Novel compound heterozygous mutations in inositol polyphosphate phosphatase-like 1 in a family with severe opsismodysplasia.
Novel compound heterozygous mutations in inositol polyphosphate phosphatase-like 1 in a family with severe opsismodysplasia.
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DOI：
10.1097/mcd.0000000000000136
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发表时间：
2016-10
影响因子：
0.7
通讯作者：
Fitzgerald J
中科院分区：
文献类型：
--
作者：
Feist C;Holden P;Fitzgerald J
确定严重骨骼致死性发育不良的遗传基础。两个受影响胎儿的主要临床特征包括：四肢短，干骺端向外张开，桡骨、股骨和胫骨弯曲，手足骨化不规则，颈椎明显。对受影响和未受影响的家庭成员进行全外显子组测序，然后对从受影响个体之一分离的羊水细胞进行免疫印迹分析。在这两个受影响的个体中，编码 SHIP2 蛋白的 INPPL1（肌醇多磷酸磷酸酶样 1）基因中发现了独特的复合杂合变异体。每个未受影响的父母都遗传了一种变异。两个等位基因变体 c.[ 2327-1G>C];[1150_1151delGA] 预计会导致过早终止密码子，导致突变等位基因无义介导的 mRNA 衰变，并且不产生 SHIP2。先证者羊水细胞的免疫印迹分析证实了SHIP2的缺失。这种骨骼疾病是由于 SHIP2 蛋白完全缺失引起的。据报道，OPS 发育不良 (OPS) 存在 INPPL1 突变，OPS 是一种常染色体隐性遗传性骨骼发育不良，骨形成明显延迟。我们的发现强调了 INPPL1/SHIP2 在骨骼发育中发挥的关键作用。
To identify the genetic basis of a severe skeletal lethal dysplasia. The main clinical features of two affected fetuses included: short limbs with flared metaphyses, bowed radii, femora and tibiae, irregular ossification of hands and feet and marked platyspondyly. Affected and non-affected family members were subjected to whole exome sequencing followed by immunoblot analysis on amniocytes isolated from one of the affected individuals. Unique compound heterozygous variants in the INPPL1 (inositol polyphosphate phosphatase-like 1) gene encoding the SHIP2 protein were identified in both affected individuals. One variant was inherited from each unaffected parent. Both allelic variants, c.[ 2327-1G>C];[1150_1151delGA], are predicted to result in premature stop codons leading to nonsense-mediated mRNA decay of the mutant alleles and no production of SHIP2. The absence of SHIP2 was confirmed by immunoblot analysis of proband amniocytes. This skeletal disorder is caused by the complete absence of SHIP2 protein. INPPL1 mutations have been reported in opsismodysplasia (OPS), an autosomal recessive skeletal dysplasias with significant delayed bone formation. Our finding highlights the critical role that INPPL1/SHIP2 plays in skeletal development.