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1.
Artigo em Inglês | MEDLINE | ID: mdl-31721432

RESUMO

CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference ≥2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (≤15% each). These results suggest that, in addition to its established link with autism and intellectual disability, CHD8 causes an overgrowth phenotype, and should be considered in the differential diagnosis of patients presenting with increased height and/or head circumference in association with intellectual disability.

2.
Genet Med ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31700164

RESUMO

PURPOSE: Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions. METHODS: We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGUeye) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants. RESULTS: Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease. CONCLUSION: Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants.

3.
Genet Med ; 21(10): 2216-2223, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30976099

RESUMO

PURPOSE: To provide a detailed electroclinical description and expand the phenotype of PIGT-CDG, to perform genotype-phenotype correlation, and to investigate the onset and severity of the epilepsy associated with the different genetic subtypes of this rare disorder. Furthermore, to use computer-assisted facial gestalt analysis in PIGT-CDG and to the compare findings with other glycosylphosphatidylinositol (GPI) anchor deficiencies. METHODS: We evaluated 13 children from eight unrelated families with homozygous or compound heterozygous pathogenic variants in PIGT. RESULTS: All patients had hypotonia, severe developmental delay, and epilepsy. Epilepsy onset ranged from first day of life to two years of age. Severity of the seizure disorder varied from treatable seizures to severe neonatal onset epileptic encephalopathies. The facial gestalt of patients resembled that of previously published PIGT patients as they were closest to the center of the PIGT cluster in the clinical face phenotype space and were distinguishable from other gene-specific phenotypes. CONCLUSION: We expand our knowledge of PIGT. Our cases reaffirm that the use of genetic testing is essential for diagnosis in this group of disorders. Finally, we show that computer-assisted facial gestalt analysis accurately assigned PIGT cases to the multiple congenital anomalies-hypotonia-seizures syndrome phenotypic series advocating the additional use of next-generation phenotyping technology.

4.
J Biol Chem ; 293(6): 2041-2052, 2018 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-29275331

RESUMO

The complex disorder Cantu syndrome (CS) arises from gain-of-function mutations in either KCNJ8 or ABCC9, the genes encoding the Kir6.1 and SUR2 subunits of ATP-sensitive potassium (KATP) channels, respectively. Recent reports indicate that such mutations can increase channel activity by multiple molecular mechanisms. In this study, we determined the mechanism by which KATP function is altered by several substitutions in distinct structural domains of SUR2: D207E in the intracellular L0-linker and Y985S, G989E, M1060I, and R1154Q/R1154W in TMD2. We engineered substitutions at their equivalent positions in rat SUR2A (D207E, Y981S, G985E, M1056I, and R1150Q/R1150W) and investigated functional consequences using macroscopic rubidium (86Rb+) efflux assays and patch-clamp electrophysiology. Our results indicate that D207E increases KATP channel activity by increasing intrinsic stability of the open state, whereas the cluster of Y981S/G985E/M1056I substitutions, as well as R1150Q/R1150W, augmented Mg-nucleotide activation. We also tested the responses of these channel variants to inhibition by the sulfonylurea drug glibenclamide, a potential pharmacotherapy for CS. None of the D207E, Y981S, G985E, or M1056I substitutions had a significant effect on glibenclamide sensitivity. However, Gln and Trp substitution at Arg-1150 significantly decreased glibenclamide potency. In summary, these results provide additional confirmation that mutations in CS-associated SUR2 mutations result in KATP gain-of-function. They help link CS genotypes to phenotypes and shed light on the underlying molecular mechanisms, including consequences for inhibitory drug sensitivity, insights that may inform the development of therapeutic approaches to manage CS.

5.
Mol Genet Genomic Med ; 5(5): 495-507, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28944233

RESUMO

BACKGROUND: Syntaxin-binding protein 1, encoded by STXBP1, is highly expressed in the brain and involved in fusing synaptic vesicles with the plasma membrane. Studies have shown that pathogenic loss-of-function variants in this gene result in various types of epilepsies, mostly beginning early in life. We were interested to model pathogenic missense variants on the protein structure to investigate the mechanism of pathogenicity and genotype-phenotype correlations. METHODS: We report 11 patients with pathogenic de novo mutations in STXBP1 identified in the first 4293 trios of the Deciphering Developmental Disorder (DDD) study, including six missense variants. We analyzed the structural locations of the pathogenic missense variants from this study and the literature, as well as population missense variants extracted from Exome Aggregation Consortium (ExAC). RESULTS: Pathogenic variants are significantly more likely to occur at highly conserved locations than population variants, and be buried inside the protein domain. Pathogenic mutations are also more likely to destabilize the domain structure compared with population variants, increasing the proportion of (partially) unfolded domains that are prone to aggregation or degradation. We were unable to detect any genotype-phenotype correlation, but unlike previously reported cases, most of the DDD patients with STXBP1 pathogenic variants did not present with very early-onset or severe epilepsy and encephalopathy, though all have developmental delay with intellectual disability and most display behavioral problems and suffered seizures in later childhood. CONCLUSION: Variants across STXBP1 that cause loss of function can result in severe intellectual disability with or without seizures, consistent with a haploinsufficiency mechanism. Pathogenic missense mutations act through destabilization of the protein domain, making it prone to aggregation or degradation. The presence or absence of early seizures may reflect ascertainment bias in the literature as well as the broad recruitment strategy of the DDD study.

6.
Mol Genet Genomic Med ; 5(5): 608-613, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28944244

RESUMO

BACKGROUND: Microdeletions of 2q23.1 disrupting MBD5 and loss of function mutations of MBD5 cause MBD5-Associated Neurodevelopmental disorders (MAND). Nearly all reported patients have been isolated cases of de novo origin. METHODS: This study investigates three families with inherited MBD5 mutations from three different Regional Genetics Centres in the UK. RESULTS: Two of the parents in the study had MBD5 deletions in a mosaic form. The parent with an MBD5 deletion in an apparently nonmosaic form has a psychiatric disorder in the absence of developmental delay or dysmorphism. CONCLUSIONS: Inherited forms of MBD5 deletions are rare, but do occur, especially in a mosaic form. The phenotypic spectrum of MAND may be wider than previously thought.

7.
Best Pract Res Clin Obstet Gynaecol ; 42: 100-113, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28684328

RESUMO

From genomic imbalances associated with developmental abnormalities of the female genital tract to the molecular mechanisms underpinning endometriosis and uterine leiomyomatosis, new technologies have allowed the exploration of the genetic contribution and mapping the molecular pathways underpinning common and rare gynaecological conditions. While some of these conditions have historically been considered sporadic, recent research has demonstrated their potentially heritable nature linked to single genes or copy number variants. The phenotypic variability including non-penetrance indicates their multifactorial, complex aetiology encompassing genetic, epigenetic and environmental influences. Although genetic tests are not routinely conducted in gynaecological practice, there is an increasing body of evidence suggesting that, in appropriate cases, molecular investigations such as array CGH analysis may be an important part of the diagnostic algorithm. The subtlety of clinical features, especially in the context of syndromic diagnoses, requires the practitioner to become familiar with those conditions and the approach to diagnostic investigations. This chapter combines the recent research output related to gynaecological disorders with a clinical genetics approach aiming to highlight the multisystem character of some of these conditions, their implications for management, reproductive risks and options, and the importance of genetic counselling.


Assuntos
Variações do Número de Cópias de DNA , Neoplasias dos Genitais Femininos/genética , Hibridização Genômica Comparativa , Feminino , Aconselhamento Genético , Testes Genéticos , Neoplasias dos Genitais Femininos/classificação , Humanos
8.
Am J Hum Genet ; 100(1): 75-90, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-28041643

RESUMO

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.


Assuntos
Análise Mutacional de DNA , Variação Genética/genética , Genoma Humano/genética , Doenças Retinianas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Alelos , Sequência de Bases , Coroideremia/genética , Grupos Étnicos/genética , Exoma/genética , Feminino , Genes Recessivos/genética , Humanos , Íntrons/genética , Masculino , Mutação , Doenças Raras/genética
9.
Am J Med Genet A ; 170(12): 3069-3082, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27648933

RESUMO

Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia. © 2016 Wiley Periodicals, Inc.


Assuntos
Proteína de Ligação a CREB/genética , Proteína p300 Associada a E1A/genética , Pré-Eclâmpsia/genética , Síndrome de Rubinstein-Taybi/genética , Adulto , Montagem e Desmontagem da Cromatina/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Pré-Eclâmpsia/fisiopatologia , Gravidez , Síndrome de Rubinstein-Taybi/patologia , Deleção de Sequência
10.
J Med Genet ; 53(8): 536-47, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27073233

RESUMO

BACKGROUND: The pseudoautosomal short stature homeobox-containing (SHOX) gene encodes a homeodomain transcription factor involved in cell-cycle and growth regulation. SHOX/SHOX enhancers deletions cause short stature and skeletal abnormalities in a female-dominant fashion; duplications appear to be rare. Neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASDs), are complex disorders with high heritability and skewed sex ratio; several rare (<1% frequency) CNVs have been implicated in risk. METHODS: We analysed data from a discovery series of 90 adult ASD cases, who underwent clinical genetic testing by array-comparative genomic hybridisation (CGH). Twenty-seven individuals harboured CNV abnormalities, including two unrelated females with microduplications affecting SHOX. To determine the prevalence of SHOX duplications and delineate their associated phenotypic spectrum, we subsequently examined array-CGH data from a follow-up sample of 26 574 patients, including 18 857 with NDD (3541 with ASD). RESULTS: We found a significant enrichment of SHOX microduplications in the NDD cases (p=0.00036; OR 2.21) and, particularly, in those with ASD (p=9.18×10(-7); OR 3.63) compared with 12 594 population-based controls. SHOX duplications affecting the upstream or downstream enhancers were enriched only in females with NDD (p=0.0043; OR 2.69/p=0.00020; OR 7.20), but not in males (p=0.404; OR 1.38/p=0.096; OR 2.21). CONCLUSIONS: Microduplications at the SHOX locus are a low penetrance risk factor for ASD/NDD, with increased risk in both sexes. However, a concomitant duplication of SHOX enhancers may be required to trigger a NDD in females. Since specific SHOX isoforms are exclusively expressed in the developing foetal brain, this may reflect the pathogenic effect of altered SHOX protein dosage on neurodevelopment.


Assuntos
Transtorno do Espectro Autista/genética , Variações do Número de Cópias de DNA/genética , Duplicação Gênica/genética , Proteínas de Homeodomínio/genética , Transtornos do Neurodesenvolvimento/genética , Regiões Pseudoautossômicas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Hibridização Genômica Comparativa/métodos , Feminino , Testes Genéticos/métodos , Transtornos do Crescimento/genética , Humanos , Masculino , Pessoa de Meia-Idade , Deleção de Sequência/genética , Proteína de Homoeobox de Baixa Estatura , Fatores de Transcrição/genética , Adulto Jovem
11.
Hum Mol Genet ; 25(11): 2158-2167, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27005418

RESUMO

We identified de novo nonsense variants in KIDINS220/ARMS in three unrelated patients with spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO). KIDINS220 is an essential scaffold protein coordinating neurotrophin signal pathways in neurites and is spatially and temporally regulated in the brain. Molecular analysis of patients' variants confirmed expression and translation of truncated transcripts similar to recently characterized alternative terminal exon splice isoforms of KIDINS220 KIDINS220 undergoes extensive alternative splicing in specific neuronal populations and developmental time points, reflecting its complex role in neuronal maturation. In mice and humans, KIDINS220 is alternative spliced in the middle region as well as in the last exon. These full-length and KIDINS220 splice variants occur at precise moments in cortical, hippocampal, and motor neuron development, with splice variants similar to the variants seen in our patients and lacking the last exon of KIDINS220 occurring in adult rather than in embryonic brain. We conducted tissue-specific expression studies in zebrafish that resulted in spasms, confirming a functional link with disruption of the KIDINS220 levels in developing neurites. This work reveals a crucial physiological role of KIDINS220 in development and provides insight into how perturbation of the complex interplay of KIDINS220 isoforms and their relative expression can affect neuron control and human metabolism. Altogether, we here show that de novo protein-truncating KIDINS220 variants cause a new syndrome, SINO. This is the first report of KIDINS220 variants causing a human disease.


Assuntos
Deficiência Intelectual/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Nistagmo Congênito/genética , Obesidade/genética , Paraplegia/genética , Proteínas de Peixe-Zebra/genética , Processamento Alternativo/genética , Animais , Códon sem Sentido , Modelos Animais de Doenças , Humanos , Deficiência Intelectual/fisiopatologia , Neuritos/metabolismo , Neuritos/patologia , Neurogênese/genética , Neurônios/metabolismo , Neurônios/patologia , Nistagmo Congênito/fisiopatologia , Obesidade/patologia , Células PC12 , Paraplegia/fisiopatologia , Ligação Proteica/genética , Ratos , Transdução de Sinais
12.
J Med Genet ; 51(10): 659-68, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25125236

RESUMO

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS. METHODS: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing. RESULTS: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as 'NIPBL-like'. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases. CONCLUSIONS: Future diagnostic testing in 'mutation-negative' CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.


Assuntos
Síndrome de Lange/genética , Heterogeneidade Genética , Mosaicismo , Face/patologia , Estudos de Associação Genética , Humanos , Mutação , Fenótipo
13.
Neuromuscul Disord ; 23(5): 391-8, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23518311

RESUMO

Infantile-onset X-linked spinal muscular atrophy (SMAX2) is a rare lethal disorder linked to mutations in the UBA1 (previously UBE1) gene, encoding ubiquitin-activating enzyme 1 that has an important role in the ubiquitin-proteasome pathway. Published pathological reports are scarce. Here we report a male infant who presented from birth with predominantly truncal hypotonia following an antenatal history of reduced fetal movements. He had a myopathic face, profound weakness, multiple contractures and areflexia. Creatine kinase was moderately raised. Brain MRI showed non-specific symmetrical periventricular white matter changes. Neurophysiology revealed evidence of motor and sensory involvement and muscle biopsy showed marked inflammatory changes with subtle features suggestive of acute denervation. UBA1 sequencing revealed a novel hemizygous missense mutation (c.1670A>T; p.Glu557Val). He died from progressive respiratory failure at 4 months. On post mortem assessment, in addition to severe ventral motor neuron pathology, there was widespread involvement of the sensory system, as well as developmental and degenerative cerebellar abnormalities. In contrast to typical SMN1-associated SMA, the thalamus was unaffected. These findings indicate that SMAX2 is more accurately classified as a motor sensory neuronopathy rather than a pure anterior horn cell disorder. Ubiquitin-proteasome pathway defects may not only cause neurodegeneration but also affect normal neuronal development.


Assuntos
Artrogripose/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação/genética , Proteínas do Complexo SMN/genética , Atrofias Musculares Espinais da Infância/fisiopatologia , Enzimas Ativadoras de Ubiquitina/genética , Evolução Fatal , Genes Ligados ao Cromossomo X/genética , Humanos , Recém-Nascido , Masculino , Atrofias Musculares Espinais da Infância/complicações , Atrofias Musculares Espinais da Infância/diagnóstico
14.
J Clin Endocrinol Metab ; 98(4): E737-43, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23526466

RESUMO

INTRODUCTION: CHARGE syndrome is a multisystem disorder that, in addition to Kallmann syndrome/isolated hypogonadotrophic hypogonadism, has been associated with anterior pituitary hypoplasia (APH). However, structural abnormalities such as an ectopic posterior pituitary (EPP) have not yet been described in such patients. OBJECTIVE: The aims of the study were: 1) to describe the association between CHARGE syndrome and a structurally abnormal pituitary gland; and 2) to investigate whether CHD7 variants, which are identified in 65% of CHARGE patients, are common in septo-optic dysplasia /hypopituitarism. METHODS: We describe 2 patients with features of CHARGE and EPP. CHD7 was sequenced in these and other patients with septo-optic dysplasia/hypopituitarism. RESULTS: EPP, APH, and GH, TSH, and probable LH/FSH deficiency were present in 1 patient, and EPP and APH with GH, TSH, LH/FSH, and ACTH deficiency were present in another patient, both of whom had features of CHARGE syndrome. Both had variations in CHD7 that were novel and undetected in control cohorts or in the international database of CHARGE patients, but were also present in their unaffected mothers. No CHD7 variants were detected in the patients with septo-optic dysplasia/hypopituitarism without additional CHARGE features. CONCLUSION: We report a novel association between CHARGE syndrome and structural abnormalities of the pituitary gland in 2 patients with variations in CHD7 that are of unknown significance. However, CHD7 mutations are an uncommon cause of septo-optic dysplasia or hypopituitarism. Our data suggest the need for evaluation of pituitary function/anatomy in patients with CHARGE syndrome.


Assuntos
Síndrome CHARGE/complicações , Hipopituitarismo/complicações , Hipófise/anormalidades , Sequência de Aminoácidos , Sequência de Bases , Síndrome CHARGE/epidemiologia , Síndrome CHARGE/genética , Criança , Estudos de Coortes , Sequência Consenso , DNA Helicases/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Humanos , Hipopituitarismo/epidemiologia , Hipopituitarismo/etiologia , Hipopituitarismo/genética , Masculino , Modelos Biológicos , Displasia Septo-Óptica/complicações , Displasia Septo-Óptica/epidemiologia , Displasia Septo-Óptica/genética
15.
Nat Genet ; 45(1): 83-7, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23222957

RESUMO

Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 affected individuals. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies showed a severe block in autophagosomal clearance in muscle and fibroblasts from individuals with mutant EPG5, resulting in the accumulation of autophagic cargo in autophagosomes. These findings position Vici syndrome as a paradigm of human multisystem disorders associated with defective autophagy and suggest a fundamental role of the autophagy pathway in the immune system and the anatomical and functional formation of organs such as the brain and heart.


Assuntos
Agenesia do Corpo Caloso/genética , Antígenos de Neoplasias/genética , Autofagia/genética , Catarata/genética , Genes Recessivos , Mutação , Biópsia , Consanguinidade , Exoma , Família , Humanos , Lisossomos/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Proteínas/metabolismo
16.
Hum Mutat ; 33(1): 64-72, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22045651

RESUMO

Pitt-Hopkins syndrome (PTHS), characterized by severe intellectual disability and typical facial gestalt, is part of the clinical spectrum of Rett-like syndromes. TCF4, encoding a basic helix-loop-helix (bHLH) transcription factor, was identified as the disease-causing gene with de novo molecular defects. While PTHS appears to be a recognizable clinical entity, it seems to remain underdiagnosed, especially when facial gestalt is less typical. With the aim to facilitate the diagnosis of PTHS and to increase its rate and specificity, we have investigated 33 novel patients and defined a Clinical Diagnosis Score. Analysis of 112 individuals (79 previously reported and 33 novel patients) allowed us to delineate the TCF4 mutational spectrum, with 40% point mutations, 30% small deletions/insertions, and 30% deletions. Most of these were private mutations and generated premature stop codons. Missense mutations were localized in the bHLH domain, which is a mutational hotspot. No obvious difference was observed between patients harboring truncating, missense mutations, or deletions, further supporting TCF4 haploinsufficiency as the molecular mechanism underlying PTHS. In this study, we have summarized the current knowledge of TCF4 molecular pathology, reported all the mutations in the TCF4 database (http://www.LOVD.nl/TCF4), and present a novel and comprehensive diagnostic strategy for PTHS.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Cromossomos Humanos Par 18/genética , Hiperventilação/diagnóstico , Deficiência Intelectual/diagnóstico , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Cromossomos Humanos Par 18/química , Bases de Dados Genéticas , Facies , Feminino , Estudos de Associação Genética , Variação Genética , Genótipo , Haploinsuficiência , Haplótipos , Humanos , Hiperventilação/genética , Lactente , Deficiência Intelectual/genética , Masculino , Mutação de Sentido Incorreto , Fenótipo , Estrutura Terciária de Proteína , Deleção de Sequência , Inversão de Sequência , Índice de Gravidade de Doença , Fator de Transcrição 4
17.
Pediatr Neurol ; 45(5): 328-30, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22000314

RESUMO

Mutations in the CACNA1A gene were described in familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6. Familial hemiplegic migraine and episodic ataxia type 2 are caused by point mutations in the CACNA1A gene, and spinocerebellar ataxia type 6 develops as a result of a CAG triple expansion in exon 1 of the gene. Phenotypic variability and clinical overlap are well recognized. We describe a 3-year-old child with clinical and radiologic signs of early-onset cerebellar atrophy. The family history was significant for migraine, and in some members of the family, a diagnosis of hemiplegic migraine was established. The combination of cerebellar atrophy in our patient and the family history suggested involvement of the CACNA1A gene. The sequence analysis of genomic DNA from the proband identified heterozygosity for a mutation (Thr666Met) in the CACNA1A gene. Subsequently, his father, who was mildly affected, and two other relatives were demonstrated to carry the same mutation. Therefore, CACNA1A gene mutations should be considered in the differential diagnosis of congenital cerebellar atrophy.


Assuntos
Canais de Cálcio/genética , Dissinergia Cerebelar Mioclônica/diagnóstico , Dissinergia Cerebelar Mioclônica/genética , Mutação Puntual/genética , Pré-Escolar , Humanos , Masculino , Linhagem
18.
Nat Genet ; 43(8): 776-84, 2011 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-21725307

RESUMO

Mutations affecting ciliary components cause ciliopathies. As described here, we investigated Tectonic1 (Tctn1), a regulator of mouse Hedgehog signaling, and found that it is essential for ciliogenesis in some, but not all, tissues. Cell types that do not require Tctn1 for ciliogenesis require it to localize select membrane-associated proteins to the cilium, including Arl13b, AC3, Smoothened and Pkd2. Tctn1 forms a complex with multiple ciliopathy proteins associated with Meckel and Joubert syndromes, including Mks1, Tmem216, Tmem67, Cep290, B9d1, Tctn2 and Cc2d2a. Components of this complex co-localize at the transition zone, a region between the basal body and ciliary axoneme. Like Tctn1, loss of Tctn2, Tmem67 or Cc2d2a causes tissue-specific defects in ciliogenesis and ciliary membrane composition. Consistent with a shared function for complex components, we identified a mutation in TCTN1 that causes Joubert syndrome. Thus, a transition zone complex of Meckel and Joubert syndrome proteins regulates ciliary assembly and trafficking, suggesting that transition zone dysfunction is the cause of these ciliopathies.


Assuntos
Membrana Celular/fisiologia , Cílios/metabolismo , Cílios/patologia , Proteínas de Membrana/fisiologia , Mutação/genética , Anormalidades Múltiplas , Animais , Doenças Cerebelares/genética , Cerebelo/anormalidades , Galinhas , Transtornos da Motilidade Ciliar/genética , Encefalocele/genética , Anormalidades do Olho/genética , Humanos , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfogênese , Especificidade de Órgãos , Fragmentos de Peptídeos/imunologia , Doenças Renais Policísticas/genética , Coelhos , Retina/anormalidades , Retinite Pigmentosa , Transdução de Sinais , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
19.
Am J Hum Genet ; 86(3): 485-9, 2010 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-20206331

RESUMO

Brown-Vialetto-Van Laere syndrome is a rare neurological disorder with a variable age at onset and clinical course. The key features are progressive ponto-bulbar palsy and bilateral sensorineural deafness. A complex neurological phenotype with a mixed picture of upper and lower motor neuron involvement reminiscent of amyotrophic lateral sclerosis evolves with disease progression. We identified a candidate gene, C20orf54, by studying a consanguineous family with multiple affected individuals and subsequently demonstrated that mutations in this gene were the cause of disease in other, unrelated families.


Assuntos
Paralisia Bulbar Progressiva/genética , Cromossomos Humanos Par 20/genética , Surdez/genética , Proteínas de Membrana/genética , Mutação de Sentido Incorreto , Sequência de Aminoácidos , Substituição de Aminoácidos , Criança , Pré-Escolar , Feminino , Perda Auditiva Neurossensorial/genética , Humanos , Lactente , Masculino , Proteínas de Membrana Transportadoras , Dados de Sequência Molecular , Doença dos Neurônios Motores/genética , Fases de Leitura Aberta , Fenótipo , Homologia de Sequência de Aminoácidos , Síndrome
20.
Eur J Hum Genet ; 18(7): 852-5, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20234391

RESUMO

Dystroglycan is a protein which binds directly to two proteins defective in muscular dystrophies (dystrophin and laminin alpha2) and whose own aberrant post-translational modification is the common aetiological route of neuromuscular diseases associated with mutations in genes encoding at least six other proteins (POMT1, POMT2, POMGnT1, LARGE, FKTN and FKRP). It is surprising, therefore, that to our knowledge no mutations of the human dystroglycan gene itself have yet been reported. In this study, we describe a patient with a heterozygous de novo deletion of a approximately 2-Mb region of chromosome 3, which includes the dystroglycan gene (DAG1). The patient is a 16-year-old female with learning difficulties, white matter abnormalities, elevated serum creatine kinase, oral-motor dyspraxia and facial hypotonia but minimal clinically significant involvement of other muscles. As these symptoms are a subset of those observed in disorders of dystroglycan glycosylation (muscle-eye-brain disease and Warker-Warburg syndrome), we assess the likely contribution to her phenotype of her heterogosity for a null mutation of DAG1. We also show that the transcriptional compensation observed in the Dag1(+/-) mouse is not observed in the patient. Although we cannot show that haploinsufficiency of DAG1 is the sole cause of this patient's myopathy and white matter changes, this case serves to constrain our ideas of the severity of the phenotypic consequences of heterozygosity for null DAG1 mutations.


Assuntos
Apraxias/genética , Distroglicanas/genética , Heterozigoto , Hipotonia Muscular/genética , Doenças Musculares/genética , Doenças Neurodegenerativas/genética , Deleção de Sequência/genética , Adolescente , Apraxias/complicações , Pareamento de Bases/genética , Criança , Face , Facies , Feminino , Humanos , Hipotonia Muscular/complicações , Doenças Musculares/complicações , Doenças Neurodegenerativas/complicações
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