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1.
Genet Med ; 18(6): 554-62, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26355662

RESUMO

PURPOSE: Retinal dystrophies (RD) are heterogeneous hereditary disorders of the retina that are usually progressive in nature. The aim of this study was to clinically and molecularly characterize a large cohort of RD patients. METHODS: We have developed a next-generation sequencing assay that allows known RD genes to be sequenced simultaneously. We also performed mapping studies and exome sequencing on familial and on syndromic RD patients who tested negative on the panel. RESULTS: Our panel identified the likely causal mutation in >60% of the 292 RD families tested. Mapping studies on all 162 familial RD patients who tested negative on the panel identified two novel disease loci on Chr2:25,550,180-28,794,007 and Chr16:59,225,000-72,511,000. Whole-exome sequencing revealed the likely candidate as AGBL5 and CDH16, respectively. We also performed exome sequencing on negative syndromic RD cases and identified a novel homozygous truncating mutation in GNS in a family with the novel combination of mucopolysaccharidosis and RD. Moreover, we identified a homozygous truncating mutation in DNAJC17 in a family with an apparently novel syndrome of retinitis pigmentosa and hypogammaglobulinemia. CONCLUSION: Our study expands the clinical and allelic spectrum of known RD genes, and reveals AGBL5, CDH16, and DNAJC17 as novel disease candidates.Genet Med 18 6, 554-562.


Assuntos
Caderinas/genética , Carboxipeptidases/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Distrofias Retinianas/genética , Feminino , Homozigoto , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Retina/patologia , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/patologia , Sequenciamento do Exoma
2.
Am J Hum Genet ; 91(2): 330-6, 2012 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-22840364

RESUMO

Primordial dwarfism (PD) is a phenotype characterized by profound growth retardation that is prenatal in onset. Significant strides have been made in the last few years toward improved understanding of the molecular underpinning of the limited growth that characterizes the embryonic and postnatal development of PD individuals. These include impaired mitotic mechanics, abnormal IGF2 expression, perturbed DNA-damage response, defective spliceosomal machinery, and abnormal replication licensing. In three families affected by a distinct form of PD, we identified a founder truncating mutation in POC1A. This gene is one of two vertebrate paralogs of POC1, which encodes one of the most abundant proteins in the Chlamydomonas centriole proteome. Cells derived from the index individual have abnormal mitotic mechanics with multipolar spindles, in addition to clearly impaired ciliogenesis. siRNA knockdown of POC1A in fibroblast cells recapitulates this ciliogenesis defect. Our findings highlight a human ciliopathy syndrome caused by deficiency of a major centriolar protein.


Assuntos
Centríolos/genética , Cílios/genética , Nanismo/genética , Nanismo/patologia , Proteínas/genética , Sequência de Bases , Proteínas de Ciclo Celular , Centríolos/metabolismo , Cílios/patologia , Proteínas do Citoesqueleto , Feminino , Componentes do Gene , Humanos , Imuno-Histoquímica , Masculino , Dados de Sequência Molecular , Mutação/genética , Linhagem , Interferência de RNA , RNA Interferente Pequeno/genética , Análise de Sequência de DNA , Fuso Acromático/genética , Fuso Acromático/patologia
3.
Am J Hum Genet ; 89(2): 328-33, 2011 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-21820096

RESUMO

Adams-Oliver syndrome (AOS) is defined by the combination of aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). It is usually inherited as an autosomal-dominant trait, but autosomal-recessive inheritance has also been documented. In an individual with autosomal-recessive AOS, we combined autozygome analysis with exome sequencing to identify a homozygous truncating mutation in dedicator of cytokinesis 6 gene (DOCK6) which encodes an atypical guanidine exchange factor (GEF) known to activate two members of the Rho GTPase family: Cdc42 and Rac1. Another homozygous truncating mutation was identified upon targeted sequencing of DOCK6 in an unrelated individual with AOS. Consistent with the established role of Cdc42 and Rac1 in the organization of the actin cytoskeleton, we demonstrate a cellular phenotype typical of a defective actin cytoskeleton in patient cells. These findings, combined with a Dock6 expression profile that is consistent with an AOS phenotype as well as the very recent demonstration of dominant mutations of ARHGAP31 in AOS, establish Cdc42 and Rac1 as key molecules in the pathogenesis of AOS and suggest that other regulators of these Rho GTPase proteins might be good candidates in the quest to define the genetic spectrum of this genetically heterogeneous condition.


Assuntos
Actinas/metabolismo , Citoesqueleto/patologia , Displasia Ectodérmica/genética , Genes Recessivos/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Deformidades Congênitas dos Membros/genética , Mutação/genética , Dermatoses do Couro Cabeludo/congênito , Animais , Sequência de Bases , Pré-Escolar , Citoesqueleto/metabolismo , Análise Mutacional de DNA , Desenvolvimento Embrionário/genética , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Lactente , Masculino , Camundongos , Dados de Sequência Molecular , Linhagem , Dermatoses do Couro Cabeludo/genética
4.
Hum Mutat ; 32(6): 573-8, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21462283

RESUMO

Meckel Gruber syndrome (MKS) is an autosomal recessive multisystem disorder that represents a severe form of ciliopathy in humans and is characterized by significant genetic heterogeneity. In this article, we describe the identification of a novel MKS locus MKS8 that we map to TCTN2, in a multiplex consanguineous family. TCTN2 is a paralog of the recently identified Tectonic 1, which has been shown to modulate sonic hedgehog signaling. Expression analysis at different developmental stages of the murine ortholog revealed a spatial and temporal pattern consistent with the MKS phenotype observed in our patient. The exclusion of this and the other seven MKS genes in our collection of consanguineous Arab MKS families confirms the existence of two additional MKS loci.


Assuntos
Transtornos da Motilidade Ciliar/genética , Encefalocele/genética , Proteínas de Membrana/genética , Doenças Renais Policísticas/genética , Animais , Transtornos da Motilidade Ciliar/diagnóstico , Transtornos da Motilidade Ciliar/patologia , Modelos Animais de Doenças , Encefalocele/diagnóstico , Encefalocele/patologia , Heterogeneidade Genética , Proteínas Hedgehog/metabolismo , Humanos , Proteínas de Membrana/classificação , Camundongos , Mutação/genética , Linhagem , Fenótipo , Filogenia , Doenças Renais Policísticas/diagnóstico , Doenças Renais Policísticas/patologia , Polidactilia/genética , Retinose Pigmentar
5.
Gene ; 512(2): 450-2, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23124037

RESUMO

Several neurodegenerative disorders are known to predominantly affect the white matter of the brain including vanishing white matter disease (VWMD), an autosomal recessive disorder characterized by leukodystrophy of varying severity in addition to variable systemic involvement. We report a consanguineous Arab family with three affected children, all of whom presented with severe neonatal epilepsy and profound neurodegenerative disease characterized by marked leukodystrophy with white matter cavitation mimicking VWMD. We combined autozygome and exome analysis to identify a novel variant in the gene encoding a member of the eIF2B-related family of proteins (MRI1). This is a poorly understood family of proteins of unclear function. Our results represent the first link between a variant in a member of this family and a human disease, and suggest that it converges with the highly homologous eIF2B, known to be mutated in VWMD, on the molecular pathogenesis of neurodegeneration.


Assuntos
Aldose-Cetose Isomerases/genética , Epilepsias Mioclônicas/genética , Loci Gênicos , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Leucoencefalopatias/genética , Adulto , Aldose-Cetose Isomerases/metabolismo , Árabes , Epilepsias Mioclônicas/diagnóstico por imagem , Epilepsias Mioclônicas/enzimologia , Feminino , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/enzimologia , Humanos , Lactente , Recém-Nascido , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/enzimologia , Masculino , Radiografia
6.
Gene ; 511(2): 447-50, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-23010198

RESUMO

Brittle cornea syndrome (BCS) is a genetically heterogeneous disorder characterized by extreme corneal fragility and thinning, which may lead to spontaneous or trauma-induced corneal rupture. BCS-1 and BCS-2 are caused by recessive mutations in ZNF469 and PRDM5, respectively. Both genes play a role in the regulatory pathway of corneal development and maintenance. We report a consanguineous family with five patients affected with the cardinal ocular features of BCS and significant musculoskeletal findings primarily in the form of joint hypermobility and severe kyphoscoliosis. The patients had thin velvety skin, hallux valgus, variable sensorineural hearing loss and arachnodactyly. Interestingly, one of the patients additionally had phenylketonuria and showed a milder ophthalmological and musculoskeletal phenotype than his affected siblings. The urinary pyridinoline and deoxypyridinoline concentrations and their ratios were mildly elevated indicating increased bone-collagen turnover. A novel homozygous 14 bp duplication in exon 2 of ZNF469 (c.8817_8830dup) was uncovered by direct sequencing. This family highlights the phenotypic overlap between BCS and Ehlers-Danlos syndrome.


Assuntos
Síndrome de Ehlers-Danlos/genética , Mutação , Fatores de Transcrição/genética , Adolescente , Adulto , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Adulto Jovem
7.
Nat Genet ; 43(12): 1186-8, 2011 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-22019780

RESUMO

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that causes substantial morbidity. As is typical for many other multifactorial disorders, much of the heritability of SLE remains unknown. We identified a rare autosomal recessive form of SLE, in which autozygome analysis revealed a null mutation in the DNASE1L3 gene. The DNASE1L3-related SLE we describe was always pediatric in onset and correlated with a high frequency of lupus nephritis. Our findings confirm the critical role of impaired clearance of degraded DNA in SLE pathogenesis.


Assuntos
Endodesoxirribonucleases/genética , Lúpus Eritematoso Sistêmico/genética , Deleção de Sequência , Adolescente , Criança , Pré-Escolar , Consanguinidade , Feminino , Estudos de Associação Genética , Hereditariedade , Homozigoto , Humanos , Escore Lod , Masculino , Adulto Jovem
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