Tumurkhuu Munkhtuya, Batbuyan Uranchimeg, Yuzawa Satoru, Munkhsaikhan Yanjinlkham, Batmunkh Ganbayar, Nishimura Wataru
Department of Molecular Biology, International University of Health and Welfare, School of Medicine, Narita, Chiba, Japan.
Department of Genetics and Molecular Biology, School of Bio-Medicine, Mongolian National University of Medical Sciences, Mongolia.
Intractable Rare Dis Res. 2021 May;10(2):102-108. doi: 10.5582/irdr.2021.01004.
The bicaudal D homolog 2 () gene encodes a protein required for the stable complex of dynein and dynactin, which functions as a motor protein working along the microtubule cytoskeleton. Both inherited and variants of are reported with autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED2). Here, we report a male patient with a novel mutation in the gene caused by a heterozygous substitution of arginine with cysteine at residue 162 (Arg162Cys); inherited from his asymptomatic mother. The patient showed typical clinical symptoms of SMALED2, which was genetically confirmed by sequencing. The Arg162Cys mutant clusters with four previously reported variants (c.361C>G, p.Leu121Val; c.581A>G, p.Gln194Arg; c.320C>T, p.Ser107Leu; c.565A>T, p.Ile189Phe) in a region that binds to the dynein-dynactin complex (DDC). The BICD2 domain structures were predicted and the Arg162Cys mutation was localized in the N-terminus coiled-coil segment 1 (CC1) domain. Protein modeling of BICD2's CC1 domain predicted that the Arg162Cys missense variant disrupted interactions with dynein cytoplasmic 1 heavy chain 1 within the DDC. The mutant did this by either changing the electrostatic surface potential or making a broader hydrophobic unit with the neighboring residues. This hereditary case supports the complex and broad genotype-phenotype correlation of mutations, which could be explained by incomplete penetrance or variable expressivity in the next generation.
双尾D同源物2（BICD2）基因编码一种蛋白质，该蛋白质是动力蛋白和动力蛋白激活蛋白稳定复合物所必需的，其作为一种沿微管细胞骨架起作用的运动蛋白。BICD2的遗传性和新发变异均与常染色体显性遗传的以下肢为主的脊髓性肌萎缩症（SMALED2）有关。在此，我们报告一名男性患者，其BICD2基因发生了新的突变，该突变由第162位残基处的精氨酸被半胱氨酸杂合取代（Arg162Cys）引起，从其无症状的母亲遗传而来。该患者表现出SMALED2的典型临床症状，经测序在基因上得到证实。Arg162Cys突变体与先前报道的四个变异体（c.361C>G，p.Leu121Val；c.581A>G，p.Gln194Arg；c.320C>T，p.Serio7Leu；c.565A>T，p.Ile189Phe）聚集在与动力蛋白-动力蛋白激活蛋白复合物（DDC）结合的区域。预测了BICD2的结构域结构，并且Arg162Cys突变定位于N端卷曲螺旋片段1（CC1）结构域。BICD2的CC1结构域的蛋白质建模预测，Arg162Cys错义变异破坏了与DDC内动力蛋白胞质1重链1的相互作用。该突变体通过改变静电表面电位或与相邻残基形成更宽的疏水单元来实现这一点。这一遗传病例支持了BICD2突变复杂且广泛的基因型-表型相关性，这可能由下一代的不完全外显率或可变表达性来解释。
