Journal
HUMAN MUTATION
Volume 35, Issue 3, Pages 350-355Publisher
WILEY-HINDAWI
DOI: 10.1002/humu.22498
Keywords
PIGA; GPI-anchor; intellectual disability; frameshift; start codon
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Funding
- University of Leuven (Leuven, Belgium) [GOA/12/015]
- Interuniversity Attraction Poles' program from the Belgian Government [P7/43]
- National Institute of Health [P01 CA70970]
- German Ministry of Education and Research through the MRNET
- European Union [241995]
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The phosphatidylinositol glycan class A (PIGA) protein is a member of the glycosylphosphatidylinositol 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 because of 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 cosegregates with the disease in a large family diagnosed with a severe syndromic form of X-linked intellectual disability. 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. Hum Mutat 35:350-355, 2014. (c) 2013 Wiley Periodicals, Inc.
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