In-frame de novo mutation in BICD2 in two patients with muscular atrophy and arthrogryposis
In-frame de novo mutation in BICD2 in two patients with muscular atrophy and arthrogryposis
复制标题
DOI：
10.1101/mcs.a003160
复制
发表时间：
2018-10-01
影响因子：
1.8
通讯作者：
White, Peter
中科院分区：
文献类型：
--
作者：
Koboldt, Daniel C.;Kastury, Rama D.;White, Peter
我们描述了两个不相关的患者，一个12岁的女性和一个6岁的男性，先天性挛缩和严重的先天性肌肉萎缩。先显子及其未受影响父母的外显子组和基因组测序显示，他们在BICD2中具有相同的从头缺失（c.1636_1638delAAT）。这一从未被报道过的变异导致框架内3-bp的缺失，预计会导致蛋白质中546位进化上保守的天冬酰胺残基的丢失。BICD2错义突变导致常染色体显性脊髓性肌萎缩，下肢显性2 (SMALED2)，这是一种以肌肉无力和关节挛缩为特征的疾病，发病早，进展缓慢。p.Asn546del在一个可能结合分子马达KIF5A的区域聚集了四个致病性错义变异体。蛋白质模型表明，去除高度保守的天冬酰胺残基会改变BICD2的蛋白质结构。我们的研究结果支持更广泛的BICD2突变表型谱，可能包括严重的表现，如脑萎缩、癫痫发作、面部特征畸形和深度肌肉萎缩。
We describe two unrelated patients, a 12-yr-old female and a 6-yr-old male, with congenital contractures and severe congenital muscular atrophy. Exome and genome sequencing of the probands and their unaffected parents revealed that they have the same de novo deletion in BICD2(c.1636_1638delAAT). The variant, which has never been reported, results in an in-frame 3-bp deletion and is predicted to cause loss of an evolutionarily conserved asparagine residue at position 546 in the protein. Missense mutations in BICD2 cause autosomal dominant spinal muscular atrophy, lower-extremity predominant 2 (SMALED2), a disease characterized by muscle weakness and arthrogryposis of early onset and slow progression. The p.Asn546del clusters with four pathogenic missense variants in a region that likely binds molecular motor KIF5A. Protein modeling suggests that removing the highly conserved asparagine residue alters BICD2 protein structure. Our findings support a broader phenotypic spectrum of BICD2 mutations that may include severe manifestations such as cerebral atrophy, seizures, dysmorphic facial features, and profound muscular atrophy.