National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
National Institute of Nursing Research, National Institutes of Health, Bethesda, Maryland.
JAMA Neurol. 2015 Jun;72(6):689-98. doi: 10.1001/jamaneurol.2015.37.
New genomic strategies can now be applied to identify a diagnosis in patients and families with previously undiagnosed rare genetic conditions. The large family evaluated in the present study was described in 1966 and now expands the phenotype of a known neuromuscular gene.
To determine the genetic cause of a slowly progressive, autosomal dominant, scapuloperoneal neuromuscular disorder by using linkage and exome sequencing.
DESIGN, SETTING, AND PARTICIPANTS: Fourteen affected individuals in a 6-generation family with a progressive scapuloperoneal disorder were evaluated. Participants were examined at pediatric, neuromuscular, and research clinics from March 1, 2005, to May 31, 2014. Exome and linkage were performed in genetics laboratories of research institutions.
Examination and evaluation by magnetic resonance imaging, ultrasonography, electrodiagnostic studies, and muscle biopsies (n = 3). Genetic analysis included linkage analysis (n = 17) with exome sequencing (n = 7).
Clinical findings included progressive muscle weakness in an initially scapuloperoneal and distal distribution, including wrist extensor weakness, finger and foot drop, scapular winging, mild facial weakness, Achilles tendon contractures, and diminished or absent deep tendon reflexes. Both age at onset and progression of the disease showed clinical variability within the family. Muscle biopsy specimens demonstrated type I fiber atrophy and trabeculated fibers without nemaline rods. Analysis of exome sequences within the linkage region (4.8 megabases) revealed missense mutation c.591C>A p.Glu197Asp in a highly conserved residue in exon 4 of ACTA1. The mutation cosegregated with disease in all tested individuals and was not present in unaffected individuals.
This family defines a new scapuloperoneal phenotype associated with an ACTA1 mutation. A highly conserved protein, ACTA1 is implicated in multiple muscle diseases, including nemaline myopathy, actin aggregate myopathy, fiber-type disproportion, and rod-core myopathy. To our knowledge, mutations in Glu197 have not been reported previously. This residue is highly conserved and located in an exposed position in the protein; the mutation affects the intermolecular and intramolecular electrostatic interactions as shown by structural modeling. The mutation in this residue does not appear to lead to rod formation or actin accumulation in vitro or in vivo, suggesting a different molecular mechanism from that of other ACTA1 diseases.
现在可以应用新的基因组策略来识别以前未诊断出的罕见遗传疾病患者和家庭的诊断。本研究中评估的大型家族于 1966 年描述，现在扩展了已知神经肌肉基因的表型。
通过连锁和外显子组测序确定一种进行性常染色体显性遗传性肩胛肱骨肌病的遗传原因。
设计、设置和参与者：对 6 代有进行性肩胛肱骨疾病的 14 名受影响个体进行评估。参与者于 2005 年 3 月 1 日至 2014 年 5 月 31 日在儿科、神经肌肉和研究诊所进行检查。外显子组和连锁在研究机构的遗传实验室进行。
对 3 名患者进行磁共振成像、超声、电诊断研究和肌肉活检检查（n=3）。遗传分析包括连锁分析（n=17）和外显子组测序（n=7）。
临床发现包括最初肩胛肱骨和远端分布的进行性肌肉无力，包括腕伸肌无力、手指和足下垂、肩胛翼状、轻度面部无力、跟腱挛缩以及深部腱反射减弱或消失。家族内疾病的发病年龄和进展均表现出临床变异性。肌肉活检标本显示 I 型纤维萎缩和小梁纤维，无杆状纤维。在连锁区域（480 万个碱基对）内分析外显子组序列显示，在 ACTA1 外显子 4 中高度保守的残基 c.591C>A p.Glu197Asp 存在错义突变。该突变与所有受检个体的疾病共分离，而在未受影响的个体中不存在。
该家族定义了一种与 ACTA1 突变相关的新肩胛肱骨表型。高度保守的蛋白 ACTA1 参与多种肌肉疾病，包括杆状体肌病、肌动蛋白聚集性肌病、纤维型比例失调和杆-核肌病。据我们所知，以前没有报道过 Glu197 突变。该残基高度保守，位于蛋白质的暴露位置；结构建模表明，该突变影响分子间和分子内的静电相互作用。该残基中的突变似乎不会导致体外或体内的杆形成或肌动蛋白积累，表明与其他 ACTA1 疾病的分子机制不同。
