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Am J Hum Genet ; 95(6): 754-62, 2014 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-25480036

RESUMO

Premature ovarian failure (POF) is genetically heterogeneous and manifests as hypergonadotropic hypogonadism either as part of a syndrome or in isolation. We studied two unrelated consanguineous families with daughters exhibiting primary amenorrhea, short stature, and a 46,XX karyotype. A combination of SNP arrays, comparative genomic hybridization arrays, and whole-exome sequencing analyses identified homozygous pathogenic variants in MCM9, a gene implicated in homologous recombination and repair of double-stranded DNA breaks. In one family, the MCM9 c.1732+2T>C variant alters a splice donor site, resulting in abnormal alternative splicing and truncated forms of MCM9 that are unable to be recruited to sites of DNA damage. In the second family, MCM9 c.394C>T (p.Arg132(∗)) results in a predicted loss of functional MCM9. Repair of chromosome breaks was impaired in lymphocytes from affected, but not unaffected, females in both families, consistent with MCM9 function in homologous recombination. Autosomal-recessive variants in MCM9 cause a genomic-instability syndrome associated with hypergonadotropic hypogonadism and short stature. Preferential sensitivity of germline meiosis to MCM9 functional deficiency and compromised DNA repair in the somatic component most likely account for the ovarian failure and short stature.


Assuntos
Amenorreia/genética , Instabilidade Cromossômica/genética , Nanismo/genética , Proteínas de Manutenção de Minicromossomo/genética , Polimorfismo de Nucleotídeo Único/genética , Insuficiência Ovariana Primária/genética , Cariótipo Anormal , Adolescente , Adulto , Sequência de Bases , Linhagem Celular , Consanguinidade , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Exoma/genética , Feminino , Recombinação Homóloga , Homozigoto , Humanos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Linhagem , Sítios de Splice de RNA , Análise de Sequência de DNA , Adulto Jovem
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