Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/114231
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Type: Journal article
Title: Variant in the X-chromosome spliceosomal gene GPKOW causes male-lethal microcephaly with intrauterine growth restriction
Author: Carroll, R.
Kumar, R.
Shaw, M.
Slee, J.
Kalscheuer, V.
Corbett, M.
Gecz, J.
Citation: European Journal of Human Genetics, 2017; 25(9):1078-1082
Publisher: Nature Publishing Group
Issue Date: 2017
ISSN: 1018-4813
1476-5438
Statement of
Responsibility: 
Renée Carroll, Raman Kumar, Marie Shaw, Jennie Slee, Vera M Kalscheuer, Mark A Corbett and Jozef Gecz
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.
Keywords: Microcephaly
Rights: © The Author(s) 2017 This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http:// creativecommons.org/licenses/by/4.0/
RMID: 0030071569
DOI: 10.1038/ejhg.2017.97
Grant ID: http://purl.org/au-research/grants/nhmrc/1041920
http://purl.org/au-research/grants/nhmrc/1091593
Appears in Collections:Medicine publications

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