Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 18 de 18
Filtrar
1.
Hum Genet ; 140(6): 885-896, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33417013

RESUMO

The 22q11.2 deletion syndrome (22q11DS) is associated with a wide spectrum of cognitive and psychiatric symptoms. Despite the considerable work performed over the past 20 years, the genetic etiology of the neurodevelopmental phenotype remains speculative. Here, we report de novo heterozygous truncating variants in the HIRA (Histone cell cycle regulation defective, S. Cerevisiae, homolog of, A) gene associated with a neurodevelopmental disorder in two unrelated patients. HIRA is located within the commonly deleted region of the 22q11DS and encodes a histone chaperone that regulates neural progenitor proliferation and neurogenesis, and that belongs to the WD40 Repeat (WDR) protein family involved in brain development and neuronal connectivity. To address the specific impact of HIRA haploinsufficiency in the neurodevelopmental phenotype of 22q11DS, we combined Hira knock-down strategies in developing mouse primary hippocampal neurons, and the direct study of brains from heterozygous Hira+/- mice. Our in vitro analyses revealed that Hira gene is mostly expressed during neuritogenesis and early dendritogenesis stages in mouse total brain and in developing primary hippocampal neurons. Moreover, shRNA knock-down experiments showed that a twofold decrease of endogenous Hira expression level resulted in an impaired dendritic growth and branching in primary developing hippocampal neuronal cultures. In parallel, in vivo analyses demonstrated that Hira+/- mice displayed subtle neuroanatomical defects including a reduced size of the hippocampus, the fornix and the corpus callosum. Our results suggest that HIRA haploinsufficiency would likely contribute to the complex pathophysiology of the neurodevelopmental phenotype of 22q11DS by impairing key processes in neurogenesis and by causing neuroanatomical defects during cerebral development.


Assuntos
Proteínas de Ciclo Celular/genética , Síndrome de DiGeorge/genética , Haploinsuficiência , Chaperonas de Histonas/genética , Transtornos do Neurodesenvolvimento/genética , Plasticidade Neuronal/genética , Neurônios/metabolismo , Fatores de Transcrição/genética , Animais , Sequência de Bases , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/metabolismo , Criança , Pré-Escolar , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Síndrome de DiGeorge/metabolismo , Síndrome de DiGeorge/patologia , Feminino , Fórnice/metabolismo , Fórnice/patologia , Expressão Gênica , Heterozigoto , Hipocampo/metabolismo , Hipocampo/patologia , Chaperonas de Histonas/antagonistas & inibidores , Chaperonas de Histonas/deficiência , Chaperonas de Histonas/metabolismo , Humanos , Camundongos , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Neurogênese/genética , Neurônios/patologia , Cultura Primária de Células , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/deficiência , Fatores de Transcrição/metabolismo
2.
Hum Mutat ; 39(6): 790-805, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29637653

RESUMO

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked multiple congenital anomalies and overgrowth syndrome caused by a defect in the glypican-3 gene (GPC3). Until now, GPC3 mutations have been reported in isolated cases or small series and the global genotypic spectrum of these mutations has never been delineated. In this study, we review the 57 previously described GPC3 mutations and significantly expand this mutational spectrum with the description of 29 novel mutations. Compiling our data and those of the literature, we provide an overview of 86 distinct GPC3 mutations identified in 120 unrelated families, ranging from single nucleotide variations to complex genomic rearrangements and dispersed throughout the entire coding region of GPC3. The vast majority of them are deletions or truncating mutations (frameshift, nonsense mutations) predicted to result in a loss-of-function. Missense mutations are rare and the two which were functionally characterized, impaired GPC3 function by preventing GPC3 cleavage and cell surface addressing respectively. This report by describing for the first time the wide mutational spectrum of GPC3 could help clinicians and geneticists in interpreting GPC3 variants identified incidentally by high-throughput sequencing technologies and also reinforces the need for functional validation of non-truncating mutations (missense, in frame mutations, duplications).


Assuntos
Arritmias Cardíacas/genética , Genes Ligados ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Gigantismo/genética , Glipicanas/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Arritmias Cardíacas/patologia , Códon sem Sentido/genética , Feminino , Mutação da Fase de Leitura/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/patologia , Cardiopatias Congênitas/patologia , Humanos , Deficiência Intelectual/patologia , Masculino , Linhagem , Fenótipo
3.
Am J Med Genet A ; 164A(3): 774-7, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24357529

RESUMO

Simpson-Golabi-Behmel syndrome type 1 (SGBS1) -OMIM 312870- is a rare X-linked inherited overgrowth syndrome caused by a loss of function mutation in the GPC3 gene. Affected patients present a variable phenotype with pre- and post-natal macrosomia, distinctive facial dysmorphism, organomegaly, and multiple congenital anomalies. Intellectual disability is not constant. About 10% of patients have an increased risk of developing embryonic tumors in early childhood. Only one case of biliary disease has been described so far. GPC3 is localized on Xq26. It encodes for glypican 3, a heparan sulfate proteoglycan, which among its different known roles, negatively regulates liver regeneration and hepatocyte proliferation. This report concerns a male with a SGBS1, carrier of a GPC3 pathogenic mutation, and neonatal liver disease, who developed an early biliary cirrhosis. Together with the associated risk of cancer and developmental delay, liver transplantation was discussed and then successfully performed at the age of 19 months. A hypothesis on the role of GPC3 in the patient's liver disease is also proposed.


Assuntos
Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/terapia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Gigantismo/diagnóstico , Gigantismo/terapia , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/terapia , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/terapia , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/terapia , Transplante de Fígado , Arritmias Cardíacas/genética , Biópsia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Gigantismo/genética , Glipicanas/genética , Cardiopatias Congênitas/genética , Humanos , Lactente , Deficiência Intelectual/genética , Fígado/patologia , Cirrose Hepática Biliar/genética , Masculino , Mutação , Fenótipo , Resultado do Tratamento
5.
Am J Med Genet C Semin Med Genet ; 163C(2): 92-105, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23606591

RESUMO

Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked multiple congenital abnormality/intellectual disability syndrome characterized by pre- and post-natal overgrowth, distinctive craniofacial features, macrocephaly, variable congenital malformations, organomegaly, increased risk of tumor and mild/moderate intellectual deficiency. In 1996, Glypican 3 (GPC3) was identified as the major gene causing SGBS but the mutation detection rate was only 28-70%, suggesting either genetic heterogeneity or that some patients could have alternative diagnoses. This was particularly suggested by some reports of atypical cases with more severe prognoses. In the family reported by Golabi and Rosen, a duplication of GPC4 was recently identified, suggesting that GPC4 could be the second gene for SGBS but no point mutations within GPC4 have yet been reported. In the genetics laboratory in Tours Hospital, GPC3 molecular testing over more than a decade has detected pathogenic mutations in only 8.7% of individuals with SGBS. In addition, GPC4 mutations have not been identified thus raising the question of frequent misdiagnosis. In order to better delineate the phenotypic spectrum of SGBS caused by GPC3 mutations, and to try to define specific clinical criteria for GPC3 molecular testing, we reviewed the clinical features of all male cases with a GPC3 mutation identified in the two molecular laboratories providing this test in France (Tours and Paris). We present here the results of the analysis of 42 patients belonging to 31 families and including five fetuses and three deceased neonates.


Assuntos
Arritmias Cardíacas/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Gigantismo/genética , Glipicanas/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Mutação , Humanos , Fenótipo
6.
Am J Med Genet A ; 161A(12): 3063-71, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24039113

RESUMO

FG syndrome, Lujan syndrome, and Ohdo syndrome, the Maat-Kievit-Brunner type, have been described as distinct syndromes with overlapping non-specific features and different missense mutations of the MED12 gene have been reported in all of them. We report a family including 10 males and 1 female affected with profound non-specific intellectual disability (ID) which was linked to a 30-cM region extending from Xp11.21 (ALAS2) to Xq22.3 (COL4A5). Parallel sequencing of all X-chromosome exons identified a frameshift mutation (c.5898dupC) of MED12. Mutated mRNA was not affected by non-sense mediated RNA decay and induced an additional abnormal isoform due to activation of cryptic splice-sites in exon 41. Dysmorphic features common to most affected males were long narrow face, high forehead, flat malar area, high nasal bridge, and short philtrum. Language was absent or very limited. Most patients had a friendly personality. Cognitive impairment, varying from borderline to profound ID was similarly observed in seven heterozygous females. There was no correlation between cognitive function and X-chromosome inactivation profiles in blood cells. The severe degree of ID in male patients, as well as variable cognitive impairment in heterozygous females suggests that the duplication observed in the present family may have a more severe effect on MED12 function than missense mutations. In a cognitively impaired male from this family, who also presented with tall stature and dysmorphism and did not have the MED12 mutation, a 600-kb duplication at 17p13.3 including the YWHAE gene, was found in a mosaic state.


Assuntos
Anormalidades Múltiplas/genética , Agenesia do Corpo Caloso/genética , Anus Imperfurado/genética , Blefarofimose/genética , Blefaroptose/genética , Constipação Intestinal/genética , Doenças Genéticas Ligadas ao Cromossomo X , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Complexo Mediador/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Hipotonia Muscular/congênito , Proteínas 14-3-3/genética , Anormalidades Múltiplas/fisiopatologia , Adulto , Idoso , Agenesia do Corpo Caloso/fisiopatologia , Anus Imperfurado/fisiopatologia , Blefarofimose/fisiopatologia , Blefaroptose/fisiopatologia , Cromossomos Humanos X/genética , Constipação Intestinal/fisiopatologia , Éxons , Feminino , Mutação da Fase de Leitura , Cardiopatias Congênitas/fisiopatologia , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/fisiopatologia , Pessoa de Meia-Idade , Hipotonia Muscular/genética , Hipotonia Muscular/fisiopatologia , Mutação , Inativação do Cromossomo X/genética
7.
Nat Genet ; 30(4): 436-40, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11889465

RESUMO

X-linked mental retardation (XLMR) is an inherited condition that causes failure to develop cognitive abilities, owing to mutations in a gene on the X chromosome. The latest XLMR update lists up to 136 conditions leading to 'syndromic', or 'specific', mental retardation (MRXS) and 66 entries leading to 'nonspecific' mental retardation (MRX). For 9 of the 66 MRX entries, the causative gene has been identified. Our recent discovery of the contiguous gene deletion syndrome ATS-MR (previously known as Alport syndrome, mental retardation, midface hypoplasia, elliptocytosis, OMIM #300194), characterized by Alport syndrome (ATS) and mental retardation (MR), indicated Xq22.3 as a region containing one mental retardation gene. Comparing the extent of deletion between individuals with ATS-MR and individuals with ATS alone allowed us to define a critical region for mental retardation of approximately 380 kb, containing four genes. Here we report the identification of two point mutations, one missense and one splice-site change, in the gene FACL4 in two families with nonspecific mental retardation. Analysis of enzymatic activity in lymphoblastoid cell lines from affected individuals of both families revealed low levels compared with normal cells, indicating that both mutations are null mutations. All carrier females with either point mutations or genomic deletions in FACL4 showed a completely skewed X-inactivation, suggesting that the gene influences survival advantage. FACL4 is the first gene shown to be involved in nonspecific mental retardation and fatty-acid metabolism.


Assuntos
Coenzima A Ligases/genética , Coenzima A Ligases/fisiologia , Ligação Genética , Deficiência Intelectual/genética , Proteínas Repressoras , Proteínas de Saccharomyces cerevisiae , Cromossomo X , Sequência de Aminoácidos , Sequência de Bases , Sítios de Ligação , Cerebelo/metabolismo , Criança , Pré-Escolar , Coenzima A Ligases/metabolismo , Éxons , Saúde da Família , Feminino , Hipocampo/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Modelos Genéticos , Dados de Sequência Molecular , Mutação , Linhagem , Mutação Puntual , Polimorfismo Conformacional de Fita Simples , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência do Ácido Nucleico
8.
Turk J Pediatr ; 52(5): 525-8, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21434539

RESUMO

Simpson-Golabi-Behmel Syndrome (SGBS) is a rare recessive X-linked disorder characterized by pre- and postnatal overgrowth, distinctive dysmorphic facies and variable congenital malformations. Most cases have been attributed to mutations in the Glypican-3 (GPC3) gene located at Xq26. Glypican-3 plays essential roles in development by modulating cellular responses to growth factors and morphogens. We report here a novel nonsense mutation of the GPC3 gene in a five-year-old Moroccan patient of consanguineous parents who had SGBS phenotype associated with congenital hypothyroidism.


Assuntos
Códon sem Sentido , Hipotireoidismo Congênito/genética , Glipicanas/genética , Adulto , Arritmias Cardíacas/genética , Consanguinidade , Feminino , Doenças Genéticas Ligadas ao Cromossomo X , Gigantismo/genética , Cardiopatias Congênitas/genética , Humanos , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Marrocos
9.
Hum Mutat ; 30(6): 934-45, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19367636

RESUMO

UMD-DMD France is a knowledgebase developed through a multicenter academic effort to provide an up-to-date resource of curated information covering all identified mutations in patients with a dystrophinopathy. The current release includes 2,411 entries consisting in 2,084 independent mutational events identified in 2,046 male patients and 38 expressing females, which corresponds to an estimated number of 39 people per million with a genetic diagnosis of dystrophinopathy in France. Mutations consist in 1,404 large deletions, 215 large duplications, and 465 small rearrangements, of which 39.8% are nonsense mutations. The reading frame rule holds true for 96% of the DMD patients and 93% of the BMD patients. Quality control relies on the curation by four experts for the DMD gene and related diseases. Data on dystrophin and RNA analysis, phenotypic groups, and transmission are also available. About 24% of the mutations are de novo events. This national centralized resource will contribute to a greater understanding of prevalence of dystrophinopathies in France, and in particular, of the true frequency of BMD, which was found to be almost half (43%) that of DMD. UMD-DMD is a searchable anonymous database that includes numerous newly developed tools, which can benefit to all the scientific community interested in dystrophinopathies. Dedicated functions for genotype-based therapies allowed the prediction of a new multiexon skipping (del 45-53) potentially applicable to 53% of the deleted DMD patients. Finally, such a national database will prove to be useful to implement the international global DMD patients' registries under development.


Assuntos
Bases de Dados Genéticas , Distrofina/genética , Bases de Conhecimento , Distrofia Muscular de Duchenne/genética , Mutação/genética , Software , Quebra Cromossômica , Códon sem Sentido/genética , Éxons/genética , Feminino , França , Rearranjo Gênico , Genótipo , Heterozigoto , Humanos , Íntrons/genética , Masculino , Fenótipo , Mutação Puntual/genética , Sítios de Splice de RNA/genética
11.
Eur J Hum Genet ; 27(4): 663-668, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30683921

RESUMO

NAME OF THE DISEASE (SYNONYMS): Simpson-Golabi-Behmel syndrome (SGBS). OMIM# OF THE DISEASE: 312870. NAME OF THE ANALYSED GENES OR DNA/CHROMOSOME SEGMENTS: GPC3. OMIM# OF THE GENE(S): 300037. Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the GPC3 gene(s) in ⊠ diagnostic, ☐ predictive and ⊠ prenatal settings and for ⊠ risk assessment in relatives.


Assuntos
Anormalidades Múltiplas/genética , Arritmias Cardíacas/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Predisposição Genética para Doença , Gigantismo/genética , Glipicanas/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Anormalidades Múltiplas/fisiopatologia , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Testes Genéticos , Gigantismo/diagnóstico , Gigantismo/fisiopatologia , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/fisiopatologia , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Masculino , Mutação/genética , Fenótipo
12.
Am J Med Genet A ; 146A(4): 464-7, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18203194

RESUMO

We report on the case of a 44-year-old man affected with the Simpson-Golabi-Behmel syndrome (SGBS) (OMIM 312870) presenting with ischemic stroke due to a dissection of the right internal carotid. Molecular genetic analysis revealed the p.Gly556Arg mutation in exon 8 of the gene encoding glypican 3 (GPC3). This is the second case of a GPC3 missense mutation to be reported. The only risk factor found in this patient was carotid redundancy, a deformation that is significantly associated with spontaneous carotid dissection. The natural history of SGBS in adults is poorly known, and this case raises the question of a possible vascular risk associated with the disease.


Assuntos
Anormalidades Múltiplas/genética , Dissecação da Artéria Carótida Interna/complicações , Adulto , Sequência de Bases , Dissecação da Artéria Carótida Interna/genética , Fissura Palatina/complicações , Fissura Palatina/genética , Criptorquidismo/complicações , Criptorquidismo/genética , Análise Mutacional de DNA , Macrossomia Fetal/genética , Glipicanas/genética , Humanos , Masculino , Polidactilia/complicações , Polidactilia/genética , Síndrome
13.
Hum Mutat ; 28(2): 196-202, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17041910

RESUMO

Approximately two-thirds of Duchenne muscular dystrophy (DMD) patients show intragenic deletions ranging from one to several exons of the DMD gene and leading to a premature stop codon. Other deletions that maintain the translational reading frame of the gene result in the milder Becker muscular dystrophy (BMD) form of the disease. Thus the opportunity to transform a DMD phenotype into a BMD phenotype appeared as a new treatment strategy with the development of antisense oligonucleotides technology, which is able to induce an exon skipping at the pre-mRNA level in order to restore an open reading frame. Because the DMD gene contains 79 exons, thousands of potential transcripts could be produced by exon skipping and should be investigated. The conventional approach considers skipping of a single exon. Here we report the comparison of single- and multiple-exon skipping strategies based on bioinformatic analysis. By using the Universal Mutation Database (UMD)-DMD, we predict that an optimal multiexon skipping leading to the del45-55 artificial dystrophin (c.6439_8217del) could transform the DMD phenotype into the asymptomatic or mild BMD phenotype. This multiple-exon skipping could theoretically rescue up to 63% of DMD patients with a deletion, while the optimal monoskipping of exon 51 would rescue only 16% of patients.


Assuntos
Distrofina/genética , Éxons , Distrofia Muscular de Duchenne/genética , Deleção de Sequência , Adolescente , Adulto , Criança , Códon sem Sentido , Biologia Computacional , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Muscular de Duchenne/terapia , Oligonucleotídeos Antissenso , Fases de Leitura Aberta , Fenótipo , Análise de Sequência de RNA
14.
Hum Mutat ; 28(2): 207-8, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17221867

RESUMO

The EuroMRX family cohort consists of about 400 families with non-syndromic and 200 families with syndromic X-linked mental retardation (XLMR). After exclusion of Fragile X (Fra X) syndrome, probands from these families were tested for mutations in the coding sequence of 90 known and candidate XLMR genes. In total, 73 causative mutations were identified in 21 genes. For 42% of the families with obligate female carriers, the mental retardation phenotype could be explained by a mutation. There was no difference between families with (lod score >2) or without (lod score <2) significant linkage to the X chromosome. For families with two to five affected brothers (brother pair=BP families) only 17% of the MR could be explained. This is significantly lower (P=0.0067) than in families with obligate carrier females and indicates that the MR in about 40% (17/42) of the BP families is due to a single genetic defect on the X chromosome. The mutation frequency of XLMR genes in BP families is lower than can be expected on basis of the male to female ratio of patients with MR or observed recurrence risks. This might be explained by genetic risk factors on the X chromosome, resulting in a more complex etiology in a substantial portion of XLMR patients. The EuroMRX effort is the first attempt to unravel the molecular basis of cognitive dysfunction by large-scale approaches in a large patient cohort. Our results show that it is now possible to identify 42% of the genetic defects in non-syndromic and syndromic XLMR families with obligate female carriers.


Assuntos
Deficiência Intelectual Ligada ao Cromossomo X/genética , Mutação , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Genes , Humanos , Escore Lod , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Fenótipo
15.
Am J Med Genet ; 112(1): 6-11, 2002 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-12239712

RESUMO

FG syndrome (OMIM 305450) is an X-linked condition comprising mental retardation, congenital hypotonia, constipation or anal malformations, and a distinctive appearance with disproportionately large head, tall and broad forehead, cowlicks and telecanthus. In a first linkage analysis carried out on 10 families, we demonstrated heterogeneity and assigned one gene [FGS1] to region Xq12-q21.31 [Briault et al., 1997: Am J Med Genet 73:87-90] corroborated by Graham et al. [1998: Am J Med Genet 80:145-156]. Heterogeneity was supported by the study of one family with apparent FG syndrome co-segregating with an inversion of X chromosome [inv(X)(q11q28)] ([FGS2], OMIM 300321) [Briault et al., 1999: Am J Med Genet 86:112-114 and Briault et al., 2000: Am J Med Genet 95:178-181]. We present the results of a new linkage analysis carried out on two families with FG syndrome. The two earlier known loci for FG syndrome, FGS1 and FGS2 (Xq11 or Xq28) were excluded by multipoint analysis of both families. Linkage was found, however, with locus DXS1060 suggesting that a third FG locus might be located at Xp22.3. In this region, two potential candidate genes, VCX-A and PRKX, were excluded by sequence analysis of the coding region in patients of the two reported FG families. The search for new candidate genes is in progress.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos X , Deficiência Intelectual/genética , Sequência de Bases , DNA/genética , Primers do DNA , Feminino , Humanos , Masculino , Linhagem , Polimorfismo Genético , Síndrome
16.
Am J Med Genet ; 112(4): 400-4, 2002 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-12376945

RESUMO

The TM4SF2 gene (localized at Xp11.4 between the loci DXS564 and DXS556) has been found to be mutated in one MRX family. In order to define the corresponding behavioral phenotype, global IQ and specific cognitive skills were assessed in seven males and three females of this family, independent of subject status. Mental retardation (MR) was mild in three patients and moderate in three others. Despite the broad variability of severity of MR, a cognitive profile specific to the MR in this family was documented. It was characterized by language disorder that was more marked in the articulatory component and spatial/verbal short-term memory dissociation with larger mnemonic span for spatial than for verbal cues. Linkage analysis was then performed on the basis of the cognitively determined status. Recombinations were observed with the loci DXS556 at Xp11.4 and DXS441 at Xq13.2 (maximum LOD score = 2.23 at theta = 0 for ALAS2). This localization region does not include the TM4SF2 gene that has been found mutated in both patients with MR and in one non-MR male subject of this family. The present results suggest two main hypotheses. First, TM4SF2 gene mutation could be involved in MR in this family, therefore representing accentuated intra familial phenotypic variability. Second, the structural particularity detected in the TM4SF2 gene might reflect a rare polymorphism rather than a pathogenic mutation, with the gene responsible for MR in this family being therefore more likely to be searched for in the pericentromeric region of the X chromosome.


Assuntos
Cromossomos Humanos X/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Adulto , Criança , Saúde da Família , Feminino , Ligação Genética , Humanos , Deficiência Intelectual/patologia , Deficiência Intelectual/psicologia , Escore Lod , Masculino , Proteínas de Membrana , Repetições de Microssatélites , Pessoa de Meia-Idade , Mutação , Testes Neuropsicológicos , Linhagem , Tetraspaninas
18.
Am J Hum Genet ; 74(3): 552-7, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14963808

RESUMO

A large French family including members affected by nonspecific X-linked mental retardation, with or without autism or pervasive developmental disorder in affected male patients, has been found to have a 2-base-pair deletion in the Neuroligin 4 gene (NLGN4) located at Xp22.33. This mutation leads to a premature stop codon in the middle of the sequence of the normal protein and is thought to suppress the transmembrane domain and sequences important for the dimerization of neuroligins that are required for proper cell-cell interaction through binding to beta-neurexins. As the neuroligins are mostly enriched at excitatory synapses, these results suggest that a defect in synaptogenesis may lead to deficits in cognitive development and communication processes. The fact that the deletion was present in both autistic and nonautistic mentally retarded males suggests that the NLGN4 gene is not only involved in autism, as previously described, but also in mental retardation, indicating that some types of autistic disorder and mental retardation may have common genetic origins.


Assuntos
Transtorno Autístico/genética , Proteínas de Transporte/genética , Proteínas de Membrana/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Adolescente , Adulto , Moléculas de Adesão Celular Neuronais , Criança , Pré-Escolar , Feminino , Ligação Genética , Humanos , Masculino , Mutação , Linhagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA