Homozygous mutation of STXBP5L explains an autosomal recessive infantile-onset neurodegenerative disorder

Raman Kumar, Mark Corbett, Nicholas Smith, Lachlan Jolly, Chuan Tan, Damien Keating, Michael Duffield, Toshihiko Utsumi, Koko Moriya, Katherine Smith, Alexander Hoischen, Kym Abbott, Michael Harbord, Alison Compton, Joshua Woenig, Peer Arts, Michael Kwint, Nienke Wieskamp, Sabine Gijsen, Joris VeltmanMelanie Bahlo, Joseph Gleeson, Eric Haan, Jozef Gecz

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    14 Citations (Scopus)


    We report siblings of consanguineous parents with an infantile-onset neurodegenerative disorder manifesting a predominant sensorimotor axonal neuropathy, optic atrophy and cognitive deficit.We used homozygosity mapping to identify an ~12-Mbp interval identical by descent (IBD) between the affected individuals on chromosome 3q13.13-21.1 with an LOD score of 2.31.We combined family-based whole-exome and whole-genome sequencing of parents and affected siblings and, after filtering oflikely non-pathogenic variants, identified a unique missense variant in syntaxin-binding protein 5-like (STXBP5L c.3127G>A, p. Val1043Ile [CCDS43137.1]) in the IBD interval. Considering other modes of inheritance, we also found compound heterozygous variants in FMNL3 (c.114G>C, p.Phe38Leu and c.1372T>G, p.Ile458Leu [CCDS44874.1]) located on chromosome 12. STXBP5L (or Tomosyn-2) is expressed in the central and peripheral nervous system and is known to inhibit neurotransmitter release through inhibition of the formation of the SNARE complexes between synaptic vesicles and the plasma membrane. FMNL3 is expressed more widely and is a formin family protein that is involved in the regulation of cell morphology and cytoskeletal organization. The STXBP5L p.Val1043Ile variant enhanced inhibition of exocytosis in comparison with wild-type (WT) STXBP5L. Furthermore, WT STXBP5L, but not variant STXBP5L, promoted axonal outgrowth in manipulated mouse primary hippocampal neurons. However, the FMNL3 p.Phe38Leu and p.Ile458Leu variants showed minimal effects in these cells. Collectively, our clinical, genetic and molecular data suggest that the IBD variant in STXBP5L is the likely cause of the disorder.

    Original languageEnglish
    Pages (from-to)2000-2010
    Number of pages11
    JournalHuman Molecular Genetics
    Issue number7
    Publication statusPublished - 28 Oct 2014


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