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ABSTRACT: Monoamine oxidases (MAO-A and MAO-B) have a key role in the degradation of amine neurotransmitters, such as dopamine, norepinephrine and serotonin. We identified an inherited 240 kb deletion on Xp11.3-p11.4, which encompasses both monoamine oxidase genes but, unlike other published reports, does not affect the adjacent Norrie disease gene (NDP). The brothers who inherited the deletion, and thus have no monoamine oxidase function, presented with severe developmental delay, intermittent hypotonia and stereotypical hand movements. The clinical features accord with published reports of larger microdeletions and selective MAO-A and MAO-B deficiencies in humans and mouse models and suggest considerable functional compensation between MAO-A and MAO-B under normal conditions.
European journal of human genetics: EJHG 10/2010; 18(10):1095-9. · 3.56 Impact Factor
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Abdul Noor, Annabel Whibley,
Christian R Marshall,
Peter J Gianakopoulos,
Amelie Piton,
Andrew R Carson,
Marija Orlic-Milacic,
Anath C Lionel,
Daisuke Sato,
Dalila Pinto, [......],
Jozef Gecz,
Angela F Brady,
Charles E Schwartz,
Russell J Schachar,
Anthony P Monaco,
Guy A Rouleau,
Chi-Chung Hui,
F Lucy Raymond,
Stephen W Scherer,
John B Vincent
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ABSTRACT: Autism is a common neurodevelopmental disorder with a complex mode of inheritance. It is one of the most highly heritable of the complex disorders, although the underlying genetic factors remain largely unknown. Here, we report mutations in the X-chromosome PTCHD1 (patched-related) gene in seven families with autism spectrum disorder (ASD) and in three families with intellectual disability. A 167-kilobase microdeletion spanning exon 1 was found in two brothers, one with ASD and the other with a learning disability and ASD features; a 90-kilobase microdeletion spanning the entire gene was found in three males with intellectual disability in a second family. In 900 probands with ASD and 208 male probands with intellectual disability, we identified seven different missense changes (in eight male probands) that were inherited from unaffected mothers and not found in controls. Two of the ASD individuals with missense changes also carried a de novo deletion at another ASD susceptibility locus (DPYD and DPP6), suggesting complex genetic contributions. In additional males with ASD, we identified deletions in the 5' flanking region of PTCHD1 that disrupted a complex noncoding RNA and potential regulatory elements; equivalent changes were not found in male control individuals. Thus, our systematic screen of PTCHD1 and its 5' flanking regions suggests that this locus is involved in ~1% of individuals with ASD and intellectual disability.
Science translational medicine 09/2010; 2(49):49ra68. · 7.80 Impact Factor
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ABSTRACT: CUL4A and B encode subunits of E3-ubiquitin ligases implicated in diverse processes including nucleotide excision repair, regulating gene expression and controlling DNA replication fork licensing. But, the functional distinction between CUL4A and CUL4B, if any, is unclear. Recently, mutations in CUL4B were identified in humans associated with mental retardation, relative macrocephaly, tremor and a peripheral neuropathy. Cells from these patients offer a unique system to help define at the molecular level the consequences of defective CUL4B specifically. We show that these patient-derived cells exhibit sensitivity to camptothecin (CPT), impaired CPT-induced topoisomerase I (Topo I) degradation and ubiquitination, thereby suggesting Topo I to be a novel Cul4-dependent substrate. Consistent with this, we also find that these cells exhibit increased levels of CPT-induced DNA breaks. Furthermore, over-expression of known CUL4-dependent substrates including Cdt1 and p21 appear to be a feature of these patient-derived cells. Collectively, our findings highlight the interplay between CUL4A and CUL4B and provide insight into the pathogenesis of CUL4B-deficiency in humans.
Human Molecular Genetics 04/2010; 19(7):1324-34. · 7.64 Impact Factor
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Anna Hackett,
Patrick S Tarpey,
Andrea Licata,
James Cox, Annabel Whibley,
Jackie Boyle,
Carolyn Rogers,
John Grigg,
Michael Partington,
Roger E Stevenson, [......],
Gillian Turner,
Meredith Wilson,
Andrew P Futreal,
Mark Corbett,
Marie Shaw,
Jozef Gecz,
F Lucy Raymond,
Michael R Stratton,
Charles E Schwartz,
Fatima E Abidi
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ABSTRACT: Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported.
European journal of human genetics: EJHG 12/2009; 18(5):544-52. · 3.56 Impact Factor
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Patrick S Tarpey,
Raffaella Smith,
Erin Pleasance, Annabel Whibley,
Sarah Edkins,
Claire Hardy,
Sarah O'Meara,
Calli Latimer,
Ed Dicks,
Andrew Menzies, [......],
Michael Field,
Cindy Skinner,
Roger E Stevenson,
Martin Bobrow,
Gillian Turner,
Charles E Schwartz,
Jozef Gecz,
F Lucy Raymond,
P Andrew Futreal,
Michael R Stratton
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ABSTRACT: Large-scale systematic resequencing has been proposed as the key future strategy for the discovery of rare, disease-causing sequence variants across the spectrum of human complex disease. We have sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation (XLMR), the largest direct screen for constitutional disease-causing mutations thus far reported. The screen has discovered nine genes implicated in XLMR, including SYP, ZNF711 and CASK reported here, confirming the power of this strategy. The study has, however, also highlighted issues confronting whole-genome sequencing screens, including the observation that loss of function of 1% or more of X-chromosome genes is compatible with apparently normal existence.
Nature Genetics 05/2009; 41(5):535-43. · 35.53 Impact Factor
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ABSTRACT: A candidate gene approach to identifying novel causes of disease is concept-limiting and in the new era of high throughput sequencing there is now no need to restrict the experiment to a few interesting genes. We have recently completed a large-scale exon re-sequencing project using Sanger sequencing technology to analyse approximately 1 Mb of coding sequence of the X chromosome in probands from >200 families with various forms of intellectual disability. We review the lessons learnt from this experience. Comparing large data sets will certainly reveal pathogenic mutations in genes that were not possible to identify previously. However, the task of distinguishing pathogenic mutations from rare sequence variants is not easy and is the most substantial challenge to the next decade. High-throughput technology has the attraction of being cheap, fast and comprehensive but for projects that require detailed coverage of a genomic region at an exhaustive level they may require a combination of large-scale with a small-scale follow-up of difficult regions to sequence. The number of rare truncating variants present in coding regions of the X chromosome that are not pathogenic was 1%. The importance of the quality of the starting material both clinically and molecularly and the number of sequence variants both rare and common that any one individual has across their coding sequence is discussed.
Human Molecular Genetics 04/2009; 18(R1):R60-4. · 7.64 Impact Factor
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Gregor D Gilfillan,
Kaja K Selmer,
Ingrid Roxrud,
Raffaella Smith,
Mårten Kyllerman,
Kristin Eiklid,
Mette Kroken,
Morten Mattingsdal,
Thore Egeland,
Harald Stenmark, [......],
P Andrew Futreal,
Jon Teague,
Sarah Edkins,
Jozef Gecz,
Gillian Turner,
F Lucy Raymond,
Charles Schwartz,
Roger E Stevenson,
Dag E Undlien,
Petter Strømme
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ABSTRACT: Linkage analysis and DNA sequencing in a family exhibiting an X-linked mental retardation (XLMR) syndrome, characterized by microcephaly, epilepsy, ataxia, and absent speech and resembling Angelman syndrome, identified a deletion in the SLC9A6 gene encoding the Na(+)/H(+) exchanger NHE6. Subsequently, other mutations were found in a male with mental retardation (MR) who had been investigated for Angelman syndrome and in two XLMR families with epilepsy and ataxia, including the family designated as having Christianson syndrome. Therefore, mutations in SLC9A6 cause X-linked mental retardation. Additionally, males with findings suggestive of unexplained Angelman syndrome should be considered as potential candidates for SLC9A6 mutations.
The American Journal of Human Genetics 05/2008; 82(4):1003-10. · 10.60 Impact Factor
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Guy Froyen,
Mark Corbett,
Joke Vandewalle,
Irma Jarvela,
Owen Lawrence,
Cliff Meldrum,
Marijke Bauters,
Karen Govaerts,
Lucianne Vandeleur,
Hilde Van Esch, [......],
Rodney Scott,
Maarit Peippo,
Marjatta Sipponen,
Michael Partington,
David Mowat,
Michael Field,
Anna Hackett,
Peter Marynen,
Gillian Turner,
Jozef Gécz
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ABSTRACT: Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: RIBC1, HSD17B10, and HUWE1. RIBC1 could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of HSD17B10 and HUWE1 as well as several important genes in their molecular pathways. Loss-of-function mutations of HSD17B10 have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in HUWE1 in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of XLMR and suggest that point mutations in HUWE1 are associated with this disease too.
The American Journal of Human Genetics 03/2008; 82(2):432-43. · 10.60 Impact Factor
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Anna Hackett,
Patrick S Tarpey,
Andrea Licata,
James Cox, Annabel Whibley,
Jackie Boyle,
Carolyn Rogers,
John Grigg,
Michael Partington,
Roger E Stevenson, [......],
Gillian Turner,
Meredith Wilson,
Andrew P Futreal,
Mark Corbett,
Marie Shaw,
Jozef Gecz,
F Lucy Raymond,
Michael R Stratton,
Charles E Schwartz,
Fatima E Abidi
