Unidad de Genética, INEBIR (Instituto para el estudio de la Biología de la Reproducción Humana), Seville, Spain.
Cátedra de Reproducción y Genética Humana, INEBIR/Universidad Europea del Atlántico, Santander, Spain.
Mol Genet Genomic Med. 2020 Aug;8(8):e1290. doi: 10.1002/mgg3.1290. Epub 2020 May 18.
αB-crystallin is a promiscuous protein involved in numerous cell functions. Mutations in CRYAB have been found in patients with different pathological phenotypes that are not properly understood. Patients can present different diseases like cataracts, muscle weakness, myopathy, cardiomyopathy, respiratory insufficiency or dysphagia, but also a variable combination of these pathologies has been found. These mutations can show either autosomal dominant or recessive mode of inheritance and variable penetrance and expressivity. This is the first report of congenital cataracts and myopathy described in childhood due to a CRYAB mutation with autosomal dominant mode of inheritance.
The whole exome sequence was subjected to phenotype-driven analysis and a novel variant in CRYAB was detected: c.514delG, p.(Ala172ProfsTer14). The mutation was located in the C-terminal domain of the protein, which is essential for chaperone activity. The deduced protein was analyzed searching for alterations of the relevant physico-chemical properties described for this domain. A muscle biopsy was also tested for CRYAB with immunohistochemical and histoenzymatic techniques.
CRYAB displayed a mild immunoreactivity in the subsarcolemmal compartment with no pathological sarcoplasmic accumulation. It agrees with an alteration of the physico-chemical properties predicted for the C-terminal domain: hydrophobicity, stiffness, and isomerization.
The described mutation leads to elongation of the protein at the carboxi-terminal domain (CTD) with altered properties, which are essential for solubility and activity. It suggests that can be the cause of the severe conditions observed in this patient.
αB-晶状体蛋白是一种参与多种细胞功能的混杂蛋白。已经在具有不同病理表型的患者中发现 CRYAB 的突变，但这些突变的致病机制尚不清楚。患者可能表现出不同的疾病，如白内障、肌肉无力、肌病、心肌病、呼吸功能不全或吞咽困难，但也发现了这些病理的不同组合。这些突变可以表现为常染色体显性或隐性遗传模式，以及可变的外显率和表现度。这是首例由于 CRYAB 突变导致常染色体显性遗传的先天性白内障和肌病的报道。
对整个外显子组序列进行表型驱动分析，检测到 CRYAB 中的一个新变异：c.514delG，p.(Ala172ProfsTer14)。该突变位于蛋白的 C 末端结构域，该结构域对于伴侣活性至关重要。对推测的蛋白进行分析，寻找该结构域中描述的相关物理化学性质的改变。还对肌肉活检进行了 CRYAB 的免疫组化和组织化学技术检测。
CRYAB 在肌小节下膜区显示出轻微的免疫反应性，没有病理性的肌浆堆积。这与 C 末端结构域（CTD）预测的物理化学性质改变一致：疏水性、刚性和异构化。
描述的突变导致羧基末端结构域（CTD）的蛋白延长，改变了蛋白的溶解性和活性。这表明它可能是该患者出现严重症状的原因。
