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Published on: April 4, 2018
Novel POMT2 variants associated with limb-girdle muscular dystrophy R14: genetic, histological and functional studies
Guiguan Yang1, Xiaoqing Lv1, Wenjing Wu1
1Department 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.
Background:
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).
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
This study identifies novel POMT2 gene variants in three adult-onset limb-girdle muscular dystrophy R14 patients. Aberrant mRNA processing and molecular dynamics reveal how these variants impact protein function.
Area of Science:
- Genetics
- Molecular Biology
- Neurology
Background:
- The POMT2 gene is crucial for alpha-dystroglycan glycosylation, a process vital for muscle integrity.
- Mutations in POMT2 are associated with rare neuromuscular disorders, including limb-girdle muscular dystrophy type R14 (LGMDR14).
Purpose of the Study:
- To characterize the clinical, pathological, and genetic features of LGMDR14 patients with novel POMT2 variants.
- To elucidate the pathogenic mechanisms underlying LGMDR14 caused by POMT2 mutations through mRNA analysis and molecular simulations.
Main Methods:
- Retrospective analysis of clinical, pathological, and genetic data from three LGMDR14 patients.
- Investigation of POMT2 variant pathogenicity using aberrant mRNA processing analysis and molecular dynamics simulations.
Main Results:
- Three unrelated Chinese families presented with adult-onset proximal muscle weakness, myopathic electromyography, and reduced alpha-dystroglycan expression.
- Genetic sequencing identified compound heterozygous POMT2 variants, including novel mutations (c.700_701insCT, c.812 C>T, c.170G>A).
- Splicing analysis revealed that variants like c.1006+1G>A induce aberrant mRNA processing, leading to nonsense-mediated mRNA decay and truncated proteins, impacting protein stability and function.
Conclusions:
- This study expands the known genetic spectrum of POMT2 variants associated with LGMDR14.
- Findings highlight the significant role of POMT2 splicing defects in disease pathogenesis.
- Molecular dynamics simulations provide insights into the structural and functional consequences of POMT2 variants in LGMDR14.
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