Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
Department of Neurosciences, Biomedicine and Movement Sciences, Section of Clinical Neurology, University of Verona, Verona, Italy.
Neurol Sci. 2021 Jul;42(7):2819-2827. doi: 10.1007/s10072-020-04876-7. Epub 2020 Nov 10.
Myofibrillar myopathies (MFM) are a subgroup of protein aggregate myopathies (PAM) characterized by a common histological picture of myofibrillar dissolution, Z-disk disintegration, and accumulation of degradation products into inclusions. Mutations in genes encoding components of the Z-disk or Z-disk-associated proteins occur in some patients whereas in most of the cases, the causative gene defect is still unknown. We aimed to search for pathogenic mutations in genes not previously associated with MFM phenotype.
We performed whole-exome sequencing in four patients from three unrelated families who were diagnosed with PAM without aberrations in causative genes for MFM.
In the first patient and her affected daughter, we identified a heterozygous p.(Arg89Cys) missense mutation in LMNA gene which has not been linked with PAM pathology before. In the second patient, a heterozygous p.(Asn4807Phe) mutation in RYR1 not previously described in PAM represents a novel, candidate gene with a possible causative role in the disease. Finally, in the third patient and his symptomatic daughter, we found a previously reported heterozygous p.(Cys30071Arg) mutation in TTN gene that was clinically associated with cardiac involvement.
Our study identifies a new genetic background in PAM pathology and expands the clinical phenotype of known pathogenic mutations.
肌原纤维肌病（MFM）是蛋白聚集性肌病（PAM）的一个亚组，其特征为肌原纤维溶解、Z 盘崩解以及降解产物积累为包涵体的共同组织学图像。一些患者的 Z 盘或与 Z 盘相关的蛋白的编码成分的基因突变，但在大多数情况下，致病基因缺陷仍然未知。我们旨在寻找以前与 MFM 表型无关的基因中的致病突变。
我们对三个无家族相关性的 PAM 患者（四例）进行了全外显子组测序，这些患者的致病基因无 MFM 相关基因的突变。
在第一位患者及其患病的女儿中，我们发现了 LMNA 基因中的杂合子 p.(Arg89Cys)错义突变，该突变以前与 PAM 病理无关。在第二位患者中，RYR1 中的杂合子 p.(Asn4807Phe)突变以前未在 PAM 中描述，代表了一个新的候选基因，可能在疾病中具有潜在的致病作用。最后，在第三位患者及其有症状的女儿中，我们发现了 TTN 基因中以前报道过的杂合子 p.(Cys30071Arg)突变，该突变与心脏受累有关。
我们的研究确定了 PAM 病理学中的新遗传背景，并扩展了已知致病突变的临床表型。
