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

Am J Hum Genet. 2011 Aug 12;89(2):320-7. doi: 10.1016/j.ajhg.2011.07.012.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • DNA Mutational Analysis
  • Exons / genetics*
  • Female
  • Gene Expression Regulation
  • Genes, Recessive / genetics*
  • Homozygote*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Middle Aged
  • Molecular Sequence Data
  • Mutation / genetics*
  • Pedigree
  • Psychomotor Disorders / complications
  • Psychomotor Disorders / genetics*
  • Purkinje Cells / metabolism
  • Purkinje Cells / pathology
  • Spinocerebellar Ataxias / epidemiology
  • Spinocerebellar Ataxias / genetics*
  • Synaptotagmins / chemistry
  • Synaptotagmins / genetics*
  • Synaptotagmins / metabolism


  • SYT14P1 protein, human
  • Syt14 protein, mouse
  • Synaptotagmins