RESUMO
X-linked Charcot-Marie-Tooth disease (CMTX) is a form of hereditary neuropathy with demyelination. Recently, this disorder was mapped to chromosome Xq13.1. The gene for the gap junction protein connexin32 is located in the same chromosomal segment, which led to its consideration as a candidate gene for CMTX. With the use of Northern (RNA) blot and immunohistochemistry technique, it was found that connexin32 is normally expressed in myelinated peripheral nerve. Direct sequencing of the connexin32 gene showed seven different mutations in affected persons from eight CMTX families. These findings, a demonstration of inherited defects in a gap junction protein, suggest that connexin32 plays an important role in peripheral nerve.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Conexinas/genética , Mutação , Sequência de Aminoácidos , Animais , Sequência de Bases , Mapeamento Cromossômico , Conexinas/análise , Feminino , Ligação Genética , Humanos , Masculino , Dados de Sequência Molecular , Fibras Nervosas Mielinizadas/química , Proteínas do Tecido Nervoso/análise , Nervos Periféricos/química , Ratos , Cromossomo X , Proteína beta-1 de Junções ComunicantesAssuntos
DNA Helicases , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Mutação , Proteínas Nucleares , Fatores de Transcrição/química , Fatores de Transcrição/genética , Sequência de Aminoácidos , Animais , Sequência Conservada , Globinas/genética , Humanos , Deficiência Intelectual/genética , Camundongos , Dados de Sequência Molecular , Fenótipo , Homologia de Sequência de Aminoácidos , Síndrome , Proteína Nuclear Ligada ao X , Dedos de Zinco/genética , Talassemia alfa/genéticaRESUMO
We describe a family with parental consanguinity and five of 10 siblings affected by late-onset autoimmune myasthenia gravis. We propose a genetic mechanism as a predisposing factor in this family. Our analysis excludes the major histocompatibility complex, the beta subunit of the acetylcholine receptor, and the T-cell receptor alpha and beta subunits as candidate genes for the disorder in this family.
Assuntos
Miastenia Gravis/genética , Idoso , Autoanticorpos/genética , Southern Blotting , Feminino , Antígenos HLA/genética , Humanos , Masculino , Miastenia Gravis/imunologia , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores Colinérgicos/imunologiaAssuntos
Fosfatase Alcalina/genética , Cárie Dentária/genética , Triagem de Portadores Genéticos , Hipofosfatasia/genética , Mutação , Doenças Dentárias/genética , Adulto , Fosfatase Alcalina/sangue , Fosfatase Alcalina/deficiência , Animais , Células COS , Linhagem Celular , Criança , Pré-Escolar , Chlorocebus aethiops , Cárie Dentária/sangue , Cárie Dentária/enzimologia , Feminino , Humanos , Hipofosfatasia/sangue , Hipofosfatasia/enzimologia , Masculino , Modelos Moleculares , Mutagênese Sítio-Dirigida/genética , Mutação de Sentido Incorreto/genética , Especificidade de Órgãos/genética , Linhagem , Estrutura Quaternária de Proteína/genética , Doenças Dentárias/sangue , Doenças Dentárias/enzimologiaRESUMO
An infant with glycogen storage disease and prolonged malnourishment showed a urinary organic acid profile during an episode of fasting hypoglycaemia with inappropriate hypoketotic dicarboxylic aciduria that was indistinguishable from that reported in long-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency. Although there was a striking elevation of urinary 3-hydroxydecanedioic acid, the ratios between hydroxydicarboxylic acids were consistent with values reported to be indicate of medium-chain acyl-CoA dehydrogenase deficiency. We suspect that the fasting 3-hydroxydicarboxylic aciduria was attributable to secondarily impaired enzyme activities, the consequence of malnutrition, early infancy, and/or glycogen storage disease. Caution is advised in the interpretation of urinary organic acid patterns that indicate a 3-hydroxydicarboxylic aciduria, as well as an inappropriate hypoketotic dicarboxylic aciduria, as they may represent non-specific findings.
Assuntos
3-Hidroxiacil-CoA Desidrogenases/deficiência , Ácidos Dicarboxílicos/urina , Doença de Depósito de Glicogênio/urina , Distúrbios Nutricionais/urina , Diagnóstico Diferencial , Ácidos Graxos/urina , Humanos , Lactente , MasculinoRESUMO
Twelve infants with diaphragmatic hernias plus other anomalies who had mosaicism for tetrasomy isochromosome 12p (Pallister-Killian syndrome) are reviewed. A newborn infant with a diaphragmatic hernia plus dysmorphic features and a normal peripheral blood karyotype should have chromosome analysis performed on fibroblasts or bone marrow.
Assuntos
Anormalidades Múltiplas/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 12 , Hérnias Diafragmáticas Congênitas , Mosaicismo , Feminino , Hérnia Diafragmática/genética , Humanos , Recém-Nascido , Deficiência Intelectual/genética , Cariotipagem , MasculinoRESUMO
The congenital form of myotonic dystrophy is reported to be almost exclusively, if not exclusively, maternally transmitted. We present a case of congenital myotonic dystrophy which was inherited from a mildly affected father. This family illustrates that the congenital form of myotonic dystrophy can occur without intrauterine or other maternal factors related to the disease. The possibility of paternal transmission of the congenital form of myotonic dystrophy could be considered when counselling myotonic dystrophy patients and their families.
Assuntos
Distrofia Miotônica/congênito , Proteínas Serina-Treonina Quinases , Adolescente , Southern Blotting , DNA/análise , Sondas de DNA , Humanos , Masculino , Distrofia Miotônica/genética , Miotonina Proteína Quinase , Linhagem , Proteínas Quinases/genéticaRESUMO
Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of slowly progressive, degenerative disorders of peripheral nerve. X-linked CMT (CMTX) (McKusick 302800), a subdivision of type I, or demyelinating, CMT is an X-linked dominant condition with variable penetrance. Previous linkage analysis using RFLPs demonstrated linkage to markers on the proximal long and short arms of the X chromosome, with the more likely localization on the proximal long arm of the X chromosome. Available variable simple-sequence repeats (VSSRs) broaden the possibilities for linkage analysis. This paper presents new linkage data and recombination analysis derived from work with four VSSR markers--AR, PGKP1, DXS453, and DXYS1X--in addition to analysis using RFLP markers described elsewhere. These studies localize the CMTX gene to the proximal Xq segment between PGKP1 (Xq11.2-12) and DXS72 (Xq21.1), with a combined maximum multipoint lod score of 15.3 at DXS453 (theta = 0).
Assuntos
Doença de Charcot-Marie-Tooth/genética , Mapeamento Cromossômico/métodos , Cromossomo X , Feminino , Ligação Genética , Marcadores Genéticos , Humanos , Masculino , Meiose , Reação em Cadeia da Polimerase , Sequências Repetitivas de Ácido NucleicoRESUMO
We have sought associations with the muscle acetylcholine receptor alpha-subunit gene (CHRNA1) in autoimmune myasthenia gravis (MG) patients from three ethnic groups; Caucasians and South Africans of Black and Mixed-Ancestry. We found a significant association with the HB*15 CA repeat allele in unrelated Black myasthenics (n = 18; RR = 2.85; pX2 = 0.04) compared with 52 ethnically matched controls. A family-based association study and linkage analysis in Caucasian simplex and multiplex families supported a positive association at this locus with the longer alleles, including HB*14 to *18. However, no significant cosegregation of the disease with the HB alleles could be demonstrated in affected sib pairs. Our results suggest that the CHRNA1 locus harbours a minor susceptibility gene for developing MG, though we cannot rule out linkage disequilibrium with another major gene locus on chromosome 2.
Assuntos
População Negra/genética , Músculos/metabolismo , Miastenia Gravis/genética , Receptores Colinérgicos/genética , População Branca/genética , Biomarcadores , Estudos de Casos e Controles , Humanos , Miastenia Gravis/imunologia , Miastenia Gravis/metabolismoRESUMO
Jacobsen syndrome is caused by segmental aneusomy for the distal end of the long arm of chromosome 11. Typical features include mild to moderate psychomotor retardation, trigonocephaly, facial dysmorphism, cardiac defects, and thrombocytopenia, though none of these features are invariably present. To define the critical regions responsible for these abnormalities, we studied 17 individuals with de novo terminal deletions of 11q. The patients were characterized in a loss-of-heterozygosity analysis using polymorphic dinucleotide repeats. The breakpoints in the complete two-generation families were localized with an average resolution of 3.9 cM. Eight patients with the largest deletions extending from 11q23.3 to 11qter have breakpoints, between D11S924 and D11S1341. This cytogenetic region accounts for the majority of 11q- patients and may be related to the FRA11B fragile site in 11q23.3. One patient with a small terminal deletion distal to D11S1351 had facial dysmorphism, cardiac defects, and thrombocytopenia, suggesting that the genes responsible for these features may lie distal to D11S1351. Twelve of 15 patients with deletion breakpoints as far distal as D11S1345 had trigonocephaly, while patients with deletions distal to D11S912 did not, suggesting that, if hemizygosity for a single gene is responsible for this dysmorphic feature, the gene may lie distal to D11S1345 and proximal to D11S912.
Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 11 , Deleção de Genes , Adolescente , Criança , Pré-Escolar , Mapeamento Cromossômico , DNA/análise , Feminino , Humanos , Lactente , Masculino , Reação em Cadeia da PolimeraseRESUMO
X linked dominant Charcot-Marie-Tooth disease (CMTX1) has previously been localised to Xq13-21. Fifteen families were studied using 12 highly informative polymorphisms in the pericentric region of the X chromosome. Phase known recombinations in these families localise the X linked dominant CMT gene to the region distal to DXS106 (Xq11.2-12) and proximal to DXS559 (Xq13.1). These markers flank approximately 2 to 3 Mb of DNA to which GJB1 and CCG1 have already been mapped. A recent report of mutations in the GJB1 gene in subjects with CMTX1 makes this a strong candidate gene.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Conexinas/genética , Polimorfismo de Fragmento de Restrição , Cromossomo X , Ciclo Celular , Mapeamento Cromossômico , Feminino , Genes Dominantes , Ligação Genética , Humanos , Masculino , Recombinação Genética , Proteína beta-1 de Junções ComunicantesRESUMO
Charcot-Marie-Tooth (CMT) disease is the most common form of inherited motor and sensory neuropathy. X-linked CMT (CMTX1) has been localized to the pericentric region of the X chromosome. Recently, mutations have been defined in the connexin32 gene that cosegregate with the CMTX1 phenotype in several families. The present paper presents the results of an international consortium to fine map the gene for CMTX1 to a small segment of Xq12-13. The linkage data, together with the molecular genetic studies, support the hypothesis that connexin32 is the genetic defect in CMTX1.