Portal de Periódicos da CAPES

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

2013; Wiley; Volume: 35; Issue: 3 Linguagem: Inglês

10.1002/humu.22498

1098-1004

Stefanie Belet, Nathalie Fieremans, Xuan Yuan, Hilde Van Esch, Jelle Verbeeck, Zhaohui Ye, Linzhao Cheng, Brett R. Brodsky, Hao Hu, Vera M. Kalscheuer, Robert A. Brodsky, Guy Froyen,

Genetics and Neurodevelopmental Disorders

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.