2. Academic Validation
  3. Loss of function of SVBP leads to autosomal recessive intellectual disability, microcephaly, ataxia, and hypotonia

Loss of function of SVBP leads to autosomal recessive intellectual disability, microcephaly, ataxia, and hypotonia

  • Genet Med. 2019 Aug;21(8):1790-1796. doi: 10.1038/s41436-018-0415-8.
Zafar Iqbal 1 2,  Hasan Tawamie 3 4,  Wei Ba 1,  André Reis 3,  Bassam Al Halak 5,  Heinrich Sticht 6,  Steffen Uebe 3,  Nael Nadif Kasri 1,  Sheikh Riazuddin 7 8,  Hans van Bokhoven # 9,  Rami Abou Jamra # 10 11
Affiliations

Affiliations

  • 1 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
  • 2 Department of Neurology, Oslo University Hospital, Oslo, Norway.
  • 3 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • 4 Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany.
  • 5 Praxis of Pediatrics, Kefrenbel, Idlib, Syrian Arab Republic.
  • 6 Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • 7 Center for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad, Pakistan.
  • 8 Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan.
  • 9 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands. [email protected].
  • 10 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. [email protected].
  • 11 Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany. [email protected].
  • # Contributed equally.
PMID: 30607023 DOI: 10.1038/s41436-018-0415-8
Abstract

Purpose: Identifying and characterizing novel causes of autosomal recessive intellectual disability based on systematic clinical and genetic evaluation, followed by functional experiments.

Methods: Clinical examinations, genome-wide positional mapping, and sequencing were followed by quantitative polymerase chain reaction and western blot of the protein SVBP and its interaction partners. We then knocked down the gene in rat primary hippocampal neurons and evaluated the consequences on synapses.

Results: We identified a founder, homozygous stop-gain variant in SVBP (c.82C>T; p.[Gln28*]) in four affected individuals from two independent families with intellectual disability, microcephaly, ataxia, and muscular hypotonia. SVBP encodes a small chaperone protein that transports and stabilizes two angiogenesis regulators, VASH1 and VASH2. The altered protein is unstable and nonfunctional since transfected HeLa cells with mutant SVBP did not reveal evidence for immunoreactive SVBP protein fragments and cotransfection with VASH1 showed a severe reduction of VASH1 in medium and cell lysate. Knocking down Svbp in rat primary hippocampal neurons led to a significant decrease in the number of excitatory synapses.

Conclusion: SVBP is not only involved in angiogenesis, but also has vital functions in the central nervous system. Biallelic loss-of-function variants in SVBP lead to intellectual disability.

Keywords

CCD23; NGS; VASH1; hippocampal neurons; intellectual disability.

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