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TALEN-mediated single-base-pair editing identification of an intergenic mutation upstream of BUB1B as causative of PCS (MVA) syndrome.
Ochiai, Hiroshi; Miyamoto, Tatsuo; Kanai, Akinori; Hosoba, Kosuke; Sakuma, Tetsushi; Kudo, Yoshiki; Asami, Keiko; Ogawa, Atsushi; Watanabe, Akihiro; Kajii, Tadashi; Yamamoto, Takashi; Matsuura, Shinya.
Afiliación
  • Ochiai H; Department of Genetics and Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan.
Proc Natl Acad Sci U S A ; 111(4): 1461-6, 2014 Jan 28.
Article en En | MEDLINE | ID: mdl-24344301
Cancer-prone syndrome of premature chromatid separation with mosaic variegated aneuploidy [PCS (MVA) syndrome] is a rare autosomal recessive disorder characterized by constitutional aneuploidy and a high risk of childhood cancer. We previously reported monoallelic mutations in the BUB1B gene (encoding BUBR1) in seven Japanese families with the syndrome. No second mutation was found in the opposite allele of any of the families studied, although a conserved BUB1B haplotype and a decreased transcript were identified. To clarify the molecular pathology of the second allele, we extended our mutational search to a candidate region surrounding BUB1B. A unique single nucleotide substitution, G > A at ss802470619, was identified in an intergenic region 44 kb upstream of a BUB1B transcription start site, which cosegregated with the disorder. To examine whether this is the causal mutation, we designed a transcription activator-like effector nuclease-mediated two-step single-base pair editing strategy and biallelically introduced this substitution into cultured human cells. The cell clones showed reduced BUB1B transcripts, increased PCS frequency, and MVA, which are the hallmarks of the syndrome. We also encountered a case of a Japanese infant with PCS (MVA) syndrome carrying a homozygous single nucleotide substitution at ss802470619. These results suggested that the nucleotide substitution identified was the causal mutation of PCS (MVA) syndrome.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteínas Serina-Treonina Quinasas / Emparejamiento Base / Mutación Tipo de estudio: Diagnostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2014 Tipo del documento: Article País de afiliación: Japón

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteínas Serina-Treonina Quinasas / Emparejamiento Base / Mutación Tipo de estudio: Diagnostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2014 Tipo del documento: Article País de afiliación: Japón