont, A.S. Lebre
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[hide abstract]
ABSTRACT: Deoxyguanosine kinase (dGK) deficiency is a frequent cause of mitochondrial DNA depletion associated with a hepatocerebral phenotype. In this study, we describe a new splice site mutation in the DGUOK gene and the clinical, radiologic, and genetic features of these DGUOK patients. This new DGUOK homozygous mutation (c.444-62C>A) was identified in three patients from two North-African consanguineous families with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver. Brain MRIs are normal in DGUOK patients in the literature. Interestingly, we found subtentorial abnormal myelination and moderate hyperintensity in the bilateral pallidi in our patients. This new mutation creates a cryptic splice site in intron 3 (in position −62) and is predicted to result in a larger protein with an in-frame insertion of 20 amino acids. In silico analysis of the putative impact of the insertion shows serious clashes in protein conformation: this insertion disrupts the α5 helix of the dGK kinase domain, rendering the protein unable to bind purine deoxyribonucleosides. In addition, a common haplotype that segregated with the disease in both families was detected by haplotype reconstruction with 10 markers (microsatellites and SNPs), which span 4.6 Mb of DNA covering the DGUOK locus. In conclusion, we report a new DGUOK splice site mutation that provide insight into a critical protein domain (dGK kinase domain) and the first founder mutation in a North-African population.
Molecular Genetics and Metabolism 03/2009; · 3.19 Impact Factor
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N. Boddaert,
S. Romano,
B. Funalot,
M. Rio,
E. Sarzi, A.S. Lebre,
N. Bahi-Buisson,
V. Valayannopoulos,
I. Desguerre,
D. Seidenwurm,
F. Brunelle,
F. Brami-Zylberberg,
A. Rötig,
A. Munnich,
P. de Lonlay
[show abstract]
[hide abstract]
ABSTRACT: Cerebellar ataxia is known to occasionally occur in the course of mitochondrial disorders. We report on MR spectroscopy (1H MRS) evidence of elevated brain lactate in the cerebellar area of 11 patients with cerebellar ataxia ascribed to mitochondrial respiratory chain deficiency (RCD). 1H MRS spectroscopy evidence of lactate peak was found in the cerebellum of 9/11 cases, while no lactate was detected in the putamen in 8/11. We suggest using 1H MRS in cerebellar atrophy in the diagnosis of mitochondrial RCD.
Molecular Genetics and Metabolism 02/2008; · 3.19 Impact Factor
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ABSTRACT: Spinocerebellar ataxia 7 (SCA7) is a progressive autosomal dominant neurodegenerative disorder characterized clinically by cerebellar ataxia associated with progressive macular dystrophy. The disease affects primarily the cerebellum and the retina, but also many other CNS structures as the disease progresses. SCA7 is caused by expansion of an unstable trinucleotide CAG repeat encoding a polyglutamine tract in the corresponding protein, ataxin-7. Normal SCA7 alleles contain 4-35 CAG repeats, whereas pathological alleles contain from 36-306 CAG repeats. SCA7 has a number of features in common with other diseases with polyglutamine expansions: (i) the appearance of clinical symptoms above a threshold number of CAG repeats (>35); (ii) a correlation between the size of the expansion and the rate of progression of the disease: the larger the repeat, the faster the progression; (iii) instability of the repeat sequence (approximately 12 CAG/transmission) that accounts for the marked anticipation of approximately 20 years/generation. The CAG repeat sequence is particularly unstable and de novo mutations can occur during paternal transmissions of intermediate size alleles (28-35 CAG repeats). This can explain the persistence of the disease in spite of the anticipation that should have resulted in its extinction.
Cytogenetic and Genome Research 01/2003; 100(1-4):154-63. · 1.53 Impact Factor
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ABSTRACT: Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant polyglutamine disorder presenting with progressive cerebellar ataxia and blindness. The molecular mechanisms underlying the selective neuronal death typical of SCA7 are unknown. We have established SCA7 cell culture models in HEK293 and SH-SY5Y cells, in order to analyse the effects of overexpression of the mutant ataxin-7 protein. The cells readily formed anti-ataxin-7 positive, fibrillar inclusions and small, nuclear electron dense structures. We have compared the inclusions in cells expressing mutant ataxin-7 and in human SCA7 brain tissue. There were consistent signs of ongoing abnormal protein folding, including the recruitment of heat-shock proteins and proteasome subunits. Occasionally, sequestered transcription factors were found. Activated caspase-3 was recruited into the inclusions in both the cell models and human SCA7 brain and its expression was upregulated in cortical neurones, suggesting that it may play a role in the disease process. Finally, on the ultrastructural level, there were signs of autophagy and nuclear indentations, indicative of a major stress response in cells expressing mutant ataxin-7.
Human Molecular Genetics 11/2001; 10(22):2569-79. · 7.64 Impact Factor
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A S Lebre,
L Jamot,
J Takahashi,
N Spassky,
C Leprince,
N Ravisé,
C Zander,
H Fujigasaki,
P Kussel-Andermann,
C Duyckaerts,
J H Camonis,
A Brice
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ABSTRACT: Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease caused by expansion of a CAG repeat in the coding region of the SCA7 gene. The disease primarily affects the cerebellum and the retina, but also many other central nervous system (CNS) structures as the disease progresses. Ataxin-7, encoded by the SCA7 gene, is a protein of unknown function expressed in many tissues including the CNS. In normal brain, ataxin-7 is found in the cytoplasm and/or nucleus of neurons, but in SCA7 brain ataxin-7 accumulates in intranuclear inclusions. Ataxin-7 is expressed ubiquitously, but mutation leads to neuronal death in only certain areas of the brain. This selective pattern of degeneration might be explained by interaction with a partner that is specifically expressed in vulnerable cells. We used a two-hybrid approach to screen a human retina cDNA library for ataxin-7-binding proteins, and isolated R85, a splice variant of Cbl-associated protein (CAP). R85 and CAP are generated by alternative splicing of the gene SH3P12 which we localized on chromosome 10q23-q24. The interaction between ataxin-7 and the SH3P12 gene products (SH3P12GPs) was confirmed by pull-down and co-immunoprecipitation. SH3P12GPs are expressed in Purkinje cells in the cerebellum. Ataxin-7 colocalizes with full-length R85 (R85FL) in co-transfected Cos-7 cells and with one of the SH3P12GPs in neuronal intranuclear inclusions in brain from a SCA7 patient. We propose that this interaction is part of a physiological pathway related to the function or turnover of ataxin-7. Its role in the pathophysiological process of SCA7 disease is discussed.
Human Molecular Genetics 06/2001; 10(11):1201-13. · 7.64 Impact Factor
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H Fujigasaki,
I C Verma,
A Camuzat,
R L Margolis,
C Zander, A S Lebre,
L Jamot,
R Saxena,
I Anand,
S E Holmes,
C A Ross,
A Dürr,
A Brice
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ABSTRACT: Spinocerebellar ataxia 12 (SCA12) is an autosomal dominant cerebellar ataxia (ADCA) described in a single family with a CAG repeat expansion in the PPP2R2B gene. We screened 247 index cases, including 145 families with ADCA, for this expansion. An expanded repeat ranging from 55 to 61 triplets was detected in 6 affected and 3 unaffected individuals at risk in a single family from India. The association of the PPP2R2B CAG repeat expansion with disease in this new family provides additional evidence that the mutation is causative.
Annals of Neurology 02/2001; 49(1):117-21. · 11.09 Impact Factor
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G Cancel,
C Duyckaerts,
M Holmberg,
C Zander,
G Yvert, A S Lebre,
M Ruberg,
B Faucheux,
Y Agid,
E Hirsch,
A Brice
[show abstract]
[hide abstract]
ABSTRACT: Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease caused by the expansion of a CAG repeat encoding a polyglutamine tract in the protein ataxin-7. We developed antibodies directed against two different parts of the ataxin-7 protein and studied its distribution in brain and peripheral tissue from healthy subjects. Normal ataxin-7 was widely expressed in brain, retina and peripheral tissues, including striated muscle, testis and thyroid gland. In the brain, expression of ataxin-7 was not limited to areas in which neurones degenerate, and the level of expression was not related to the severity of neuronal loss. Immunoreactivity was low in some vulnerable populations of neurones, such as Purkinje cells. In neurones, ataxin-7 was found in the cell bodies and in processes. Nuclear labelling was also observed in some neurones, but was not related to the distribution of intranuclear inclusions observed in an SCA7 patient. In this patient, the proportion of neurones with nuclear labelling was higher, on average, in regions with neuronal loss. Double immunolabelling coupled with confocal microscopy showed that ataxin-7 colocalized with BiP, a marker of the endoplasmic reticulum, but not with markers of mitochondria or the trans-Golgi network.
Brain 01/2001; 123 Pt 12:2519-30. · 9.46 Impact Factor
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ABSTRACT: A GAG deletion at position 946 in DYT1, one of the genes responsible for autosomal dominant idiopathic torsion dystonia (ITD), has recently been identified. We tested 24 families and six isolated cases with ITD and found 14 individuals from six French families who carried this mutation, indicating that 20% of the affected families carried the DYT1 mutation. Age at onset was always before 20 years (mean, 9+/-4 years). Interestingly, the site of onset was the upper limb in all but one patient. Dystonia was generalized in seven patients and remained focal or segmental in three patients. The absence of common haplotypes among DYT1 families suggests that at least six independent founder mutations have occurred. In addition, one Ashkenazi Jewish family carried the common haplotype described previously in Ashkenazi Jewish patients, but it was absent in the other family. Moreover, the dystonia remained focal in the latter family when compared with the usual generalized phenotype in patients with the common Ashkenazi Jewish haplotype. This indicates that there are at least two founder mutations in this population.
Brain 02/1999; 122 ( Pt 1):41-5. · 9.46 Impact Factor
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G David,
A Dürr,
G Stevanin,
G Cancel,
N Abbas,
A Benomar,
S Belal, A S Lebre,
M Abada-Bendib,
D Grid,
M Holmberg,
M Yahyaoui,
F Hentati,
T Chkili,
Y Agid,
A Brice
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ABSTRACT: Spinocerebellar ataxia 7 (SCA7) is caused by the expansion of an unstable CAG repeat in the first exon of the SCA7 gene. We have analyzed the SCA7 mutation in 19 families and one isolated case of various geographical origins, presenting with autosomal dominant cerebellar ataxia with progressive macular dystrophy. The SCA7 CAG repeat was expanded in 77 patients and in 11 at-risk individuals, with alleles containing from 37 to 130 repeats, demonstrating that SCA7 is genetically homogeneous. Repeats on normal alleles contained from 7 to 35 CAGs. There was a strong negative correlation (r = -0.84) between the age at onset and the size of the CAG repeat expansion in SCA7 patients. Larger expansions were associated with earlier onset, a more severe and rapid clinical course, and a higher frequency of decreased vision, ophthalmoplegia, extensor plantar response and scoliosis. The frequency of other clinical signs such as dysphagia and sphincter disturbances increased with disease duration. The mutation was highly unstable during transmission, with a mean increase of 10 +/- 16 CAG repeats, which was significantly greater in paternal (15 +/- 20) than in maternal (5 +/- 5) transmissions. This correlated well with the marked anticipation (19 +/- 13 years) observed in the families. Gonadal mosaicism, observed in the sperm of a patient, was particularly important, with expanded alleles ranging from 42 to >155 CAG repeats. The degree of instability during transmission, resulting mostly in expansions, is greater than in the seven other neurodegenerative disorders caused by polyglutamine expansions.
Human Molecular Genetics 02/1998; 7(2):165-70. · 7.64 Impact Factor
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The American Journal of Human Genetics 07/1997; 60(6):1548-52. · 10.60 Impact Factor
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G Cancel,
A Dürr,
O Didierjean,
G Imbert,
K Bürk,
A Lezin,
S Belal,
A Benomar,
M Abada-Bendib,
C Vial, [......],
N Abbas,
F Saudou, A S Lebre,
M Yahyaoui,
F Hentati,
J C Vernant,
T Klockgether,
J L Mandel,
Y Agid,
A Brice
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ABSTRACT: Spinocerebellar ataxia 2 (SCA2) is caused by the expansion of an unstable CAG repeat encoding a polyglutamine tract. One hundred and eighty four index patients with autosomal dominant cerebellar ataxia type I were screened for this mutation. We found expansion in 109 patients from 30 families of different geographical origins (15%) and in two isolated cases with no known family histories (2%). The SCA2 chromosomes contained from 34 to 57 repeats and consisted of a pure stretch of CAG, whereas all tested normal chromosomes (14-31 repeats), except one with 14 repeats, were interrupted by 1-3 repeats of CAA. As in other diseases caused by unstable mutations, a strong negative correlation was observed between the age at onset and the size of the CAG repeat (r = -0.81). The frequency of several clinical signs such as myoclonus, dystonia and myokymia increased with the number of CAG repeats whereas the frequency of others was related to disease duration. The CAG repeat was highly unstable during transmission with variations ranging from -8 to +12, and a mean increase of +2.2, but there was no significant difference according to the parental sex. This instability was confirmed by the high degree of gonadal mosaicism observed in sperm DNA of one patient.
Human Molecular Genetics 06/1997; 6(5):709-15. · 7.64 Impact Factor
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C Néri,
V Albanèse, A S Lebre,
S Holbert,
C Saada,
L Bougueleret,
S Meier-Ewert,
I Le Gall,
P Millasseau,
H Bui, [......],
P Gervy,
E Poullier,
P Rigault,
J Weissenbach,
G Lennon,
I Chumakov,
J Dausset,
H Lehrach,
D Cohen,
H M Cann
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ABSTRACT: Expansion of polymorphic CAG and CTG repeats in transcripts is the cause of six inherited neurodegenerative or neuromuscular diseases and may be involved in several other genetic disorders of the central nervous system. To identify new candidate genes, we have undertaken a large-scale screening project for CAG and CTG repeats in human reference cDNAs. We screened 100 128 brain cDNAs by hybridization. We also scanned GenBank expressed sequence tags for the presence of long CAG/CTG repeats in the extremities of cDNAs from several human tissues. Of the selected clones, 286 were found to represent new genes, and 72 have thus far been shown to contain CAG/CTG repeats. Our data indicate that CAG/CTG repeated 10 or more times are more likely to be polymorphic, and that new 3'-directed cDNAs with such repeats are very rare (1/2862). Nine new cDNAs containing polymorphic (observed heterozygote frequency: 0.05-0.90) CAG/CTG repeats have been currently identified in cDNAs. All of the cDNAs have been assigned to chromosomes, and six of them could be mapped with YACs to 1q32-q41, 3p14, 4q28, 3p21 and 12q13.3, 13q13.1-q13.2, and 19q13.43. Three of these clones are highly polymorphic and represent the most likely candidate genes for inherited neurodegenerative diseases and, perhaps, neuropsychiatric disorders of multifactorial origin.
Human Molecular Genetics 08/1996; 5(7):1001-9. · 7.64 Impact Factor
