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1.
J Neurochem ; 143(5): 507-522, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28902413

RESUMO

Hereditary neuropathies comprise a wide variety of chronic diseases associated to more than 80 genes identified to date. We herein examined 612 index patients with either a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generation sequencing technique. In 121 cases (19.8%), we identified at least one putative pathogenic mutation. Of these, 54.4% showed an autosomal dominant, 33.9% an autosomal recessive, and 11.6% an X-linked inheritance. The most frequently affected genes were PMP22 (16.4%), GJB1 (10.7%), MPZ, and SH3TC2 (both 9.9%), and MFN2 (8.3%). We further detected likely or known pathogenic variants in HINT1, HSPB1, NEFL, PRX, IGHMBP2, NDRG1, TTR, EGR2, FIG4, GDAP1, LMNA, LRSAM1, POLG, TRPV4, AARS, BIC2, DHTKD1, FGD4, HK1, INF2, KIF5A, PDK3, REEP1, SBF1, SBF2, SCN9A, and SPTLC2 with a declining frequency. Thirty-four novel variants were considered likely pathogenic not having previously been described in association with any disorder in the literature. In one patient, two homozygous mutations in HK1 were detected in the multigene panel, but not by whole exome sequencing. A novel missense mutation in KIF5A was considered pathogenic because of the highly compatible phenotype. In one patient, the plasma sphingolipid profile could functionally prove the pathogenicity of a mutation in SPTLC2. One pathogenic mutation in MPZ was identified after being previously missed by Sanger sequencing. We conclude that panel based next generation sequencing is a useful, time- and cost-effective approach to assist clinicians in identifying the correct diagnosis and enable causative treatment considerations.


Assuntos
Predisposição Genética para Doença , Neuropatia Hereditária Motora e Sensorial/genética , Mutação/genética , Doenças Raras/genética , Doença de Charcot-Marie-Tooth/genética , Feminino , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Chaperonas Moleculares , Fenótipo
2.
Neurobiol Dis ; 47(1): 61-74, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22472189

RESUMO

A mutation in the coding region of the Tor1A gene, resulting in a deletion of a glutamic acid residue in the torsinA protein (∆ETorA), is the major cause of the inherited autosomal-dominant early onset torsion dystonia (DYT1). The pathophysiological consequences of this amino acid loss are still not understood. Currently available animal models for DYT1 dystonia provided important insights into the disease; however, they differ with respect to key features of torsinA associated pathology. We developed transgenic rat models harboring the full length human mutant and wildtype Tor1A gene. A complex phenotyping approach including classical behavioral tests, electrophysiology and neuropathology revealed a progressive neurological phenotype in ∆ETorA expressing rats. Furthermore, we were able to replicate key pathological features of torsinA associated pathology in a second species, such as nuclear envelope pathology, behavioral abnormalities and plasticity changes. We therefore suggest that this rat model represents an appropriate new model suitable to further investigate the pathophysiology of ∆ETorA and to test for therapeutic approaches.


Assuntos
Modelos Animais de Doenças , Distonia Muscular Deformante/genética , Chaperonas Moleculares/genética , Deleção de Sequência , Animais , Humanos , Ratos , Ratos Transgênicos
3.
Mov Disord ; 25(12): 1982-6, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20669277

RESUMO

Primary dystonias are a clinically and genetically heterogeneous group of movement disorders, but only for two of them, i.e., dystonia 1 and dystonia 6, the disease causing gene has been identified. Dystonia 1 is characterized by an early onset and is caused by a mutation in the TOR1A gene. Only recently, mutations in THAP1 have been shown to be the cause of DYT6 dystonia. We analyzed 610 patients with various forms of dystonia for sequence variants in the THAP1 gene by means of high resolution melting to delineate the prevalence of sequence variants and phenotypic variability. We identified seven sequence variants in patients and one sequence variant in a control. The sequence variants were not detected in 537 healthy controls. Four patients present with generalized dystonia with speech involvement of early onset, another three patients suffered exclusively from cervical dystonia of adult onset. These findings suggest that THAP1 sequence variations seem to be associated with different ages of onset and distribution of symptoms. Consequently, the phenotypic spectrum might be broader than previously assumed.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Proteínas de Ligação a DNA/genética , Distúrbios Distônicos/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Idade de Início , Feminino , Variação Genética , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , População Branca/genética
5.
Eur J Hum Genet ; 24(3): 459-62, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26153215

RESUMO

Several genes have been implicated in the autosomal recessive form of cone-rod dystrophy (CRD), but the majority of cases remain unsolved. We identified a homozygous interval comprising two known genes associated with the autosomal recessive form of CRD, namely RAB28 and PROM1, in a consanguineous family with clinical evidence of CRD. Both genes proved to be mutation negative upon sequencing of exons and canonical splice sites but whole-genome sequencing revealed a private variant located deep in intron 18 of PROM1. In silico and functional analyses of this variant using minigenes as splicing reporters revealed the integration of a pseudoexon in the mutant transcript, thereby leading to a premature termination codon and presumably resulting in a functional null allele. This is the first report of a deep intronic variant that acts as a splicing mutation in PROM1. The detection of such variants escapes the exon-focused techniques typically used in genetic analyses. Sequencing the entire genomic regions of known disease genes might identify more causal mutations in the autosomal recessive form of CRD.


Assuntos
Antígenos CD/genética , Éxons/genética , Predisposição Genética para Doença , Genoma Humano , Glicoproteínas/genética , Íntrons/genética , Mutação/genética , Peptídeos/genética , Retinose Pigmentar/genética , Antígeno AC133 , Sequência de Aminoácidos , Antígenos CD/química , Sequência de Bases , Análise Mutacional de DNA , Feminino , Glicoproteínas/química , Células HEK293 , Homozigoto , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Peptídeos/química , Splicing de RNA/genética
6.
PLoS One ; 11(1): e0145951, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26766544

RESUMO

Retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different nonsyndromic and syndromic forms of RD can be attributed to mutations in more than 200 genes. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. We screened a large cohort of patients comprising 89 independent cases and families with various subforms of RD applying different NGS platforms. While mutation screening in 50 cases was performed using a RD gene capture panel, 47 cases were analyzed using whole exome sequencing. One family was analyzed using whole genome sequencing. A detection rate of 61% was achieved including mutations in 34 known and two novel RD genes. A total of 69 distinct mutations were identified, including 39 novel mutations. Notably, genetic findings in several families were not consistent with the initial clinical diagnosis. Clinical reassessment resulted in refinement of the clinical diagnosis in some of these families and confirmed the broad clinical spectrum associated with mutations in RD genes.


Assuntos
Mutação , Distrofias Retinianas/genética , Variações do Número de Cópias de DNA , Exoma , Proteínas do Olho/genética , Feminino , Estudos de Associação Genética , Heterogeneidade Genética , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Taxa de Mutação , Linhagem , Fenótipo , Distrofias Retinianas/diagnóstico
7.
Acta Ophthalmol ; 93(4): e281-6, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25429852

RESUMO

PURPOSE: Mutations in the RLBP1 gene encoding the cellular retinaldehyde-binding protein (CRALBP) cause autosomal recessive progressive retinopathy, such as retinitis punctata albescens (RPA), Bothnia-type dystrophy (BD), Newfoundland rod-cone dystrophy (NFRCD), retinitis pigmentosa (RP) and fundus albipunctatus (FA). We present the clinical heterogeneity and genetic findings of seven patients from five families with RLBP1 mutations, including three novel mutations. METHODS: Seven patients underwent complete ophthalmological examination including psychophysical tests (visual acuity, colour vision, visual field, dark adaptation) and electrophysiology (Ganzfeld and multifocal ERG). Additionally, fundus photography, autofluorescence (FAF) and spectral domain optical coherence tomography (OCT) recordings were performed. Genomic DNA was analysed by high-throughput sequencing for all RP-related genes in a diagnostic set-up. RESULTS: The patients presented with variable phenotypes, including RPA, BD, RP and a mild form of NFRCD. No detectable or severely depressed responses in electrophysiological examinations were seen in all cases. Visual field constriction was variable among individuals. Severely reduced visual acuity was only observed in the patient presenting with BD. The other patients retained mild to moderate reduction of visual function. Despite the morphological differences, central retinal thinning - as a common feature - could be observed. CONCLUSIONS: The fact that different mutations in RLBP1 are correlated with quite different morphological and functional characteristics outlines the complexity of the protein. Identifying new mutations and comparing the different phenotypes may help to better understand the function of the protein and the consequences in pathological changes that involve RPE and choroid.


Assuntos
Proteínas de Transporte/genética , Mutação , Distrofias Retinianas/genética , Adulto , Idoso , Criança , Eletrorretinografia , Feminino , Angiofluoresceinografia , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Distrofias Retinianas/diagnóstico , Irmãos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Adulto Jovem
8.
Eur J Hum Genet ; 22(1): 99-104, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23591405

RESUMO

Hereditary retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different forms of RD can be caused by mutations in >100 genes, including >1600 exons. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. So far, NGS is not routinely used in gene diagnostics. We developed a diagnostic NGS pipeline to identify mutations in 170 genetically and clinically unselected RD patients. NGS was applied to 105 RD-associated genes. Underrepresented regions were examined by Sanger sequencing. The NGS approach was successfully established using cases with known sequence alterations. Depending on the initial clinical diagnosis, we identified likely causative mutations in 55% of retinitis pigmentosa and 80% of Bardet-Biedl or Usher syndrome cases. Seventy-one novel mutations in 40 genes were newly associated with RD. The genes USH2A, EYS, ABCA4, and RHO were more frequently affected than others. Occasionally, cases carried mutations in more than one RD-associated gene. In addition, we found possible dominant de-novo mutations in cases with sporadic RD, which implies consequences for counseling of patients and families. NGS-based mutation analyses are reliable and cost-efficient approaches in gene diagnostics of genetically heterogeneous diseases like RD.


Assuntos
Predisposição Genética para Doença , Patologia Molecular , Distrofias Retinianas/genética , Retinose Pigmentar/genética , Síndromes de Usher/genética , Transportadores de Cassetes de Ligação de ATP/genética , Éxons , Proteínas da Matriz Extracelular/genética , Proteínas do Olho/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Linhagem , Distrofias Retinianas/etiologia , Distrofias Retinianas/patologia , Retinose Pigmentar/etiologia , Análise de Sequência de DNA , Síndromes de Usher/etiologia , Síndromes de Usher/patologia
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