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  Variant in the X-chromosome spliceosomal gene GPKOW causes male-lethal microcephaly with intrauterine growth restriction

Carroll, R., Kumar, R., Shaw, M., Slee, J., Kalscheuer, V., Corbett, M. A., et al. (2017). Variant in the X-chromosome spliceosomal gene GPKOW causes male-lethal microcephaly with intrauterine growth restriction. European journal of human genetics, 25(9), 1078-1082. doi:10.1038/ejhg.2017.97.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-CE96-F Version Permalink: http://hdl.handle.net/21.11116/0000-0000-CE97-E
Genre: Journal Article

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 Creators:
Carroll, R., Author
Kumar, R., Author
Shaw, M., Author
Slee, J., Author
Kalscheuer, Vera1, Author              
Corbett, M. A., Author
Gecz, J., Author
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385702              

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Free keywords: Cells, Cultured Female Fetal Growth Retardation/diagnosis/*genetics Genetic Diseases, X-Linked/diagnosis/*genetics Humans Male Microcephaly/diagnosis/*genetics *Mutation Pregnancy RNA Splicing RNA-Binding Proteins/*genetics/metabolism Syndrome
 Abstract: Congenital microcephaly, with or without additional developmental defects, is a heterogeneous disorder resulting from impaired brain development during early fetal life. The majority of causative genetic variants identified thus far are inherited in an autosomal recessive manner and impact key cellular pathways such as mitosis, DNA damage response and repair, apoptosis and splicing. Here, we report a novel donor splice site variant in the G-patch domain and KOW motifs (GPKOW) gene (NG_021310.2:g.6126G>A, NM_015698.4:c.331+5G>A) that segregates with affected and carrier status in a multigenerational family with an X-linked perinatal lethal condition characterized by severe microcephaly and intrauterine growth restriction (IUGR). GPKOW is a core member of the spliceosome that has been shown in numerous model organisms and in human cells to be essential for survival. By investigating GPKOW transcripts in lymphoblastoid cell lines (LCLs) of three carrier females, we show that the GPKOW c.331+5G>A variant disrupts normal splicing of its pre-mRNAs. In a clonal culture expressing only the c.331+5G>A allele isolated from one carrier female LCL, we observed an 80% reduction in wild type GPKOW mRNA, 70% reduction in the full length GPKOW protein and the presence of a truncated GPKOW protein with possible dominant negative effect. Based on our and published data we propose that the GPKOW gene is essential for fetal development and when disrupted, leads to a severe, male-lethal phenotype characterised by microcephaly and IUGR.

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Language(s): eng - English
 Dates: 2017-06-142017-09
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1038/ejhg.2017.97
ISSN: 1476-5438 (Electronic)1018-4813 (Print)
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Title: European journal of human genetics
  Other : Eur. J. Hum. Genet.
Source Genre: Journal
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Publ. Info: Nature Publishing Group
Pages: - Volume / Issue: 25 (9) Sequence Number: - Start / End Page: 1078 - 1082 Identifier: ISSN: 1018-4813
CoNE: /journals/resource/954925585277_1