Homozygous nonsense mutation in SCHIP1/IQCJ-SCHIP1 causes a neurodevelopmental brain malformation syndrome

M. F. Elsaid, Nader Chalhoub, T. Ben-Omran, H. Kamel, M. AL Mureikhi, K. Ibrahim, M. Elizabeth Ross, Alice Kamal Abd El Aleem

Research output: Contribution to journalArticle

Abstract

We report a consanguineous Arab family with 3 affected siblings who display a disorder of global developmental delay, learning difficulties, facial dysmorphism, hearing impairments, and cataract. The clinical phenotype was associated with characteristic brain magnetic resonance imaging (MRI) features of axonal guidance defects involving anterior commissure agenesis as well as scattered areas of polymicrogyria-cobblestone complex. Whole genome sequencing revealed a novel nonsense mutation (159609921C>T) that segregated in the family consistent in an autosomal recessive pattern. This mutation located in the C-terminal region shared by the Schwanomin-Interacting Protein1 (SCHIP1) isoforms including the IQCJ-SCHIP1. The in vitro expression of SCHIP1 and IQCJ-SCHIP1 truncated mutant isoforms (NM_001197109.1; p.R209* and NM_001197114.1; p.R501*, respectively) were markedly reduced as compared to their full-length versions suggesting protein stability/folding impairment. The pathogenic nature of this mutation is supported by a previously reported mouse knockout of Schip1 isoforms, which phenocopied the human axon guidance abnormality. This is the first report of a SCHIP1/IQCJ-SCHIP1 point mutation in humans associated with a neurological-developmental phenotype.

Original languageEnglish
Pages (from-to)387-391
Number of pages5
JournalClinical Genetics
Volume93
Issue number2
DOIs
Publication statusPublished - 1 Feb 2018

Fingerprint

Nonsense Codon
Protein Isoforms
Cobblestone Lissencephaly
Brain
DEET
Phenotype
Developmental Disabilities
Mutation
Protein Stability
Protein Folding
Hearing Loss
Point Mutation
Knockout Mice
Cataract
Siblings
Magnetic Resonance Imaging
Learning
Genome

Keywords

  • absent anterior commissure
  • axonal guidance defects
  • IQCJ-SCHIP1
  • PMG
  • SCHIP1

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Homozygous nonsense mutation in SCHIP1/IQCJ-SCHIP1 causes a neurodevelopmental brain malformation syndrome. / Elsaid, M. F.; Chalhoub, Nader; Ben-Omran, T.; Kamel, H.; AL Mureikhi, M.; Ibrahim, K.; Elizabeth Ross, M.; Kamal Abd El Aleem, Alice.

In: Clinical Genetics, Vol. 93, No. 2, 01.02.2018, p. 387-391.

Research output: Contribution to journalArticle

Elsaid, M. F. ; Chalhoub, Nader ; Ben-Omran, T. ; Kamel, H. ; AL Mureikhi, M. ; Ibrahim, K. ; Elizabeth Ross, M. ; Kamal Abd El Aleem, Alice. / Homozygous nonsense mutation in SCHIP1/IQCJ-SCHIP1 causes a neurodevelopmental brain malformation syndrome. In: Clinical Genetics. 2018 ; Vol. 93, No. 2. pp. 387-391.
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