Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome
Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome
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DOI：
10.1038/ejhg.2013.241
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发表时间：
2014-06-01
影响因子：
5.2
通讯作者：
Krawitz, Peter
中科院分区：
文献类型：
--
作者：
Horn, Denise;Wieczorek, Dagmar;Krawitz, Peter
糖基磷脂酰肌醇锚定合成途径的三个不同基因PIGV、PIGO和PGAP2最近被认为与高磷酸症-智力迟钝综合征（HPMRS）有关，也被称为Mabry综合征，一种罕见的常染色体隐性智力残疾。本研究的目的是在16个以智力残疾和血清碱性磷酸盐升高为最低诊断标准诊断为HPMRS的个体中，描述PIGV突变谱以及相关表型谱。对16个个体的所有PIGV外显子和内含子边界进行了测序。在16个无亲缘关系的HPMRS家族中，有8个发现了猪病毒双等位基因突变。在约80%的受影响家庭（包括本文报道的病例）中检测到的最常见突变是c.1022C>A PIGV突变，该突变在纯合子和杂合子状态下均被发现。本研究中发现的另外四个突变（C . 176t >G, C . 53g >A, C . 905t >C和C . 1405c >T）是新的。我们在迄今为止报道的最大队列中的研究结果显著扩展了与PIGV突变相关的报告表现的范围，并表明临床谱系的严重端表现为多发性先天性畸形综合征，伴有先天性巨结肠疾病、膀胱输尿管、肾脏异常以及肛肠畸形的高频率。猪流感病毒（PIGV）突变是导致HPMRS的主要原因，它在相关畸形和生长模式方面表现出广泛的临床变异性。严重的发育迟缓、特殊的面部异常、短端指骨和高磷酸酶血症在pigv阳性个体中普遍存在。
Three different genes of the glycosylphosphatidylinositol anchor synthesis pathway, PIGV, PIGO, and PGAP2, have recently been implicated in hyperphosphatasia- mental retardation syndrome (HPMRS), also known as Mabry syndrome, a rare autosomal recessive form of intellectual disability. The aim of this study was to delineate the PIGV mutation spectrum as well as the associated phenotypic spectrum in a cohort of 16 individuals diagnosed with HPMRS on the basis of intellectual disability and elevated serum alkaline phosphate as minimal diagnostic criteria. All PIGV exons and intronic boundaries were sequenced in 16 individuals. Biallelic PIGV mutations were identified in 8 of 16 unrelated families with HPMRS. The most frequent mutation detected in about 80% of affected families including the cases reported here is the c.1022C>A PIGV mutation, which was found in both the homozygous as well as the heterozygous state. Four further mutations found in this study (c.176T>G, c.53G>A, c.905T>C, and c.1405C>T) are novel. Our findings in the largest reported cohort to date significantly extend the range of reported manifestations associated with PIGV mutations and demonstrate that the severe end of the clinical spectrum presents as a multiple congenital malformation syndrome with a high frequency of Hirschsprung disease, vesicoureteral, and renal anomalies as well as anorectal malformations. PIGV mutations are the major cause of HPMRS, which displays a broad clinical variability regarding associated malformations and growth patterns. Severe developmental delays, particular facial anomalies, brachytelephalangy, and hyperphosphatasia are consistently found in PIGV-positive individuals.