Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 1 de 1
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Am J Hum Genet ; 97(2): 302-10, 2015 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-26166480

RESUMO

Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.


Assuntos
Transporte Ativo do Núcleo Celular/genética , Cromossomos Humanos X/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Modelos Moleculares , Mutação de Sentido Incorreto/genética , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Sequência de Aminoácidos , Sequência de Bases , Humanos , Deficiência Intelectual Ligada ao Cromossomo X/patologia , Dados de Sequência Molecular , Linhagem , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/química , Análise de Sequência de DNA , Síndrome
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA