Get access

Early Frameshift Mutation in PIGA Identified in a Large XLID Family Without Neonatal Lethality


  • Contract grant sponsors: University of Leuven (Leuven, Belgium) (GOA/12/015); the Interuniversity Attraction Poles’ program (P7/43: Belgian Medical Genomics Initiative; BeMGI) from the Belgian Government; the National Institute of Health (P01 CA70970); the German Ministry of Education and Research through the MRNET; the European Union Framework Programme 7 (241995).

  • Communicated by Maria Rita Passos-Bueno


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.