title: Novel mutation in C10orf2 associated with multiple mtDNA deletions, chronic progressive external ophthalmoplegia and premature aging.
abstract: Chronic progressive external ophthalmoplegia (CPEO) is caused by defects in both mitochondrial and nuclear genes, however, the causal genetic factors in large number of patients remains undetermined. Therefore, our aim was to screen 12 unrelated patients with CPEO for mutation/multiple deletions in mtDNA and mutations in the coding regions of C10orf2, which is essential for mtDNA replication. Histopathological study of muscle biopsy revealed cytochrome c oxidase-deficient fibers and ragged blue fibers in all the patients. Long-range PCR of DNA from skeletal muscle revealed multiple mtDNA deletions in all the 12 patients. Further, sequencing coding regions of C10orf2 revealed three variants in three different patients, of which two were novel (c.1964G>A/p.G655D; c.204G>A/p.G68G) variants and one was reported (c.1052A>G/p. N351S). Sequencing of other nuclear genes that are associated with CPEO and multiple mtDNA deletions, such as; POLG1, POLG2, TK2, ANT1, DGUOK, MPV17 and RRM2B did not reveal any pathogenic mutation in patients with C10orf2 mutation. Since in silico analyses revealed p.G655D could be a potentially pathogenic and it was absent in 200 healthy controls, p.G655D could be the causative factor for CPEO. Therefore, we suggest that C10orf2 gene should be screened in CPEO individuals with multiple mtDNA deletions, which might help in prognosis of this disease and appropriate genetic counseling.
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.
authors.forename: Arumugam
authors.initials: A
authors.lastname: Paramasivam
authors.affiliation: Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, India.
authors.forename: Angamuthu Kannan
authors.initials: AK
authors.lastname: Meena
authors.affiliation: Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, India.
authors.forename: Lalitha
authors.initials: L
authors.lastname: Pedaparthi
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.
authors.forename: Vuskamalla
authors.initials: V
authors.lastname: Jyothi
authors.affiliation: Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, India.
authors.forename: Megha S
authors.initials: MS
authors.lastname: Uppin
authors.affiliation: Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, India.
authors.forename: Shaikh Afshan
authors.initials: SA
authors.lastname: Jabeen
authors.affiliation: Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, India.
authors.forename: Challa
authors.initials: C
authors.lastname: Sundaram
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India. Electronic address: thangs@ccmb.res.in.
authors.forename: Kumarasamy
authors.initials: K
authors.lastname: Thangaraj
mesh_terms: D000328:Adult; D019588:Aging, Premature / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D004265:DNA Helicases / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics*; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation; D017384:Sequence Deletion
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D004265:DNA Helicases; C431576:TWNK protein, human
keywords: C10orf2 mutation; CPEO; Multiple mtDNA deletions; Ptosis; mtDNA