Early Frameshift Mutation in PIGA Identified in a Large XLID Family Without Neonatal Lethality
Early Frameshift Mutation in PIGA Identified in a Large XLID Family Without Neonatal Lethality
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DOI：
10.1002/humu.22498
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发表时间：
2014-03-01
期刊：
影响因子：
3.9
通讯作者：
Froyen, Guy
中科院分区：
文献类型：
--
作者：
Belet, Stefanie;Fieremans, Nathalie;Froyen, Guy
磷脂酰肌醇聚糖A类（PIGA）蛋白是糖基磷脂酰肌醇锚途径的成员。位于Xp22.2的PIGA中的种系突变被认为在男性中是致命的。然而，最近在患有多发性先天性异常-肌张力减退-癫痫发作综合征2（MCAHS 2）的两个兄弟中描述了最后一个编码外显子中的无义突变，他们可能由于截短蛋白质的亚型性质而在出生后存活，但在出生后的第一周内死亡。在这里，我们报告了一个移码突变早期的PIGA cDNA（c.76dupT; p.Y26Lfs * 3），共分离的疾病在一个大家庭诊断为严重的综合征形式的X连锁智力残疾。出乎意料的是，CD59表面表达表明产生了具有残余功能性的较短PIGA蛋白。我们提供的证据表明，第二个甲硫氨酸在位置37可用于翻译的36个氨基酸短PIGA。互补分析证实，这种较短的PIGA cDNA能够部分拯救PIGA无效细胞系中CD59的表面表达。综上所述，我们的数据强烈表明PIGA的早期移码突变产生了截短的亚型，这足以挽救男性的致死性，但不能挽救MCAHS 2样表型。2014年，《突变》35：350 - 355。(c)2013 Wiley Periodicals，Inc.
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.