Clinico-pathological and Molecular Spectrum of Mitochondrial Polymerase γ Mutations in a Cohort from India


Polymerase γ catalytic subunit (POLG), a nuclear gene, encodes the enzyme responsible for mitochondrial DNA (mtDNA) replication. POLG mutations are a major cause of inherited mitochondrial diseases. They present with varied phenotypes, age of onset, and severity. Reports on POLG mutations from India are limited. Hence, this study aimed to describe the clinico-pathological and molecular observations of POLG mutations. A total of 446 patients with clinical diagnosis of mitochondrial disorders were sequenced for all exons and intron-exon boundaries of POLG. Of these, 19 (4.26%) patients (M:F: 10:9) had POLG mutations. The age of onset ranged from 5 to 55 years with an overlapping phenotypic spectrum. Ptosis, peripheral neuropathy, seizures, and ataxia were the common neurological features observed. The most common clinical phenotype was chronic progressive external ophthalmoplegia (CPEO) and CPEO plus (n = 14). Muscle biopsy showed characteristic features of mitochondrial myopathy in fourteen patients (14/19) and respiratory chain enzyme deficiency in eleven patients (11/19). Multiple mtDNA deletions were seen in 47.36% (9/19) patients. Eight pathogenic POLG variations including two novel variations (p.G132R and p.V1106A) were identified. The common pathogenic mutation identified was p.L304R, being present in eight patients (42.1%) predominantly in the younger age group followed by p.W748S in four patients (21%). To the best of our knowledge, this is the first extensive study from India, highlights the clinico-pathological and molecular spectrum of POLG mutations.

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The authors thank the patients and family members who participated in this study. SD acknowledges the Indian Council of Medical Research (ICMR), Government of India, for her Senior Research Fellowship (SRF). PG was supported by National Post-Doctoral Fellowship (N-PDF) from the Science and Engineering Research Board (SERB), Department of Science and Technology (DST), Government of India (PDF/2016/001625). KT was supported by JC Bose Fellowship from SERB, DST, Government of India.


This study was supported by a grant from the Department of Biotechnology, Government of India (Grant No. BT/PR7470/MED/14/1011/2006) and Indian Council of Medical Research (Grant No. 5/4-5/145/Neuro/2014-NCD-I).

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Study concept and design: GN, ABT, KT, PBS, PG; acquisition, analysis and interpretation of data: SD, PG, PBS, SC, CK, VN, MN, SS, TK, ABT, GN; manuscript drafting: SD, PG; critical revision for intellectual content: PG, PBS, KT, ABT, GN.

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Correspondence to Narayanappa Gayathri.

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The written informed consent for publication was taken from all the participants.

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The study was approved by the Institute Ethics Committee (Approval No: NIMHANS: SI No.1 Clinical Neurosciences dated 03.09.2014), and written informed consent was taken from all the participants.

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Deepha, S., Govindaraj, P., Sankaran, B.P. et al. Clinico-pathological and Molecular Spectrum of Mitochondrial Polymerase γ Mutations in a Cohort from India. J Mol Neurosci (2021).

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  • POLG
  • Mitochondrial disease
  • CPEO
  • Mutations
  • mtDNA deletions