Tlili Abdelaziz, Al Mutery Abdullah
Department of Applied Biology, College of Sciences, University of Sharjah, Building W8 - Room 107, P.O. Box: 27272, Sharjah, United Arab Emirates.
Human Genetics and Stem cell laboratory, Research Institute of Sciences and Engineering, University of Sharjah, Sharjah, United Arab Emirates.
Hum Genomics. 2025 Aug 13;19(1):91. doi: 10.1186/s40246-025-00809-7.
Limb-girdle muscular dystrophies (LGMDs) constitute a genetically diverse group of disorders characterized by progressive proximal muscle weakness and atrophy. Despite advances in genetic diagnostics, numerous cases remain unresolved due to extensive genetic heterogeneity, emphasizing the necessity for continued identification of novel pathogenic variants.
Using whole-exome sequencing (WES) in a Saudi family affected by autosomal recessive LGMD, we identified a novel homozygous frameshift mutation (c.891delT; p.Ala298ArgfsTer64) in the TRIM72 (MG53) gene, which we propose as a strong candidate gene for LGMD. Segregation analysis via Sanger sequencing confirmed that the variant co-segregated precisely with the disease phenotype and was absent in ethnically matched control cohorts. TRIM72 encodes a muscle-specific E3 ubiquitin ligase involved in sarcolemmal membrane repair, critical for maintaining muscle cell integrity. Functional parallels between TRIM72 and the LGMD-associated TRIM32, alongside corroborating evidence from animal models and cellular studies, support the candidacy of TRIM72 in LGMD pathogenesis.
Our findings identify TRIM72 as a novel candidate gene implicated in autosomal recessive LGMD, expanding the genetic spectrum of this heterogeneous disease. This discovery underscores the critical roles of TRIM family proteins in muscle pathology and reinforces the value of advanced genetic sequencing methodologies in diagnosing unresolved muscular dystrophy cases.
肢带型肌营养不良症（LGMDs）是一组具有遗传异质性的疾病，其特征为进行性近端肌无力和萎缩。尽管基因诊断取得了进展，但由于广泛的遗传异质性，仍有许多病例无法确诊，这凸显了持续鉴定新的致病变异的必要性。
我们对一个患有常染色体隐性LGMD的沙特家庭进行了全外显子组测序（WES），在TRIM72（MG53）基因中鉴定出一种新的纯合移码突变（c.891delT；p.Ala298ArgfsTer64），我们认为该基因是LGMD的一个强有力的候选基因。通过Sanger测序进行的分离分析证实，该变异与疾病表型精确共分离，在种族匹配的对照队列中不存在。TRIM72编码一种参与肌膜修复的肌肉特异性E3泛素连接酶，对维持肌肉细胞完整性至关重要。TRIM72与LGMD相关的TRIM32之间的功能相似性，以及动物模型和细胞研究的佐证，支持了TRIM72在LGMD发病机制中的候选地位。
我们的研究结果确定TRIM72是常染色体隐性LGMD的一个新的候选基因，扩展了这种异质性疾病的遗传谱。这一发现强调了TRIM家族蛋白在肌肉病理学中的关键作用，并强化了先进的基因测序方法在诊断未确诊的肌营养不良症病例中的价值。
