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A founder mutation in the GMPPB gene [c.1000G > A (p.Asp334Asn)] causes a mild form of limb-girdle muscular dystrophy/congenital myasthenic syndrome (LGMD/CMS) in South Indian patients

Abstract

Twelve patients from seven unrelated South Indian families with a limb-girdle muscular dystrophy-congenital myasthenic syndrome (LGMD/CMS) phenotype and recessive inheritance underwent deep clinical phenotyping, electrophysiological evaluation, muscle histopathology, and next-generation sequencing/Sanger sequencing–based identification of the genetic defect. Homozygosity mapping was performed using high-throughput genome-wide genotyping for mapping the mutation and to evaluate the founder effect. The age of disease onset among patients ranged from childhood to 40 years of age. The key clinical manifestations observed were progressive fatigable limb-girdle weakness, muscle hypertrophy/atrophy, and preferential weakness in a dystrophic pattern. The ages at last follow-up ranged from 30 to 64 years; nine were independently ambulant, two required assistance, and one was wheelchair-bound. Lower limb muscle MRI showed varying degrees of fat replacement in the glutei, hamstrings, anterior leg muscles, and medial gastrocnemius. All patients showed significant decrement on repetitive nerve stimulation (RNS). Muscle biopsy in 7 patients revealed varying degrees of dystrophic and neurogenic changes. Treatment with pyridostigmine and/or salbutamol resulted in variable improvement in 10 patients. Genetic analysis showed an identical homozygous GMPPB mutation c.1000G > A (p.Asp334Asn) in all affected patients. A region of homozygosity (6Mbp) was observed flanking the c.1000G > A change in carrier chromosomes. This study identifies c.1000G > A in GMPPB as a common founder mutation in an ethnic community of South Indian descent with milder yet variable degree of clinical presentation of GMPPB-associated LGMD-CMS.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article and/or its supplementary materials.

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Funding

Funded by the Council of Scientific and Industrial Research (CSIR) grant nos. ML01601 and MLP1802.

H Lochmüller receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950–232279).

M Faruq receives research support from the Council of Scientific and Industrial Research (CSIR) grant nos. ML01601 and MLP1802.

Author information

Affiliations

Authors

Contributions

Kiran Polavarapu: National Institute of Mental Health and Neurosciences, Bengaluru, India; Study design; data analysis; drafting the manuscript for intellectual content.

Aradhna Mathur: CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Conduction of genetic study; acquisition of data; drafting the manuscript for intellectual content.

Aditi Joshi: CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Genetic data analysis, revision of the manuscript.

Saraswati Nashi: National Institute of Mental Health and Neurosciences, Bengaluru, India; Clinical data collection, revision of the manuscript.

VeeramaniPreethish-Kumar: National Institute of Mental Health and Neurosciences, Bengaluru, India; Clinical data collection, revision of the manuscript.

Mainak Bardhan: National Institute of Mental Health and Neurosciences, Bengaluru, India; Clinical data collection, revision of the manuscript.

Pooja Sharma: CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Genetic data analysis, revision of the manuscript.

Shaista Parveen: CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Genetic data analysis, revision of the manuscript.

Malika Seth: CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Genetic data analysis, revision of the manuscript.

Seena Vengalil: National Institute of Mental Health and Neurosciences, Bengaluru, India; Clinical data collection, revision of the manuscript.

Tanushree Chawla: National Institute of Mental Health and Neurosciences, Bengaluru, India; Clinical data collection, revision of the manuscript.

Leena Shingavi: National Institute of Mental Health and Neurosciences, Bengaluru, I ndia; Clinical data collection, revision of the manuscript.

Uzma Shamim: CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Genetic data analysis, revision of the manuscript.

Sushmita Nayak: CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Genetic data analysis, revision of the manuscript.

A Vivekanand: CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Genetic data analysis, revision of the manuscript.

Ana Töpf: Newcastle University, Newcastle upon Tyne, UK; Data interpretation and revision of the manuscript.

Andreas Roos: University Hospital Essen, Germany; Data interpretation and revision of the manuscript.

Rita Horvath: University of Cambridge, UK; Data interpretation and revision of the manuscript.

Hanns Lochmüller: Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Canada; Data interpretation and revision of the manuscript.

Bevinahalli Nandeesh: National Institute of Mental Health and Neurosciences, Bengaluru, India; Muscle Histopathological analysis and revision of the manuscript.

Gautham Arunachal: National Institute of Mental Health and Neurosciences, Bengaluru, India; Data interpretation and revision of the manuscript.

Atchayaram Nalini: National Institute of Mental Health and Neurosciences, Bengaluru, India; Study design and conceptualization, supervision of the study, collection of clinical data, and manuscript revision.

Mohammed Faruq: CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Study design and conceptualization, conduction of the genetic study, data interpretation, and manuscript revision.

Corresponding authors

Correspondence to Atchayaram Nalini or Mohammed Faruq.

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Supplementary Information

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Supplementary file3 (MP4 102009 KB) Video S1: Fatigable weakness in Patients 1 to 4 from Family 1

Supplementary file4 (MP4 66250 KB) Video S2: Fatigable weakness in Patients 5 and 6 from Family 2

Supplementary file5 (MP4 28932 KB) Video S3: Fatigable weakness in Patient 9 from Family 4

Supplementary file6 (MP4 17542 KB) Video S4: Fatigable weakness in Patient 10 from Family

Supplementary file1 (PDF 169 KB)

Supplementary file2 (XLSX 31 KB)

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Polavarapu, K., Mathur, A., Joshi, A. et al. A founder mutation in the GMPPB gene [c.1000G > A (p.Asp334Asn)] causes a mild form of limb-girdle muscular dystrophy/congenital myasthenic syndrome (LGMD/CMS) in South Indian patients . Neurogenetics 22, 271–285 (2021). https://doi.org/10.1007/s10048-021-00658-1

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Keywords

  • Muscle disease
  • Limb girdle muscular dystrophy-congenital myasthenic syndrome (LGMD/CMS)
  • Neuromuscular disorders
  • Founder mutation
  • Muscle MRI