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1.
Mol Genet Genomic Med ; 9(11): e1645, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34582124

RESUMO

BACKGROUND: Terminal deletions of the long arm of chromosome 7 are well known and frequently associated with syndromic holoprosencephaly due to the involvement of the SHH (aliases HHG1, SMMCI, TPT, TPTPS, and MCOPCB5) gene region. However, interstitial deletions including CNTNAP2 (aliases Caspr2, KIAA0868, and NRXN4) and excluding the SHH region are less common. METHODS: We report the clinical and molecular characterization associated with pure 7q35 and 7q35q36.1 deletion in two unrelated patients as detected by oligonucleotide-based array-CGH analysis. RESULTS: The common clinical features were abnormal maternal serum screening during first-trimester pregnancy, low occipitofrontal circumference at birth, hypotonia, abnormal feet, developmental delay, impaired language development, generalized seizures, hyperactive behavior, friendly personality, and cranio-facial dysmorphism. Both deletions occurred de novo and sequencing of CNTNAP2, a candidate gene for epilepsy and autism showed absence of mutation on the contralateral allele. CONCLUSION: Combined haploinsufficiency of GALNTL5 (alias GalNAc-T5L), CUL1, SSPO (aliases SCO-spondin, KIAA0543, and FLJ36112), AOC1 (alias DAO), RHEB, and especially KMT2C (alias KIAA1506 and HALR) with monoallelic disruption of CNTNAP2 may explain neurologic abnormalities, hypotonia, and exostoses. Haploinsufficiency of PRKAG2 (aliases AAKG, AAKG2, H91620p, WPWS, and CMH6) and KCNH2 (aliases Kv11.1, HERG, and erg1) genes may be responsible of long QT syndrome observed for one patient.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 7/genética , Anormalidades Craniofaciais/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Pré-Escolar , Transtornos Cromossômicos/patologia , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Haploinsuficiência , Humanos , Masculino , Teste Pré-Natal não Invasivo , Fenótipo
2.
Eur Heart J ; 37(23): 1826-34, 2016 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-26537620

RESUMO

AIMS: Increased left ventricular wall thickness (LVWT) is a common finding in cardiology. It is not known how often hereditary transthyretin-related familial amyloid cardiomyopathy (mTTR-FAC) is responsible for LVWT. Several therapeutic modalities for mTTR-FAC are currently in clinical trials; thus, it is important to establish the prevalence of TTR mutations (mTTR) and the clinical characteristics of the patients with mTTR-FAC. METHODS AND RESULTS: In a prospective multicentre, cross-sectional study, the TTR gene was sequenced in 298 consecutive patients diagnosed with increased LVWT in primary cardiology clinics in France. Among the included patients, median (25-75th percentiles) age was 62 [50;74]; 74% were men; 23% were of African origin; and 36% were in NYHA Class III-IV. Median LVWT was 18 (16-21) mm. Seventeen (5.7%; 95% confidence interval [CI]: [3.4;9.0]) patients had mTTR of whom 15 (5.0%; 95% CI [2.9;8.2]) had mTTR-FAC. The most frequent mutations were V142I (n = 8), V50M (n = 2), and I127V (n = 2). All mTTR-FAC patients were older than 63 years with a median age of 74 [69;79]. Of the 15 patients with mTTR-FAC, 8 were of African descent while 7 were of European descent. In the African descendants, mTTR-FAC median age was 74 [72;79] vs. 55 [46;65] years in non-mTTR-FAC (P < 0.001). In an adjusted multivariate model, African origin, neuropathy, carpal tunnel syndrome, electrocardiogram (ECG) low voltage, and late gadolinium enhancement (LGE) at cardiac-magnetic resonance imaging were all independently associated with mTTR-FAC. CONCLUSION: Five per cent of patients diagnosed with hypertrophic cardiomyopathy have mTTR-FAC. Mutated transthyretin genetic screening is warranted in elderly subjects with increased LVWT, particularly, those of African descent with neuropathy, carpal tunnel syndrome, ECG low voltage, or LGE.


Assuntos
Neuropatias Amiloides Familiares/patologia , Cardiomiopatia Hipertrófica/patologia , Idoso , Idoso de 80 Anos ou mais , Amiloide/genética , Neuropatias Amiloides Familiares/epidemiologia , Neuropatias Amiloides Familiares/genética , Cardiomiopatia Hipertrófica/epidemiologia , Cardiomiopatia Hipertrófica/genética , Estudos Transversais , Feminino , França/epidemiologia , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Ventrículos do Coração/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Pré-Albumina/genética , Prevalência , Estudos Prospectivos
3.
Eur J Med Genet ; 58(11): 591-6, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26386246

RESUMO

We report the prenatal detection of a de novo unbalanced complex chromosomal rearrangement (CCR), in a fetus with growth delay and bilateral cataracts. Standard karyotype and FISH analyses on amniotic fluid revealed a complex de novo translocation, resulting in a 46,XY,t(1;12;14)(q42;q14;q32) karyotype. CGH-array showed a significant deletion of 387  kb at 12q14.3, at a distance of only 200-700 kb from the breakpoint at 12q14, which encompassed the HMGA2 gene and occurred de novo. Although 12q14 microdeletions are associated with growth delay in several reports in the literature, we present here the smallest deletion prenatally detected, and we detail the clinical description of the fetus. The correlation between cataracts and this complex genotype is puzzling. Among the genes disrupted by the breakpoint in 12q14, GRIP1 has been associated with abnormal eye development in mice, including lens degeneration. Interestingly, HMGA2 is expressed in the mouse's developing lens, and its expression is decreased in lens of elderly humans, correlated with the severity of lens opacity. In this report, we refine the link between HMGA2 loss of function and growth delay during prenatal development. We also discuss the correlation between cataracts and genotype in this unbalanced CCR case of unexpected complexity.


Assuntos
Catarata/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 1/genética , Retardo do Crescimento Fetal/genética , Proteína HMGA2/genética , Translocação Genética , Adulto , Catarata/diagnóstico por imagem , Catarata/patologia , Pontos de Quebra do Cromossomo , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Deleção de Genes , Humanos , Gravidez , Síndrome , Ultrassonografia
4.
Eur J Med Genet ; 58(9): 497-501, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26162704

RESUMO

We report paternally inherited duplication of 1q12q21.2 of 5.8 Mb associated with maternally inherited deletion of 16p11.2 of 545 Kb, this latter first identified in a fetus exhibiting an absent nasal bone detected during pregnancy. During the neonatal period, the young boy presented developmental delay, epilepsy, congenital anomalies and overweight. The clinical features of the proband with two rearrangements were more severe than in either of the parents carrying only one or the other mutation. Thus our data support a two-hit model in which the concomitant presence of these two copy-number variations exacerbates the neurodevelopmental phenotype.


Assuntos
Duplicação Cromossômica , Cromossomos Humanos Par 16/genética , Deficiências do Desenvolvimento/genética , Pré-Escolar , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/diagnóstico , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Osso Nasal/anormalidades , Fenótipo
5.
Mol Cytogenet ; 8: 8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25670966

RESUMO

BACKGROUND: Here we report the clinical and molecular characterization of two Xp11.22 deletions including SHROOM4 and CLCN5 genes. These deletions appeared in the same X chromosome of the same patient. RESULTS: The patient is a six-year-old boy who presented hydrocephalus, severe psychomotor and growth retardation, facial dysmorphism and renal proximal tubulopathy associated with low-molecular-weight proteinuria, hypercalciuria, hyperaminoaciduria, hypophosphatemia and hyperuricemia. Standard and high resolution karyotypes showed a 46,XY formula. Array-CGH revealed two consecutive cryptic deletions in the region Xp11.22, measuring respectively 148 Kb and 2.6 Mb. The two deletions were inherited from the asymptomatic mother. CONCLUSIONS: Array-CGH allowed us to determine candidate genes in the deleted region. The disruption and partial loss of CLCN5 confirmed the diagnostic of Dent disease for this patient. Moreover, the previously described involvement of SHROOM4 in neuronal development is discussed.

6.
Hum Mol Genet ; 23(17): 4479-90, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-24714983

RESUMO

Hemochromatosis type 4 is a rare form of primary iron overload transmitted as an autosomal dominant trait caused by mutations in the gene encoding the iron transport protein ferroportin 1 (SLC40A1). SLC40A1 mutations fall into two functional categories (loss- versus gain-of-function) underlying two distinct clinical entities (hemochromatosis type 4A versus type 4B). However, the vast majority of SLC40A1 mutations are rare missense variations, with only a few showing strong evidence of causality. The present study reports the results of an integrated approach collecting genetic and phenotypic data from 44 suspected hemochromatosis type 4 patients, with comprehensive structural and functional annotations. Causality was demonstrated for 10 missense variants, showing a clear dichotomy between the two hemochromatosis type 4 subtypes. Two subgroups of loss-of-function mutations were distinguished: one impairing cell-surface expression and one altering only iron egress. Additionally, a new gain-of-function mutation was identified, and the degradation of ferroportin on hepcidin binding was shown to probably depend on the integrity of a large extracellular loop outside of the hepcidin-binding domain. Eight further missense variations, on the other hand, were shown to have no discernible effects at either protein or RNA level; these were found in apparently isolated patients and were associated with a less severe phenotype. The present findings illustrate the importance of combining in silico and biochemical approaches to fully distinguish pathogenic SLC40A1 mutations from benign variants. This has profound implications for patient management.


Assuntos
Proteínas de Transporte de Cátions/deficiência , Hemocromatose/genética , Anotação de Sequência Molecular , Mutação de Sentido Incorreto/genética , Adulto , Idoso , Substituição de Aminoácidos/genética , Transporte Biológico , Proteínas de Transporte de Cátions/sangue , Proteínas de Transporte de Cátions/genética , Simulação por Computador , Feminino , Ferritinas/sangue , Frequência do Gene/genética , Estudos de Associação Genética , Células HEK293 , Hemocromatose/sangue , Hepcidinas/farmacologia , Humanos , Espaço Intracelular/metabolismo , Ferro/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Splicing de RNA/genética , Relação Estrutura-Atividade , População Branca/genética , Adulto Jovem
7.
Mol Cytogenet ; 7(1): 17, 2014 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-24581273

RESUMO

BACKGROUND: Microdeletions of 14q22q23 have been associated with eye abnormalities and pituitary defects. Other phenotypic features in deletion carriers including hearing loss and response to growth hormone therapy are less well recognized. We studied genotype and phenotype of three newly identified children with 14q22q23 deletions, two girls and one boy with bilateral anophthalmia, and compared them with previously published deletion patients and individuals with intragenic defects in genes residing in the region. RESULTS: The three deletions were de novo and ranged in size between 5.8 and 8.9 Mb. All three children lacked one copy of the OTX2 gene and in one of them the deletion involved also the BMP4 gene. All three patients presented partial conductive hearing loss which tended to improve with age. Analysis of endocrine and growth phenotypes showed undetectable anterior pituitary, growth hormone deficiency and progressive growth retardation in all three patients. Growth hormone therapy led to partial catch-up growth in two of the three patients but just prevented further height loss in the third. CONCLUSIONS: The pituitary hypoplasia, growth hormone deficiency and growth retardation associated with 14q22q23 microdeletions are very remarkable, and the latter appears to have an atypical response to growth hormone therapy in some of the cases.

8.
Hum Mutat ; 35(7): 805-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24633926

RESUMO

Cystic fibrosis may be revealed by nasal polyposis (NP) starting early in life. We performed cystic fibrosis transmembrane conductance regulator (CFTR) DNA and mRNA analyses in the family of a 12-year-old boy presenting with NP and a normal sweat test. Routine DNA analysis only showed the heterozygous c.2551C>T (p.Arg851*) mutation in the child and the father. mRNA analysis showed partial exon skipping due to c.2551C>T and a significant increase in total CFTR mRNA in the patient and the mother, which was attributable to the heterozygous c. -2954G>A variant in the distant promoter region, as demonstrated by in vitro luciferase assays. The 5' rapid amplification of cDNA ends analysis showed the presence of a novel transcript, where the canonical exon 1 was replaced by an alternative exon called 1a-Long. This case report could represent the first description of a CFTR-related disorder associated with the presence of a 5' alternative, probably nonfunctional transcript, similar to those of fetal origin.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Mutação , Pólipos Nasais/genética , Isoformas de RNA , RNA Mensageiro/genética , Regiões 5' não Traduzidas , Processamento Alternativo , Criança , Análise Mutacional de DNA , Ordem dos Genes , Humanos , Masculino , Pólipos Nasais/diagnóstico , Linhagem
9.
Eur J Hum Genet ; 22(4): 471-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24129437

RESUMO

Obesity is a common but highly, clinically, and genetically heterogeneous disease. Deletion of the terminal region of the short arm of chromosome 2 is rare and has been reported in about 13 patients in the literature often associated with a Prader-Willi-like phenotype. We report on five unrelated patients with 2p25 deletion of paternal origin presenting with early-onset obesity, hyperphagia, intellectual deficiency, and behavioural difficulties. Among these patients, three had de novo pure 2pter deletions, one presented with a paternal derivative der(2)t(2;15)(p25.3;q26) with deletion in the 2pter region and the last patient presented with an interstitial 2p25 deletion. The size of the deletions was characterized by SNP array or array-CGH and was confirmed by fluorescence in situ hybridization (FISH) studies. Four patients shared a 2p25.3 deletion with a minimal critical region estimated at 1.97 Mb and encompassing seven genes, namely SH3HYL1, ACP1, TMEMI8, SNTG2, TPO, PXDN, and MYT1L genes. The fifth patient had a smaller interstitial deletion encompassing the TPO, PXDN, and MYT1L genes. Paternal origin of the deletion was determined by genotyping using microsatellite markers. Analysis of the genes encompassed in the deleted region led us to speculate that the ACP1, TMEM18, and/or MYT1L genes might be involved in early-onset obesity. In addition, intellectual deficiency and behavioural troubles can be explained by the heterozygous loss of the SNTG2 and MYT1L genes. Finally, we discuss the parent-of-origin of the deletion.


Assuntos
Cromossomos Humanos Par 2/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Obesidade/genética , Proteínas Tirosina Fosfatases/genética , Proteínas Proto-Oncogênicas/genética , Deleção de Sequência , Fatores de Transcrição/genética , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hibridização in Situ Fluorescente , Masculino , Obesidade/complicações , Obesidade/diagnóstico , Fenótipo , Polimorfismo de Nucleotídeo Único , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/genética , Análise de Sequência de DNA
10.
Am J Hum Genet ; 92(5): 707-24, 2013 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-23643381

RESUMO

Transcription factor SOX10 plays a role in the maintenance of progenitor cell multipotency, lineage specification, and cell differentiation and is a major actor in the development of the neural crest. It has been implicated in Waardenburg syndrome (WS), a rare disorder characterized by the association between pigmentation abnormalities and deafness, but SOX10 mutations cause a variable phenotype that spreads over the initial limits of the syndrome definition. On the basis of recent findings of olfactory-bulb agenesis in WS individuals, we suspected SOX10 was also involved in Kallmann syndrome (KS). KS is defined by the association between anosmia and hypogonadotropic hypogonadism due to incomplete migration of neuroendocrine gonadotropin-releasing hormone (GnRH) cells along the olfactory, vomeronasal, and terminal nerves. Mutations in any of the nine genes identified to date account for only 30% of the KS cases. KS can be either isolated or associated with a variety of other symptoms, including deafness. This study reports SOX10 loss-of-function mutations in approximately one-third of KS individuals with deafness, indicating a substantial involvement in this clinical condition. Study of SOX10-null mutant mice revealed a developmental role of SOX10 in a subpopulation of glial cells called olfactory ensheathing cells. These mice indeed showed an almost complete absence of these cells along the olfactory nerve pathway, as well as defasciculation and misrouting of the nerve fibers, impaired migration of GnRH cells, and disorganization of the olfactory nerve layer of the olfactory bulbs.


Assuntos
Surdez/genética , Predisposição Genética para Doença/genética , Síndrome de Kallmann/genética , Neuroglia/patologia , Condutos Olfatórios/patologia , Fatores de Transcrição SOXE/genética , Animais , Análise Mutacional de DNA , Surdez/patologia , Feminino , França , Galactosídeos , Células HeLa , Humanos , Indóis , Síndrome de Kallmann/patologia , Masculino , Camundongos , Mutação/genética , Plasmídeos/genética
11.
Hum Mol Genet ; 22(13): 2652-61, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23466526

RESUMO

Mowat-Wilson syndrome (MWS) is a severe intellectual disability (ID)-distinctive facial gestalt-multiple congenital anomaly syndrome, commonly associating microcephaly, epilepsy, corpus callosum agenesis, conotruncal heart defects, urogenital malformations and Hirschsprung disease (HSCR). MWS is caused by de novo heterozygous mutations in the ZEB2 gene. The majority of mutations lead to haplo-insufficiency through premature stop codons or large gene deletions. Only three missense mutations have been reported so far; none of which resides in a known functional domain of ZEB2. In this study, we report and analyze the functional consequences of three novel missense mutations, p.Tyr1055Cys, p.Ser1071Pro and p.His1045Arg, identified in the highly conserved C-zinc-finger (C-ZF) domain of ZEB2. Patients' phenotype included the facial gestalt of MWS and moderate ID, but no microcephaly, heart defects or HSCR. In vitro studies showed that all the three mutations prevented binding and repression of the E-cadherin promoter, a characterized ZEB2 target gene. Taking advantage of the zebrafish morphant technology, we performed rescue experiments using wild-type (WT) and mutant human ZEB2 mRNAs. Variable, mutation-dependent, embryo rescue, correlating with the severity of patients' phenotype, was observed. Our data provide evidence that these missense mutations cause a partial loss of function of ZEB2, suggesting that its role is not restricted to repression of E-cadherin. Functional domains other than C-ZF may play a role in early embryonic development. Finally, these findings broaden the clinical spectrum of ZEB2 mutations, indicating that MWS ought to be considered in patients with lesser degrees of ID and a suggestive facial gestalt, even in the absence of congenital malformation.


Assuntos
Alelos , Doença de Hirschsprung/genética , Proteínas de Homeodomínio/genética , Deficiência Intelectual/genética , Microcefalia/genética , Mutação de Sentido Incorreto , Proteínas Repressoras/genética , Sequência de Aminoácidos , Animais , Linhagem Celular , DNA/metabolismo , Modelos Animais de Doenças , Fácies , Feminino , Ordem dos Genes , Proteínas de Homeodomínio/química , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Dados de Sequência Molecular , Fenótipo , Ligação Proteica , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Transcrição Gênica , Peixe-Zebra , Homeobox 2 de Ligação a E-box com Dedos de Zinco , Dedos de Zinco/genética
12.
Hum Mol Genet ; 22(12): 2387-99, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23427148

RESUMO

Goldberg-Shprintzen syndrome (GOSHS, MIM #609460) is an autosomal recessive disorder of intellectual disability, specific facial gestalt and Hirschsprung's disease (HSCR). In 2005, homozygosity mapping in a large consanguineous family identified KIAA1279 as the disease-causing gene. KIAA1279 encodes KIF-binding protein (KBP), whose function is incompletely understood. Studies have identified either the mitochondria or the cytoskeleton as the site of KBP localization and interactions. To better delineate the KIAA1279-related clinical spectrum and the molecular mechanisms involved in GOSHS, we studied five new patients from three different families. The homozygous KIAA1279 mutations in these patients (p.Arg90X, p.Ser200X or p.Arg202IlefsX2) led to nonsense-mediated mRNA decay and loss of KBP function. Despite the absence of functional KBP, respiratory chain complex activity in patient fibroblasts was normal. KBP did not co-localize with mitochondria in control human fibroblasts, but interacted with the actin and tubulin cytoskeleton. KBP expression directly affected neurite growth in a neuron-like cell line (human neuroblastoma SH-SY5Y), in keeping with the central (polymicrogyria) and enteric (HSCR) neuronal developmental defects seen in GOSHS patients. The KBP interactions with actin filaments and microtubules (MTs) demonstrated in our study constitute the first evidence that an actin MT cross-link protein is involved in neuronal development in humans.


Assuntos
Anormalidades Craniofaciais/metabolismo , Doença de Hirschsprung/metabolismo , Microtúbulos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Actinas/genética , Actinas/metabolismo , Adolescente , Adulto , Criança , Anormalidades Craniofaciais/genética , Feminino , França , Doença de Hirschsprung/genética , Humanos , Lactente , Iraque , Masculino , Microtúbulos/genética , Mutação , Proteínas do Tecido Nervoso/genética , Linhagem , Ligação Proteica , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , População Branca/genética
13.
Hum Mutat ; 34(6): 873-81, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23420618

RESUMO

With the increased number of identified nucleotide sequence variations in genes, the current challenge is to classify them as disease causing or neutral. These variants of unknown clinical significance can alter multiple processes, from gene transcription to RNA splicing or protein function. Using an approach combining several in silico tools, we identified some exons presenting weaker splicing motifs than other exons in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. These exons exhibit higher rates of basal skipping than exons harboring no identifiable weak splicing signals using minigene assays. We then screened 19 described mutations in three different exons, and identified exon-skipping substitutions. These substitutions induced higher skipping levels in exons having one or more weak splicing motifs. Indeed, this level remained under 2% for exons with strong splicing motifs and could reach 40% for exons having at least one weak motif. Further analysis revealed a functional exon splicing enhancer within exon 3 that was associated with the SR protein SF2/ASF and whose disruption induced exon skipping. Exon skipping was confirmed in vivo in two nasal epithelial cell brushing samples. Our approach, which point out exons with some splicing signals weaknesses, will help spot splicing mutations of clinical relevance.


Assuntos
Processamento Alternativo , Biologia Computacional , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Éxons , Biologia Computacional/métodos , Simulação por Computador , Humanos , Modelos Biológicos , Mutação de Sentido Incorreto , Proteínas Nucleares/metabolismo , Proteínas de Ligação a RNA/metabolismo , Sequências Reguladoras de Ácido Nucleico , Fatores de Processamento de Serina-Arginina , Transcrição Gênica
14.
Hum Mutat ; 34(2): 287-91, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23065710

RESUMO

The correction of premature termination codons (PTCs) by agents that promote readthrough represents a promising emerging tool for the treatment of many genetic diseases. The efficiency of the treatment, however, varies depending on the stop codon itself and the amount of correctible transcripts related to the efficiency of nonsense-mediated decay. In the current study, a screen by in vitro minigene assay of all six PTCs described in exon 15 of the CFTR gene demonstrated alternative splicing to differing degrees for five of them. Of the five, PTC mutations c.2537G>A (p.Trp846*(UAG) ) and c.2551C>T (p.Arg851*) cause the greatest proportion of transcripts lacking exon 15; both mutations altering exonic splicing regulatory elements. In order to increase the amount of full-length transcripts, different pharmacological treatments were performed showing both negative and positive effects on exon inclusion for the same mutation. Therefore, the total amount of transcripts together with the splicing profile should be assessed to anticipate and improve efficacy of readthrough therapy.


Assuntos
Processamento Alternativo/genética , Códon sem Sentido/genética , Éxons , Fases de Leitura/genética , Brônquios/citologia , Brônquios/metabolismo , Linhagem Celular , Fibrose Cística/genética , Fibrose Cística/terapia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Células Epiteliais , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
15.
Eur J Med Genet ; 55(12): 737-42, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23017438

RESUMO

In this report, we describe a case of multiple small supernumerary marker chromosomes (sSMC) presenting with recurrent abortions. Peripheral blood lymphocytes of a young, healthy and non-consanguineous couple who asked for genetic evaluation after two spontaneous miscarriages were obtained for karyotypes. Lymphocytes of the woman were analyzed by FISH techniques and DNA was extracted and used for array CGH investigation. Karyotyping revealed 48,XX,+2mar[24]/47,XX,+mar[5]/46,XX[3] for the woman and 46,XY for her husband. FISH analysis showed that the two sSMC consisted of chromosomes 6 and 20. Array CGH analysis showed gains of the 6p11.2q12 (9 Mb) and 20 p11.21 (3.3 Mb) chromosomal regions with a total of 42 genes present on both sSMC. Our findings support also the hypothesis that the modification of the expression of some genes involved in embryo implantation, like THBD gene, could be responsible in the recurrent abortions. This report underpins the necessity of array CGH for characterizing precisely sSMC and helping in genotype-phenotype correlations. Furthermore, a literature review on sSMC is included.


Assuntos
Aborto Espontâneo/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 20 , Cromossomos Humanos Par 6 , Adulto , Hibridização Genômica Comparativa , Feminino , Marcadores Genéticos , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Gravidez
16.
PLoS One ; 7(7): e41927, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22848661

RESUMO

Waardenburg syndrome (WS) is a rare auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and pigmentation defects. Four subtypes are clinically defined based on the presence or absence of additional symptoms. WS type 2 (WS2) can result from mutations within the MITF or SOX10 genes; however, 70% of WS2 cases remain unexplained at the molecular level, suggesting that other genes might be involved and/or that mutations within the known genes escaped previous screenings. The recent identification of a deletion encompassing three of the SOX10 regulatory elements in a patient presenting with another WS subtype, WS4, defined by its association with Hirschsprung disease, led us to search for deletions and point mutations within the MITF and SOX10 regulatory elements in 28 yet unexplained WS2 cases. Two nucleotide variations were identified: one in close proximity to the MITF distal enhancer (MDE) and one within the U1 SOX10 enhancer. Functional analyses argued against a pathogenic effect of these variations, suggesting that mutations within regulatory elements of WS genes are not a major cause of this neurocristopathy.


Assuntos
Análise Mutacional de DNA , Fator de Transcrição Associado à Microftalmia/genética , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição SOXE/genética , Síndrome de Waardenburg/genética , Adolescente , Animais , Sequência de Bases , Feminino , Células HeLa , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Mutação Puntual/genética , Deleção de Sequência/genética
17.
Hum Reprod ; 27(5): 1460-5, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22416012

RESUMO

BACKGROUND: Kallmann syndrome (KS) is a genetic disorder associating pubertal failure with congenitally absent or impaired sense of smell. KS is related to defective neuronal development affecting both the migration of olfactory nerve endings and GnRH neurons. The discovery of several genetic mutations responsible for KS led to the identification of signaling pathways involved in these processes, but the mutations so far identified account for only 30% of cases of KS. Here, we attempted to identify new genes responsible for KS by using a pan-genomic approach. METHODS: From a cohort of 120 KS patients, we selected 48 propositi with no mutations in known KS genes. They were analyzed by comparative genomic hybridization array, using Agilent 105K oligonucleotide chips with a mean resolution of 50 kb. RESULTS: One propositus was found to have a heterozygous deletion of 213 kb at locus 7q21.11, confirmed by real-time qPCR, deleting 11 of the 17 SEMA3A exons. This deletion cosegregated in the propositus' family with the KS phenotype, that was transmitted in autosomal dominant fashion and was not associated with other neurological or non-neurological clinical disorders. SEMA3A codes for semaphorin 3A, a protein that interacts with neuropilins. Mice lacking semaphorin 3A expression have been showed to have a Kallmann-like phenotype. CONCLUSIONS: SEMA3A is therefore a new gene whose loss-of-function is involved in KS. These findings validate the specific role of semaphorin 3A in the development of the olfactory system and in neuronal control of puberty in humans.


Assuntos
Deleção de Genes , Síndrome de Kallmann/genética , Semaforina-3A/genética , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Puberdade/genética , Puberdade/fisiologia , Semaforina-3A/fisiologia , Olfato/genética , Olfato/fisiologia
18.
Eur J Hum Genet ; 20(9): 990-4, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22378281

RESUMO

Waardenburg syndrome type 4 (WS4) is a rare neural crest disorder defined by the combination of Waardenburg syndrome (sensorineural hearing loss and pigmentation defects) and Hirschsprung disease (intestinal aganglionosis). Three genes are known to be involved in this syndrome, that is, EDN3 (endothelin-3), EDNRB (endothelin receptor type B), and SOX10. However, 15-35% of WS4 remains unexplained at the molecular level, suggesting that other genes could be involved and/or that mutations within known genes may have escaped previous screenings. Here, we searched for deletions within recently identified SOX10 regulatory sequences and describe the first characterization of a WS4 patient presenting with a large deletion encompassing three of these enhancers. Analysis of the breakpoint region suggests a complex rearrangement involving three Alu sequences that could be mediated by a FosTes/MMBIR replication mechanism. Taken together with recent reports, our results demonstrate that the disruption of highly conserved non-coding elements located within or at a long distance from the coding sequences of key genes can result in several neurocristopathies. This opens up new routes to the molecular dissection of neural crest disorders.


Assuntos
Elementos Alu , Elementos Facilitadores Genéticos , Fatores de Transcrição SOXE/genética , Deleção de Sequência , Síndrome de Waardenburg/genética , Pré-Escolar , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 22 , Endotelina-3/genética , Doença de Hirschsprung , Humanos , Masculino , Dados de Sequência Molecular , Crista Neural/metabolismo , Crista Neural/patologia , Receptor de Endotelina B/genética , Síndrome de Waardenburg/patologia
19.
Eur J Hum Genet ; 20(5): 584-7, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22258527

RESUMO

The microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor, which regulates melanocyte development and the biosynthetic melanin pathway. A notable relationship has been described between non-truncating mutations of its basic domain and Tietz syndrome, which is characterized by albinoid-like hypopigmentation of the skin and hair, rather than the patchy depigmentation seen in Waardenburg syndrome, and severe hearing loss. Twelve patients with new or recurrent non-truncating mutations of the MITF basic domain from six families were enrolled in this study. We observed a wide range of phenotypes and some unexpected features. All the patients had blue irides and pigmentation abnormalities that ranged from diffuse hypopigmentation to Waardenburg-like patches. In addition, they showed congenital complete hearing loss, diffuse hypopigmentation of the skin, freckling and ocular abnormalities, more frequently than patients with MITF mutations outside the basic domain. In conclusion, the non-truncating mutations of the basic domain do not always lead to Tietz syndrome but rather to a large range of phenotypes. Sun-exposed freckles are interestingly observed more frequently in Asian populations. This variability argues for the possible interaction with modifier loci.


Assuntos
Albinismo Oculocutâneo/genética , Surdez/genética , Variação Genética , Fator de Transcrição Associado à Microftalmia/genética , Síndrome de Waardenburg/genética , Adulto , Pré-Escolar , Feminino , Genótipo , Humanos , Mutação , Fenótipo
20.
Hemoglobin ; 36(2): 177-82, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22273484

RESUMO

We report three cases with very heterogeneous Hb A(2) levels caused by known chromosomal rearrangements in the ß-globin locus. These rearrangements had their breakpoints at the same region in the δ gene, leading either to the Senegalese δ(0)ß(+)-thalassemia (δ(0)ß(+)-thal) deletion or to an insertion of a δ gene, known as Anti-Lepore. One patient showed, apart from drastically increased Hb A(2) values of 17.0%, inconspicuous hematological values. He had an Anti-Lepore mutation with three copies of the δ gene, thus explaining the high Hb A(2) level. Two other patients had Hb A(2) levels in the lower borderline range and increased Hb F levels. Molecular analysis showed the Senegalese δ(0)ß(+)-thal deletion. One of them presented with an additional mild ß-thal mutation leading to ß-thal intermedia. These cases illustrate that different gene rearrangements with the same breakpoints in the δ gene can lead to different levels of Hb A(2) depending on the remaining number of δ genes.


Assuntos
Dosagem de Genes , Rearranjo Gênico/genética , Talassemia beta/genética , Globinas delta/genética , Adulto , DNA/química , DNA/genética , Quebras de DNA , Feminino , Hemoglobina Fetal/genética , Genótipo , Hemoglobina A2/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Índice de Gravidade de Doença
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