El Sherif Rasha, Saito Yoshihiko, Awaya Tomonari, Noguchi Satoru, Nishino Ichizo
From the Myo-Care Neuromuscular Center (R.E.S.), Myo-Care National Foundation, Cairo; School of Medicine (R.E.S.), New Giza University, Cairo, Egypt; Department of Neuromuscular Research (Y.S., S.N., I.N.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo; and Department of Anatomy and Developmental Biology (T.A.), Graduate School of Medicine and Faculty of Medicine, The University of Kyoto, Japan.
Neurol Genet. 2024 Mar 25;10(2):e200137. doi: 10.1212/NXG.0000000000200137. eCollection 2024 Apr.
Collagen VI-related myopathy spans a clinical continuum from severe Ullrich congenital muscular dystrophy to milder Bethlem myopathy, caused by genetic variants in , , and genes. Our objective was to report a newly identified patient with the pathogenic variants restricted to a polyadenylation signal in the 3'-untranslated region, which have not been reported in hereditary muscle disease.
We performed clinicopathologic diagnosis and analysis using whole-genome and RNA sequencing.
We report Ullrich congenital muscular dystrophy caused by a homozygous deletion, c.*198_*466del, which includes a polyadenylation signal in the canonical last exon of the gene. The parents were consanguineously married and had the heterozygous variant, but they were completely asymptomatic. In the patient's muscles, collagen VI was deficient in the sarcolemma, but present in the interstitium, showing the pattern of sarcolemma-specific collagen VI deficiency rather than a pattern of complete deficiency despite the lack of a polyadenylation signal. The RNA sequencing of the patient's muscle showed that alternative last exons were raised in transcript.
Our case provides a valuable example of the mechanism of alternative splicing switches for polyadenylation selection.
VI型胶原相关肌病涵盖了从严重的乌尔里希先天性肌营养不良到较轻的贝斯勒姆肌病的临床连续谱，由COL6A1、COL6A2和COL6A3基因的遗传变异引起。我们的目的是报告一名新确诊的患者，其致病变异局限于3'非翻译区的一个聚腺苷酸化信号，这在遗传性肌肉疾病中尚未见报道。
我们采用全基因组和RNA测序进行临床病理诊断和分析。
我们报告了一例由纯合缺失c.*198_*466del引起的乌尔里希先天性肌营养不良，该缺失包括COL6A3基因典型最后一个外显子中的一个聚腺苷酸化信号。父母为近亲结婚，携带杂合变异，但完全无症状。在患者的肌肉中，VI型胶原在肌膜中缺乏，但在间质中存在，显示出肌膜特异性VI型胶原缺乏的模式，而不是尽管缺乏聚腺苷酸化信号但完全缺乏的模式。患者肌肉的RNA测序显示，在COL6A3转录本中出现了替代的最后外显子。
我们的病例为聚腺苷酸化选择的可变剪接开关机制提供了一个有价值的例子。
