title: Relative frequency of known causes of multiple mtDNA deletions: two novel POLG mutations.
abstract: Diseases affecting mtDNA stability, termed nuclear-mitochondrial intergenomic communication disorders, are caused by a primary nuclear gene defect resulting in multiple mtDNA deletions. The aim of this study was to estimate the frequency of known etiologies and the spectrum of mutations in a cohort of 21 patients harboring multiple mtDNA deletions in skeletal muscle. We showed that 10 cases (48%) display mutations in POLG, including eight previously reported variants and two novel mutations (namely, p.Trp585X and p.Arg1081Gln). The novel mutations affect evolutionary conserved residues and were absent in a large set of control chromosomes. These findings expand the array of mutations associated with multiple rearranged mtDNA attributed to mutations in POLG. The relatively high diagnostic yield (about one in two cases) supports the notion that it is recommended to test POLG routinely in diagnostic laboratories whenever multiple mtDNA deletions are present, regardless of the age of onset of patients and their clinical phenotype.
authors.affiliation: Centro de Genética Médica Jacinto de Magalhães, Instituto Nacional Saúde Ricardo Jorge, Porto, Portugal.
authors.forename: Mariana
authors.initials: M
authors.lastname: Ferreira
authors.forename: Teresinha
authors.initials: T
authors.lastname: Evangelista
authors.forename: Lígia S
authors.initials: LS
authors.lastname: Almeida
authors.forename: João
authors.initials: J
authors.lastname: Martins
authors.forename: Maria Carmo
authors.initials: MC
authors.lastname: Macario
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Martins
authors.forename: Ana
authors.initials: A
authors.lastname: Moleirinho
authors.forename: Luísa
authors.initials: L
authors.lastname: Azevedo
authors.forename: Laura
authors.initials: L
authors.lastname: Vilarinho
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
mesh_terms: D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human