2. Academic Validation
  3. Homozygous mutation of STXBP5L explains an autosomal recessive infantile-onset neurodegenerative disorder

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

  • Hum Mol Genet. 2015 Apr 1;24(7):2000-10. doi: 10.1093/hmg/ddu614.
Raman Kumar 1,  Mark A Corbett 2,  Nicholas J C Smith 3,  Lachlan A Jolly 2,  Chuan Tan 2,  Damien J Keating 4,  Michael D Duffield 4,  Toshihiko Utsumi 5,  Koko Moriya 5,  Katherine R Smith 6,  Alexander Hoischen 7,  Kim Abbott 8,  Michael G Harbord 9,  Alison G Compton 10,  Joshua A Woenig 1,  Peer Arts 7,  Michael Kwint 7,  Nienke Wieskamp 7,  Sabine Gijsen 7,  Joris A Veltman 7,  Melanie Bahlo 11,  Joseph G Gleeson 12,  Eric Haan 13,  Jozef Gecz 14
Affiliations

Affiliations

  • 1 Women's and Children's Health Research Institute, North Adelaide and Discipline of Medicine, School of Paediatrics and Reproductive Health, Robinson Research Institute and.
  • 2 School of Paediatrics and Reproductive Health, Robinson Research Institute and.
  • 3 School of Paediatrics and Reproductive Health, Robinson Research Institute and, Department of Neurology, Women's and Children's Health Network, Adelaide, SA, Australia.
  • 4 Department of Human Physiology and Centre for Neuroscience, Flinders University of South Australia, Adelaide, SA, Australia.
  • 5 Applied Molecular Bioscience, Yamaguchi University, Yamaguchi, Japan.
  • 6 The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology.
  • 7 Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
  • 8 Department of Neurology, Women's and Children's Health Network, Adelaide, SA, Australia.
  • 9 Centre for Disability Health, Modbury Hospital, Adelaide, SA, Australia.
  • 10 Department of Paediatrics and, Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia.
  • 11 The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, Department of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC, Australia.
  • 12 Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, CA, USA and.
  • 13 School of Paediatrics and Reproductive Health, Robinson Research Institute and, South Australian Clinical Genetics Service, SA Pathology, Adelaide, SA, Australia.
  • 14 Women's and Children's Health Research Institute, North Adelaide and Discipline of Medicine, School of Paediatrics and Reproductive Health, Robinson Research Institute and, School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, SA, Australia, [email protected].
PMID: 25504045 DOI: 10.1093/hmg/ddu614
Abstract

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 of likely 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.

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