Exome sequencing identifies variants in two genes encoding the LIM-proteins NRAP and FHL1 in an Italian patient with BAG3 myofibrillar myopathy.
Exome sequencing identifies variants in two genes encoding the LIM-proteins NRAP and FHL1 in an Italian patient with BAG3 myofibrillar myopathy.
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DOI：
10.1007/s10974-016-9451-7
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发表时间：
2016-06
影响因子：
2.7
通讯作者：
Torrente Y
中科院分区：
文献类型：
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作者：
D'Avila F;Meregalli M;Lupoli S;Barcella M;Orro A;De Santis F;Sitzia C;Farini A;D'Ursi P;Erratico S;Cristofani R;Milanesi L;Braga D;Cusi D;Poletti A;Barlassina C;Torrente Y
肌原纤维肌病 (MFM) 是一种遗传异质性营养不良，其特征是 Z 盘和肌原纤维解体，与编码 Z 盘或 Z 盘相关蛋白的基因突变有关。 BAG3 基因中的 c.626 C > T (p.P209L) 突变被描述为 MFM 亚型的病因。我们报告了一名 26 岁意大利女性的散发病例，她患有 MFM，伴有轴突神经病、心肌病、脊柱僵硬，她的 BAG3 基因携带 c.626 C > T 突变。通过全外显子组测序（WES）对患者及其非近亲健康父母和兄弟进行了研究，以进一步研究这种复杂表型的遗传基础。在该患者中，我们发现 BAG3 突变与编码肌肉特异性、含有 LIM 结构域的蛋白质的 NRAP 和 FHL1 基因的变异相关。对患者肌肉活检进行的定量实时 PCR、免疫组织化学和蛋白质印迹分析显示，受影响的骨骼肌组织中不存在 NRAP 表达和 FHL1 聚集体积聚。突变 FHL1 结构域的分子动力学分析显示其表面电荷发生了变化，这可能会影响其结合靶蛋白的能力。据我们所知，这是第一项研究报告，在 BAG3 MFM 中，BAG3 和 FHL1 基因中同时存在遗传变异（之前被描述为与 MFM 独立相关），并首次将 NRAP 基因与 MFM 联系起来。
Myofibrillar myopathies (MFMs) are genetically heterogeneous dystrophies characterized by the disintegration of Z-disks and myofibrils and are associated with mutations in genes encoding Z-disk or Z-disk-related proteins. The c.626 C > T (p.P209L) mutation in the BAG3 gene has been described as causative of a subtype of MFM. We report a sporadic case of a 26-year-old Italian woman, affected by MFM with axonal neuropathy, cardiomyopathy, rigid spine, who carries the c.626 C > T mutation in the BAG3 gene. The patient and her non-consanguineous healthy parents and brother were studied with whole exome sequencing (WES) to further investigate the genetic basis of this complex phenotype. In the patient, we found that the BAG3 mutation is associated with variants in the NRAP and FHL1 genes that encode muscle-specific, LIM domain containing proteins. Quantitative real time PCR, immunohistochemistry and Western blot analysis of the patient’s muscular biopsy showed the absence of NRAP expression and FHL1 accumulation in aggregates in the affected skeletal muscle tissue. Molecular dynamic analysis of the mutated FHL1 domain showed a modification in its surface charge, which could affect its capability to bind its target proteins. To our knowledge this is the first study reporting, in a BAG3 MFM, the simultaneous presence of genetic variants in the BAG3 and FHL1 genes (previously described as independently associated with MFMs) and linking the NRAP gene to MFM for the first time.