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Early Frameshift Mutation in PIGA Identified in a Large XLID Family Without Neonatal Lethality
Author(s) -
Belet Stefanie,
Fieremans Nathalie,
Yuan Xuan,
Esch Hilde,
Verbeeck Jelle,
Ye Zhaohui,
Cheng Linzhao,
Brodsky Brett R.,
Hu Hao,
Kalscheuer Vera M.,
Brodsky Robert A.,
Froyen Guy
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22498
Subject(s) - frameshift mutation , biology , genetics , mutation , microbiology and biotechnology , germline mutation , nonsense mediated decay , stop codon , exon , nonsense mutation , complementation , phenotype , missense mutation , gene , rna splicing , rna
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 ( MCAHS 2) 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 c DNA (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, CD 59 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 c DNA was able to partially rescue the surface expression of CD 59 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 MCAHS 2‐like phenotype.