Exome sequencing reveals a homozygous SYT14 mutation in adult-onset, autosomal-recessive spinocerebellar ataxia with psychomotor retardation

Hiroshi Doi, Kunihiro Yoshida, Takao Yasuda, Mitsunori Fukuda, Yoko Fukuda, Hiroshi Morita, Shu Ichi Ikeda, Rumiko Kato, Yoshinori Tsurusaki, Noriko Miyake, Hirotomo Saitsu, Haruya Sakai, Satoko Miyatake, Masaaki Shiina, Nobuyuki Nukina, Shigeru Koyano, Shoji Tsuji, Yoshiyuki Kuroiwa, Naomichi Matsumoto

    Research output: Contribution to journalArticlepeer-review

    57 Citations (Scopus)

    Abstract

    Autosomal-recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous disorders associated with diverse neurological and nonneurological features that occur before the age of 20. Currently, mutations in more than 20 genes have been identified, but approximately half of the ARCA patients remain genetically unresolved. In this report, we describe a Japanese family in which two siblings have slow progression of a type of ARCA with psychomotor retardation. Using whole-exome sequencing combined with homozygosity mapping, we identified a homozygous missense mutation in SYT14, encoding synaptotagmin XIV (SYT14). Expression analysis of the mRNA of SYT14 by a TaqMan assay confirmed that SYT14 mRNA was highly expressed in human fetal and adult brain tissue as well as in the mouse brain (especially in the cerebellum). In an in vitro overexpression system, the mutant SYT14 showed intracellular localization different from that of the wild-type. An immunohistochemical analysis clearly showed that SYT14 is specifically localized to Purkinje cells of the cerebellum in humans and mice. Synaptotagmins are associated with exocytosis of secretory vesicles (including synaptic vesicles), indicating that the alteration of the membrane-trafficking machinery by the SYT14 mutation may represent a distinct pathomechanism associated with human neurodegenerative disorders.

    Original languageEnglish
    Pages (from-to)320-327
    Number of pages8
    JournalAmerican Journal of Human Genetics
    Volume89
    Issue number2
    DOIs
    Publication statusPublished - 2011 Aug 12

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)

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