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Sonja A de Munnik,
Barto J Otten,
Jeroen Schoots, Louise S Bicknell,
Salim Aftimos,
Jumana Y Al-Aama,
Yolande van Bever,
Michael B Bober,
George F Borm,
Jill Clayton-Smith, [......],
Annick Toutain,
Carol A Wise,
Michael Wright,
David L Skidmore,
Mark E Samuels,
Lies H Hoefsloot,
Nine V A M Knoers,
Han G Brunner,
Andrew P Jackson,
Ernie M H F Bongers
[show abstract]
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ABSTRACT: Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex is essential for DNA replication and therefore mutations are expected to impair cell proliferation and consequently could globally reduce growth. However, detailed growth characteristics of MGS patients have not been reported, and so this is addressed here through study of 45 MGS patients, the largest cohort worldwide. Here, we report that growth velocity (length) is impaired in MGS during pregnancy and first year of life, but, thereafter, height increases in paralleled normal reference centiles, resulting in a mean adult height of -4.5 standard deviations (SD). Height is dependent on ethnic background and underlying molecular cause, with ORC1 and ORC4 mutations causing more severe short stature and microcephaly. Growth hormone therapy (n = 9) was generally ineffective, though in two patients with significantly reduced IGF1 levels, growth was substantially improved by GH treatment, with 2SD and 3.8 SD improvement in height. Growth parameters for monitoring growth in future MGS patients are provided and as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) and mammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth. © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A 09/2012; 158A(11):2733-42. · 2.39 Impact Factor
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Michael B Bober,
Tim Niiler,
Angela L Duker,
Jennie E Murray,
Tara Ketterer,
Margaret E Harley,
Sabah Alvi,
Christina Flora,
Cecilie Rustad,
Ernie M H F Bongers, Louise S Bicknell,
Carol Wise,
Andrew P Jackson
[show abstract]
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ABSTRACT: Microcephalic primordial dwarfism (MPD) is a class of disorders characterized by intrauterine growth restriction (IUGR), impaired postnatal growth and microcephaly. Majewski osteodysplastic primordial dwarfism type II (MOPD II) is one of the more common conditions within this group. MOPD II is caused by truncating mutations in pericentrin (PCNT) and is inherited in an autosomal recessive manner. Detailed growth curves for length, weight, and OFC are presented here and derived from retrospective data from 26 individuals with MOPD II confirmed by molecular or functional studies. Severe pre- and postnatal growth failure is evident in MOPD II patients. The length, weight, and OFC at term (when corrected for gestational age) were -7.0, -3.9, and -4.6 standard deviation (SD) below the population mean and equivalent to the 50th centile of a 28-29-, 31-32-, and 30-31-week neonate, respectively. While at skeletal maturity, the height, weight, and OFC were -10.3, -14.3, and -8.5 SD below the population mean and equivalent to the size of 3-year 10- to 11-month-old, a 5-year 2- to 3-month-old, and 5- to 6-month-old, respectively. During childhood, MOPD II patients grow with slowed, but fairly constant growth velocities and show no evidence of any pubertal growth spurt. Treatment with human growth hormone (n = 11) did not lead to any significant improvement in final stature. The growth charts presented here will be of assistance with diagnosis and management of MOPD II, and should have particular utility in nutritional management of MOPD II during infancy. © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A 07/2012; 158A(11):2719-25. · 2.39 Impact Factor
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Sonja A de Munnik, Louise S Bicknell,
Salim Aftimos,
Jumana Y Al-Aama,
Yolande van Bever,
Michael B Bober,
Jill Clayton-Smith,
Alaa Y Edrees,
Murray Feingold,
Alan Fryer, [......],
Annick Toutain,
Carol A Wise,
Michael Wright,
David L Skidmore,
Mark E Samuels,
Lies H Hoefsloot,
Nine V A M Knoers,
Han G Brunner,
Andrew P Jackson,
Ernie M H F Bongers
[show abstract]
[hide abstract]
ABSTRACT: Meier-Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, patellar aplasia/hypoplasia, and short stature. Recently, mutations in five genes from the pre-replication complex (ORC1, ORC4, ORC6, CDT1, and CDC6), crucial in cell-cycle progression and growth, were identified in individuals with MGS. Here, we report on genotype-phenotype studies in 45 individuals with MGS (27 females, 18 males; age 3 months-47 years). Thirty-five individuals had biallelic mutations in one of the five causative pre-replication genes. No homozygous or compound heterozygous null mutations were detected. In 10 individuals, no definitive molecular diagnosis was made. The triad of microtia, absent/hypoplastic patellae, and short stature was observed in 82% of individuals with MGS. Additional frequent clinical features were mammary hypoplasia (100%) and abnormal genitalia (42%; predominantly cryptorchidism and hypoplastic labia minora/majora). One individual with ORC1 mutations only had short stature, emphasizing the highly variable clinical spectrum of MGS. Individuals with ORC1 mutations had significantly shorter stature and smaller head circumferences than individuals from other gene categories. Furthermore, compared with homozygous missense mutations, compound heterozygous mutations appeared to have a more severe effect on phenotype, causing more severe growth retardation in ORC4 and more frequently pulmonary emphysema in CDT1. A lethal phenotype was seen in four individuals with compound heterozygous ORC1 and CDT1 mutations. No other clear genotype-phenotype association was observed. Growth hormone and estrogen treatment may be of some benefit, respectively, to growth retardation and breast hypoplasia, though further studies in this patient group are needed.
European journal of human genetics: EJHG 02/2012; 20(6):598-606. · 3.56 Impact Factor
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[show abstract]
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ABSTRACT: Primary microcephaly is an autosomal recessive disorder characterized by marked reduction in human brain size. Microcephalin (MCPH1), one of the genes mutated in primary microcephaly, plays an important role in DNA damage checkpoint control and mitotic entry. Additionally, MCPH1 ensures the proper temporal activation of chromosome condensation during mitosis, by acting as a negative regulator of the condensin II complex. We previously found that deletion of the of the MCPH1 N terminus leads to the premature chromosome condensation (PCC) phenotype. In the present study, we unexpectedly observed that a truncated form of MCPH1 appears to be expressed in MCPH1(S25X/S25X) patient cells. This likely results from utilization of an alternative translational start codon, which would produce a mutant MCPH1 protein with a small deletion of its N-terminal BRCT domain. Furthermore, missense mutations in the MCPH1 cluster at its N terminus, suggesting that intact function of this BRCT protein-interaction domain is required both for coordinating chromosome condensation and human brain development. Subsequently, we identified the SET nuclear oncogene as a direct binding partner of the MCPH1 N-terminal BRCT domain. Cells with SET knockdown exhibited abnormal condensed chromosomes similar to those observed in MCPH1-deficient mouse embryonic fibroblasts. Condensin II knockdown rescued the abnormal chromosome condensation phenotype in SET-depleted cells. In addition, MCPH1 V50G/I51V missense mutations, impair binding to SET and fail to fully rescue the abnormal chromosome condensation phenotype in Mcph1(-/-) mouse embryonic fibroblasts. Collectively, our findings suggest that SET is an important regulator of chromosome condensation/decondensation and that disruption of the MCPH1-SET interaction might be important for the pathogenesis of primary microcephaly.
Journal of Biological Chemistry 06/2011; 286(24):21393-400. · 4.77 Impact Factor
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[show abstract]
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ABSTRACT: Primary microcephaly is an autosomal recessive disorder characterized by marked reduction in human brain size. Microcephalin
(MCPH1), one of the genes mutated in primary microcephaly, plays an important role in DNA damage checkpoint control and mitotic
entry. Additionally, MCPH1 ensures the proper temporal activation of chromosome condensation during mitosis, by acting as
a negative regulator of the condensin II complex. We previously found that deletion of the of the MCPH1 N terminus leads to
the premature chromosome condensation (PCC) phenotype. In the present study, we unexpectedly observed that a truncated form
of MCPH1 appears to be expressed in MCPH1S25X/S25X patient cells. This likely results from utilization of an alternative translational start codon, which would produce a mutant
MCPH1 protein with a small deletion of its N-terminal BRCT domain. Furthermore, missense mutations in the MCPH1 cluster at its N terminus, suggesting that intact function of this BRCT protein-interaction domain is required both for coordinating
chromosome condensation and human brain development. Subsequently, we identified the SET nuclear oncogene as a direct binding
partner of the MCPH1 N-terminal BRCT domain. Cells with SET knockdown exhibited abnormal condensed chromosomes similar to
those observed in MCPH1-deficient mouse embryonic fibroblasts. Condensin II knockdown rescued the abnormal chromosome condensation
phenotype in SET-depleted cells. In addition, MCPH1 V50G/I51V missense mutations, impair binding to SET and fail to fully rescue the abnormal chromosome condensation phenotype
in Mcph1−/− mouse embryonic fibroblasts. Collectively, our findings suggest that SET is an important regulator of chromosome condensation/decondensation
and that disruption of the MCPH1-SET interaction might be important for the pathogenesis of primary microcephaly.
Journal of Biological Chemistry 06/2011; 286(24):21393-21400. · 4.77 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Primary microcephaly is an autosomal recessive disorder characterized by a reduction in brain size and abnormal chromosome
condensation. Microcephalin (MCPH1), one of the genes mutated in primary microcephaly, plays an important role in DNA damage
checkpoint control and mitotic entry in cell cycle regulation. MCPH1 also acts as a negative regulator of the condensin II
complex, ensuring the proper temporal activation of chromosome condensation during mitosis. We previously found that the N-terminus
of MCPH1 is responsible for the premature chromosome condensation (PCC) phenotype. In the present study, we unexpectedly observed
that a truncated form of MCPH1 is expressed in cells derived from a patient with primary microcephaly (S25X), further confirming
that N-terminus of MCPH1 is required for proper chromosome condensation. Moreover, we identified SET nuclear oncogene, which
binds directly to the N-terminus of MCPH1. Cells with SET knockdown exhibited PCC morphology similar to that observed in MCPH1-deficient
mouse embryonic fibroblasts (MEFs). Condensin II knockdown reversed the PCC phenotype in SET-depleted cells. In addition,
we identified V50G/I51V mutations in a microcephaly patient. The mutant MCPH1 exhibited reduced binding to SET and failed
to rescue the PCC phenotype in MCPH1-/- MEFs. Collectively, our findings suggest that SET is a regulator of chromosome condensation/
decondensation and disruption of MCPH1/SET interaction contributes to the development of primary microcephaly.
Journal of Biological Chemistry 04/2011; · 4.77 Impact Factor
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Louise S Bicknell,
Sarah Walker,
Anna Klingseisen,
Tom Stiff,
Andrea Leitch,
Claudia Kerzendorfer,
Carol-Anne Martin,
Patricia Yeyati,
Nouriya Al Sanna,
Michael Bober,
Diana Johnson,
Carol Wise,
Andrew P Jackson,
Mark O'Driscoll,
Penny A Jeggo
[show abstract]
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ABSTRACT: Studies into disorders of extreme growth failure (for example, Seckel syndrome and Majewski osteodysplastic primordial dwarfism type II) have implicated fundamental cellular processes of DNA damage response signaling and centrosome function in the regulation of human growth. Here we report that mutations in ORC1, encoding a subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. We establish that these mutations disrupt known ORC1 functions including pre-replicative complex formation and origin activation. ORC1 deficiency perturbs S-phase entry and S-phase progression. Additionally, we show that Orc1 depletion in zebrafish is sufficient to markedly reduce body size during rapid embryonic growth. Our data suggest a model in which ORC1 mutations impair replication licensing, slowing cell cycle progression and consequently impeding growth during development, particularly at times of rapid proliferation. These findings establish a novel mechanism for the pathogenesis of microcephalic dwarfism and show a surprising but important developmental impact of impaired origin licensing.
Nature Genetics 02/2011; 43(4):350-5. · 35.53 Impact Factor
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Louise S Bicknell,
Ernie M H F Bongers,
Andrea Leitch,
Stephen Brown,
Jeroen Schoots,
Margaret E Harley,
Salim Aftimos,
Jumana Y Al-Aama,
Michael Bober,
Paul A J Brown, [......],
Nine V A M Knoers,
James Mackenzie,
John M Opitz,
Pierre Sarda,
Alison Ross,
I Karen Temple,
Annick Toutain,
Carol A Wise,
Michael Wright,
Andrew P Jackson
[show abstract]
[hide abstract]
ABSTRACT: Meier-Gorlin syndrome (ear, patella and short-stature syndrome) is an autosomal recessive primordial dwarfism syndrome characterized by absent or hypoplastic patellae and markedly small ears¹⁻³. Both pre- and post-natal growth are impaired in this disorder, and although microcephaly is often evident, intellect is usually normal in this syndrome. We report here that individuals with this disorder show marked locus heterogeneity, and we identify mutations in five separate genes: ORC1, ORC4, ORC6, CDT1 and CDC6. All of these genes encode components of the pre-replication complex, implicating defects in replication licensing as the cause of a genetic syndrome with distinct developmental abnormalities.
Nature Genetics 02/2011; 43(4):356-9. · 35.53 Impact Factor
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Ersan Kalay,
Gökhan Yigit,
Yakup Aslan,
Karen E Brown,
Esther Pohl, Louise S Bicknell,
Hülya Kayserili,
Yun Li,
Beyhan Tüysüz,
Gudrun Nürnberg, [......],
Karen Milstein,
Helene Dollfus,
Dagmar Wieczorek,
Han G Brunner,
Matthew Hurles,
Andrew P Jackson,
Anita Rauch,
Peter Nürnberg,
Ahmet Karagüzel,
Bernd Wollnik
[show abstract]
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ABSTRACT: Functional impairment of DNA damage response pathways leads to increased genomic instability. Here we describe the centrosomal protein CEP152 as a new regulator of genomic integrity and cellular response to DNA damage. Using homozygosity mapping and exome sequencing, we identified CEP152 mutations in Seckel syndrome and showed that impaired CEP152 function leads to accumulation of genomic defects resulting from replicative stress through enhanced activation of ATM signaling and increased H2AX phosphorylation.
Nature Genetics 01/2011; 43(1):23-6. · 35.53 Impact Factor
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Isabel Huang-Doran, Louise S Bicknell,
Francis M Finucane,
Nuno Rocha,
Keith M Porter,
Y C Loraine Tung,
Ferenc Szekeres,
Anna Krook,
John J Nolan,
Mark O'Driscoll,
Michael Bober,
Stephen O'Rahilly,
Andrew P Jackson,
Robert K Semple
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ABSTRACT: Genetic defects in human pericentrin (PCNT), encoding the centrosomal protein pericentrin, cause a form of osteodysplastic primordial dwarfism that is sometimes reported to be associated with diabetes. We thus set out to determine the prevalence of diabetes and insulin resistance among patients with PCNT defects and examined the effects of pericentrin depletion on insulin action using 3T3-L1 adipocytes as a model system.
A cross-sectional metabolic assessment of 21 patients with PCNT mutations was undertaken. Pericentrin expression in human tissues was profiled using quantitative real-time PCR. The effect of pericentrin knockdown on insulin action and adipogenesis in 3T3-L1 adipocytes was determined using Oil red O staining, gene-expression analysis, immunoblotting, and glucose uptake assays. Pericentrin expression and localization also was determined in skeletal muscle.
Of 21 patients with genetic defects in PCNT, 18 had insulin resistance, which was severe in the majority of subjects. Ten subjects had confirmed diabetes (mean age of onset 15 years [range 5-28]), and 13 had metabolic dyslipidemia. All patients without insulin resistance were younger than 4 years old. Knockdown of pericentrin in adipocytes had no effect on proximal insulin signaling but produced a twofold impairment in insulin-stimulated glucose uptake, approximately commensurate with an associated defect in cell proliferation and adipogenesis. Pericentrin was highly expressed in human skeletal muscle, where it showed a perinuclear distribution.
Severe insulin resistance and premature diabetes are common features of PCNT deficiency but are not congenital. Partial failure of adipocyte differentiation may contribute to this, but pericentrin deficiency does not impair proximal insulin action in adipocytes.
Diabetes 01/2011; 60(3):925-35. · 8.29 Impact Factor
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ABSTRACT: There are several rare syndromes combining wrinkled, redundant skin and neurological abnormalities. Although phenotypic overlap between conditions has suggested that some might be allelic to one another, the aetiology for many of them remains unknown. A consanguineous New Zealand Maori family has been characterised that segregates an autosomal recessive connective tissue disorder (joint dislocations, lax skin) associated with neurological abnormalities (severe global developmental delay, choreoathetosis) without metabolic abnormalities in four affected children. A genome-screen performed under a hypothesis of homozygosity by descent for an ancestral mutation, identified a locus at 10q23 (Z = 3.63). One gene within the candidate interval, ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), was considered a plausible disease gene since a missense mutation had previously been shown to cause progressive neurodegeneration, cataracts, skin laxity, joint dislocations and metabolic derangement in a consanguineous Algerian family. A missense mutation, 2350C>T, was identified in ALDH18A1, which predicts the substitution H784Y. H784 is invariant across all phyla and lies within a previously unrecognised, conserved C-terminal motif in P5CS. In an in vivo assay of flux through this metabolic pathway using dermal fibroblasts obtained from an affected individual, proline and ornithine biosynthetic activity of P5CS was not affected by the H784Y substitution. These data suggest that P5CS may possess additional uncharacterised functions that affect connective tissue and central nervous system function.
European Journal of HumanGenetics 05/2008; 16(10):1176-86. · 4.40 Impact Factor
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Louise S Bicknell,
Claire Farrington-Rock,
Yousef Shafeghati,
Patrick Rump,
Yasemin Alanay,
Yves Alembik,
Navid Al-Madani,
Helen Firth,
Mohammad Hassan Karimi-Nejad,
Chong Ae Kim, [......],
Jean-Pierre Fryns,
Elizabeth Sweeney,
Alan Fryer,
Sheila Unger,
L C Wilson,
Ralph S Lachman,
David L Rimoin,
Daniel H Cohn,
Deborah Krakow,
Stephen P Robertson
[show abstract]
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ABSTRACT: Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies. Recently, Larsen syndrome was shown to be caused by missense mutations or small inframe deletions in FLNB, encoding the cytoskeletal protein filamin B. To further delineate the molecular causes of Larsen syndrome, 20 probands with Larsen syndrome together with their affected relatives were evaluated for mutations in FLNB and their phenotypes studied.
Probands were screened for mutations in FLNB using a combination of denaturing high-performance liquid chromatography, direct sequencing and restriction endonuclease digestion. Clinical and radiographical features of the patients were evaluated.
The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb. All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions. Three mutations are recurrent, with one mutation, 5071G-->A, observed in 6 of 20 subjects. The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13-17 being the most common cause of Larsen syndrome. These findings collectively define autosomal dominant Larsen syndrome and demonstrate clustering of causative mutations in FLNB.
Journal of Medical Genetics 03/2007; 44(2):89-98. · 6.36 Impact Factor
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Claire Farrington-Rock,
Marc H Firestein, Louise S Bicknell,
Andrea Superti-Furga,
Carlos A Bacino,
Valerie Cormier-Daire,
Martine Le Merrer,
Clarisse Baumann,
Joelle Roume,
Patrick Rump,
Joke B G M Verheij,
Elizabeth Sweeney,
David L Rimoin,
Ralph S Lachman,
Stephen P Robertson,
Daniel H Cohn,
Deborah Krakow
[show abstract]
[hide abstract]
ABSTRACT: The filamins are a family of cytoplasmic proteins that bind to and organize actin filaments, link membrane proteins to the cytoskeleton, and provide a scaffold for signaling molecules. Mutations in the gene encoding filamin B (FLNB) cause a spectrum of osteochondrodysplasias, including atelosteogenesis type I (AOI) and atelosteogenesis type III (AOIII). AOI and AOIII are autosomal dominant lethal skeletal dysplasias characterized by overlapping clinical findings that include vertebral abnormalities, disharmonious skeletal maturation, hypoplastic long bones, and joint dislocations. Previous studies have shown that heterozygosity for missense mutations that alter the CH2 domain and repeat 6 region of filamin B produce AOI and AOIII. In this study, 14 novel missense mutations in FLNB were found in 15 unrelated patients with AOI and AOIII. The majority of the mutations resided in exon 2 and exon 3, which encode the CH2 domain of the actin-binding region of filamin B. The remaining mutations were found in exon 28 and exon 29, which encode repeats 14 and 15 of filamin B. These results show that clustering of mutations in two regions of FLNB produce AOI/AOIII, and highlight the important role of this cytoskeletal protein in normal skeletogenesis.
Human Mutation 08/2006; 27(7):705-10. · 5.69 Impact Factor
