title: Early frameshift mutation in PIGA identified in a large XLID family without neonatal lethality.
abstract: 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.
authors.affiliation: Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium; Human Genome Laboratory, Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Belet
authors.forename: Nathalie
authors.initials: N
authors.lastname: Fieremans
authors.forename: Xuan
authors.initials: X
authors.lastname: Yuan
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.forename: Jelle
authors.initials: J
authors.lastname: Verbeeck
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Ye
authors.forename: Linzhao
authors.initials: L
authors.lastname: Cheng
authors.forename: Brett R
authors.initials: BR
authors.lastname: Brodsky
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.forename: Vera M
authors.initials: VM
authors.lastname: Kalscheuer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Brodsky
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
mesh_terms: D041321:Chromosomes, Human, X / Q000235:genetics; D059472:Exome; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D050172:Genes, X-Linked; D018095:Germ-Line Mutation; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000401:mortality; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D008565:Membrane Proteins; C080086:phosphatidylinositol glycan-class A protein
keywords: GPI-anchor; PIGA; frameshift; intellectual disability; start codon