Journal Article

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

Raman Kumar, Mark A. Corbett, Nicholas J. C. Smith, Lachlan A. Jolly, Chuan Tan, Damien J. Keating, Michael D. Duffield, Toshihiko Utsumi, Koko Moriya, Katherine R. Smith, Alexander Hoischen, Kim Abbott, Michael G. Harbord, Alison G. Compton, Joshua A. Woenig, Peer Arts, Michael Kwint, Nienke Wieskamp, Sabine Gijsen, Joris A. Veltman, Melanie Bahlo, Joseph G. Gleeson, Eric Haan and Jozef Gecz

in Human Molecular Genetics

Volume 24, issue 7, pages 2000-2010
Published in print April 2015 | ISSN: 0964-6906
Published online December 2014 | e-ISSN: 1460-2083 | DOI:
Homozygous mutation of STXBP5L explains an autosomal recessive infantile-onset neurodegenerative disorder

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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.

Journal Article.  6705 words.  Illustrated.

Subjects: Genetics and Genomics

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