A nonsense mutation in the HOXD13 gene underlies synpolydactyly with incomplete penetrance.
A nonsense mutation in the HOXD13 gene underlies synpolydactyly with incomplete penetrance.
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DOI：
10.1038/jhg.2011.84
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发表时间：
2011-10
影响因子：
3.5
通讯作者：
中科院分区：
文献类型：
--
作者：
并指畸形1(Sp1；OMIM 186000)，也称为II型并指畸形，是一种以指数增加为特征的显性遗传性肢体畸形。SPD1最常见的原因是Hoxd13基因编码区的聚丙氨酸重复扩增，人们认为这是一种显性负效应。此外，Hoxd13基因的错义和框外缺失突变也被认为是引起SPD的原因，导致这种表型的机制似乎是单倍体不足。在这里，我们分析了来自巴基斯坦的一个患有SPD的大型血缘家庭，发现受影响的个体的表型有很大的差异。我们进行了遗传连锁分析，确定了2号染色体上包含Hoxd13基因的区域。微卫星标记单倍型分析表明，Hoxd13基因的表型分离，外显性不完全。对Hoxd13基因进行直接测序分析，发现了一个无义突变，命名为Q248X。所有严重SPD表型的受累个体都是突变纯合的，而那些轻度SPD表型的患者是突变杂合的。此外，一些未受影响的个体也以杂合状态携带突变，表现出不完全外显。我们的结果表明，Hoxd13基因的第一个无义突变导致了纯合状态下的严重SPD和杂合状态下约50%外显率的轻度SPD，最可能是由于与正常个体相比产生了50%的蛋白质。
Synpolydactyly 1 (SPD1; OMIM 186000), also known as type II syndactyly, is a dominantly inherited limb malformation that is characterized by an increased number of digits. SPD1 is most commonly caused by polyalanine repeat expansions in the coding region of the HOXD13 gene, which are believed to show a dominant-negative effect. In addition, missense and out-of-frame deletion mutations in the HOXD13 gene are also known to cause SPD, and the mechanism responsible for the phenotype appears to be haploinsufficiency. Here, we analyzed a large consanguineous family from Pakistan with SPD showing a wide variation in phenotype among affected individuals. We performed genetic linkage analysis, which identified a region on chromosome 2 containing the HOXD13 gene. Haplotype analysis with microsatellite markers suggested segregation of the phenotype with HOXD13 gene with incomplete penetrance. Direct sequencing analysis of HOXD13 gene revealed a nonsense mutation, designated Q248X. All affected individuals with the severe SPD phenotype are homozygous for the mutation, while those with the mild SPD phenotype are heterozygous for the mutation. Furthermore, some unaffected individuals also carry the mutation in the heterozygous state, showing incomplete penetrance. Our results demonstrate the first nonsense mutation in the HOXD13 gene underlying a severe form of SPD in the homozygous state, and a milder form of SPD with approximately 50% penetrance in the heterozygous state, most likely due to the production of 50% of protein compared to normal individuals..
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影响因子：
64.8
作者：
Zakany, J;Duboule, D
通讯作者：
Duboule, D
影响因子：
56.9
作者：
Zákány, J;Kmita, M;Duboule, D
通讯作者：
Duboule, D
影响因子：
3.5
作者：
Fantini, Sebastian;Vaccari, Giulia;Zappavigna, Vincenzo
通讯作者：
Zappavigna, Vincenzo
影响因子：
4
作者：
Debeer, P;Bacchelli, C;Goodman, FR
通讯作者：
Goodman, FR
影响因子：
4.6
作者：
Capellini, Terence D.;Di Giacomo, Giuseppina;Selleri, Licia
通讯作者：
Selleri, Licia