Yang Guiguan, Lv Xiaoqing, Wu Wenjing, Wang Guangyu, Yang Mengqi, Feng Yifei, Yan Chuanzhu, Liu Meirong, Lin Pengfei
Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Shandong University, Jinan, 250012, Shandong, China.
Department of Neurology, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, 215006, Jiangsu , China.
Orphanet J Rare Dis. 2025 Mar 3;20(1):99. doi: 10.1186/s13023-025-03578-7.
The POMT2 gene, which encodes protein O-mannosyltransferase 2, is essential for α-dystroglycan glycosylation. Variants in POMT2 cause various disorders, including the relatively rare presentation of limb-girdle muscular dystrophy R14 (LGMDR14).
This study retrospectively analyzed the clinical, pathological, and genetic data of three LGMDR14 patients. And we investigated the pathogenic mechanisms of POMT2 variants through aberrant mRNA processing analysis and molecular dynamics simulations to assess their impact on protein structure and function.
We recruited three LGMDR14 patients from unrelated Chinese families, all presenting with adult-onset proximal muscle weakness. All of these patients showed a myopathic pattern on electromyography and decreased α-dystroglycan expression on muscle biopsy. One patient had severe cardiomyopathy and mild cognitive impairment. Genetic sequencing revealed compound heterozygous variants in the POMT2 gene in all three patients: c.1006 + 1G > A and c.295 C > T in patient 1, c.1261 C > T and c.700_701insCT in patient 2, and c.812 C > T and c.170G > A in patient 3. Variants c.700_701insCT, c.812 C > T, and c.170G > A are novel. Splicing and cDNA analysis revealed that the c.1006 + 1G > A variant could cause retention of the first 26 bp of intron 8 by inducing recognition of new donor splice sites. Pyrosequencing revealed that both frameshift variant c.700_701insCT and splicing variant c.1006 + 1G > A triggered a nonsense-mediated mRNA decay. Molecular dynamics indicated that c.1006 + 1G > A, c.700_701insCT, and c.170G > A variants could lead to truncated proteins, altering stability and function.
Our study summarizes the clinical, pathological and genetic characteristics of three adult-onset LGMDR14 patients, expanding the genetic spectrum of POMT2 variants. Moreover, the finding reinforces the impact of POMT2 splicing defects on mRNA regulation, and molecular dynamics simulations predict the structural consequences of POMT2 variants, providing additional evidence for their functional effects.
编码蛋白质O-甘露糖基转移酶2的POMT2基因对于α-肌营养不良蛋白糖基化至关重要。POMT2基因的变异会导致多种疾病，包括相对罕见的肢带型肌营养不良R14（LGMDR14）。
本研究回顾性分析了3例LGMDR14患者的临床、病理和基因数据。我们通过异常mRNA加工分析和分子动力学模拟研究POMT2变异的致病机制，以评估其对蛋白质结构和功能的影响。
我们从无关的中国家庭招募了3例LGMDR14患者，均表现为成人起病的近端肌无力。所有这些患者肌电图均显示肌病模式，肌肉活检显示α-肌营养不良蛋白表达降低。1例患者有严重心肌病和轻度认知障碍。基因测序显示所有3例患者的POMT2基因均存在复合杂合变异：患者1为c.1006+1G>A和c.295 C>T；患者2为c.1261 C>T和c.700_701insCT；患者3为c.812 C>T和c.170G>A。变异c.700_701insCT、c.812 C>T和c.170G>A是新发现的。剪接和cDNA分析显示，c.1006+1G>A变异可通过诱导新的供体剪接位点识别导致第8内含子的前26 bp保留。焦磷酸测序显示，移码变异c.700_701insCT和剪接变异c.一百零六加一G>A均触发无义介导的mRNA降解。分子动力学表明，c.1006+1G>A、c.700_701insCT和c.170G>A变异可导致截短蛋白，改变稳定性和功能。
我们的研究总结了3例成人起病的LGMDR14患者的临床、病理和基因特征，扩展了POMT2变异的基因谱。此外，该发现强化了POMT2剪接缺陷对mRNA调控的影响，分子动力学模拟预测了POMT2变异的结构后果，为其功能效应提供了额外证据。
