A novel CRYAB mutation resulting in multisystemic disease
A novel CRYAB mutation resulting in multisystemic disease
复制标题
DOI：
10.1016/j.nmd.2011.07.004
复制
发表时间：
2012-01-01
影响因子：
2.8
通讯作者：
Urtizberea, Andoni
中科院分区：
文献类型：
--
作者：
Sacconi, Sabrina;Feasson, Leonard;Urtizberea, Andoni
编码α - b晶体蛋白的CRYAB基因突变可导致不同的临床表型，包括孤立性后极性白内障、肌原纤维性肌病、心肌病或结合所有这些特征的多系统疾病。基因型/表型相关性尚不清楚。迄今为止，多系统参与的报道仅发生在携带R120G替代物的亲属中。我们报告了一种新的CRYAB突变，D109H，与后极性白内障，肌原纤维性肌病和心肌病有关，在一个两代家族中有5个受影响的个体。发病年龄、临床表现和肌肉异常与R120G家族中描述的非常相似。α - b晶体蛋白可以形成二聚体，并作为许多蛋白质的伴侣。表型多样性可能与单个突变残基靶蛋白之间的各种相互作用有关。分子模拟表明，在α - b结晶蛋白二聚化过程中，残基D109和R120相互作用；有趣的是，影响这些残基的两个取代（D109H和R120G）与相同的临床表型相关，从而表明相似的致病机制。我们认为α - b结晶蛋白二聚体的损伤也可能与这些疾病的发病机制有关。(C) 2011 Elsevier B.V.版权所有
Mutations in the CRYAB gene, encoding alpha-B crystallin, cause distinct clinical phenotypes including isolated posterior polar cataract, myofibrillar myopathy, cardiomyopathy, or a multisystemic disorder combining all these features.Genotype/phenotype correlations are still unclear. To date, multisystemic involvement has been reported only in kindred harboring the R120G substitution. We report a novel CRYAB mutation, D109H, associated with posterior polar cataract, myofibrillar myopathy and cardiomyopathy in a two-generation family with five affected individuals. Age of onset, clinical presentation, and muscle abnormalities were very similar to those described in the R120G family. Alpha-B crystallin may form dimers and acts as a chaperone for a number of proteins. It has been suggested that the phenotypic diversity could be related to the various interactions between target proteins of individual mutant residues.Molecular modeling indicates that residues D109 and R120 interact with each other during dimerization of alpha-B crystallin; interestingly, the two substitutions affecting these residues (D109H and R120G) are associated with the same clinical phenotype, thus suggesting a similar pathogenic mechanism. We propose that impairment of alpha-B crystallin dimerization may also be relevant to the pathogenesis of these disorders. (C) 2011 Elsevier B.V. All rights reserved.