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Background <p>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.</p> Results <p>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 <i>TRIM72</i> (<i>MG53</i>) 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. <i>TRIM72</i> encodes a muscle-specific E3 ubiquitin ligase involved in sarcolemmal membrane repair, critical for maintaining muscle cell integrity. Functional parallels between <i>TRIM72</i> and the LGMD-associated <i>TRIM32</i>, alongside corroborating evidence from animal models and cellular studies, support the candidacy of <i>TRIM72</i> in LGMD pathogenesis.</p> Conclusion <p>Our findings identify <i>TRIM72</i> 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.</p>

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Whole-exome sequencing identifies TRIM72 as a candidate gene for autosomal recessive limb-girdle muscular dystrophy

  • 期刊论文

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  • 发表日期：

    2025年8月13日

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  • Abdelaziz Tlili,
  • Abdullah Al Mutery

摘要

Background

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.

Results

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.

Conclusion

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.