title: Homozygous mutation of STXBP5L explains an autosomal recessive infantile-onset neurodegenerative disorder.
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.
authors.affiliation: Women's and Children's Health Research Institute, North Adelaide and Discipline of Medicine, School of Paediatrics and Reproductive Health, Robinson Research Institute and.
authors.forename: Raman
authors.initials: R
authors.lastname: Kumar
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute and.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Corbett
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute and, Department of Neurology, Women's and Children's Health Network, Adelaide, SA, Australia.
authors.forename: Nicholas J C
authors.initials: NJ
authors.lastname: Smith
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute and.
authors.forename: Lachlan A
authors.initials: LA
authors.lastname: Jolly
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute and.
authors.forename: Chuan
authors.initials: C
authors.lastname: Tan
authors.affiliation: Department of Human Physiology and Centre for Neuroscience, Flinders University of South Australia, Adelaide, SA, Australia.
authors.forename: Damien J
authors.initials: DJ
authors.lastname: Keating
authors.affiliation: Department of Human Physiology and Centre for Neuroscience, Flinders University of South Australia, Adelaide, SA, Australia.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Duffield
authors.affiliation: Applied Molecular Bioscience, Yamaguchi University, Yamaguchi, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Utsumi
authors.affiliation: Applied Molecular Bioscience, Yamaguchi University, Yamaguchi, Japan.
authors.forename: Koko
authors.initials: K
authors.lastname: Moriya
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Smith
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Department of Neurology, Women's and Children's Health Network, Adelaide, SA, Australia.
authors.forename: Kim
authors.initials: K
authors.lastname: Abbott
authors.affiliation: Centre for Disability Health, Modbury Hospital, Adelaide, SA, Australia.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Harbord
authors.affiliation: Department of Paediatrics and, Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia.
authors.forename: Alison G
authors.initials: AG
authors.lastname: Compton
authors.affiliation: Women's and Children's Health Research Institute, North Adelaide and Discipline of Medicine, School of Paediatrics and Reproductive Health, Robinson Research Institute and.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Woenig
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Peer
authors.initials: P
authors.lastname: Arts
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Kwint
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Nienke
authors.initials: N
authors.lastname: Wieskamp
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gijsen
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.affiliation: 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.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.affiliation: Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, CA, USA and.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute and, South Australian Clinical Genetics Service, SA Pathology, Adelaide, SA, Australia.
authors.forename: Eric
authors.initials: E
authors.lastname: Haan
authors.affiliation: 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, jozef.gecz@adelaide.edu.au.
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics*; D008297:Male; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; C492527:STXBP5L protein, human