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Title: Early Frameshift Mutation in PIGA Identified in a Large XLID Family Without Neonatal Lethality
Authors: Belet, Stefanie ×
Fieremans, Nathalie
Yuan, Xuan
Van Esch, Hilde
Verbeeck, Jelle
Ye, Zhaohui
Cheng, Linzhao
Brodsky, Brett R
Hu, Hao
Kalscheuer, Vera M
Brodsky, Robert A
Froyen, Guy #
Issue Date: Mar-2014
Publisher: John Wiley & Sons, Inc.
Series Title: Human Mutation vol:35 issue:3 pages:350-355
Article number: 10.1002/humu.22498
Abstract: The phosphatidylinositol glycan class A (PIGA) protein is a member of the glycosylphosphatidylinositol (GPI) anchor pathway. Germline mutations in PIGA located at Xp22.2 are thought to be lethal in males. However, a nonsense mutation in the last coding exon was recently described in two brothers with multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) who survived through birth likely due to the hypomorphic nature of the truncated protein, but died in their first weeks of life. Here, we report on a frameshift mutation early in the PIGA cDNA (c.76dupT; p.Y26Lfs*3) that co-segregates with the disease in a large family diagnosed with a severe syndromic form of X-linked intellectual disability (XLID). Unexpectedly, CD59 surface expression suggested the production of a shorter PIGA protein with residual functionality. We provide evidence that the second methionine at position 37 may be used for the translation of a 36 amino acids shorter PIGA. Complementation assays confirmed that this shorter PIGA cDNA was able to partially rescue the surface expression of CD59 in a PIGA-null cell line. Taken together, our data strongly suggest that the early frameshift mutation in PIGA produces a truncated hypomorph, which is sufficient to rescue the lethality in males but not the MCAHS2-like phenotype. This article is protected by copyright. All rights reserved.
URI: 
ISSN: 1059-7794
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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