title: A novel homozygous mutation in SUCLA2 gene identified by exome sequencing.
abstract: Mitochondrial disorders with multiple mitochondrial respiratory chain (MRC) enzyme deficiency and depletion of mitochondrial DNA (mtDNA) are autosomal recessive conditions due to mutations in several nuclear genes necessary for proper mtDNA maintenance. In this report, we describe two Italian siblings presenting with encephalomyopathy and mtDNA depletion in muscle. By whole exome-sequencing and prioritization of candidate genes, we identified a novel homozygous missense mutation in the SUCLA2 gene in a highly conserved aminoacid residue. Although a recurrent mutation in the SUCLA2 gene is relatively frequent in the Faroe Islands, mutations in other populations are extremely rare. In contrast with what has been reported in other patients, methyl-malonic aciduria, a biomarker for this genetic defect, was absent in our proband and very mildly elevated in her affected sister. This report demonstrates that next-generation technologies, particularly exome-sequencing, are user friendly, powerful means for the identification of disease genes in genetically and clinically heterogeneous inherited conditions, such as mitochondrial disorders.
authors.affiliation: Unit of Molecular Neurogenetics, Fondazione Istituto Neurologico Carlo Besta, Istituto di Ricovero e Cura a Carattere Scientifico, via Temolo 4, 20126 Milan, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Lamperti
authors.forename: Mingyan
authors.initials: M
authors.lastname: Fang
authors.forename: Federica
authors.initials: F
authors.lastname: Invernizzi
authors.forename: Xuanzhu
authors.initials: X
authors.lastname: Liu
authors.forename: Hairong
authors.initials: H
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Franco
authors.initials: F
authors.lastname: Carrara
authors.forename: Isabella
authors.initials: I
authors.lastname: Moroni
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhang
authors.forename: Daniele
authors.initials: D
authors.lastname: Ghezzi
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D002648:Child; D004272:DNA, Mitochondrial / Q000235:genetics*; D059472:Exome; D005260:Female; D006720:Homozygote; D006801:Humans; D017237:Mitochondrial Encephalomyopathies / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000473:pathology; D020125:Mutation, Missense; D010375:Pedigree; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D035781:Siblings; D013389:Succinate-CoA Ligases / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D013389:Succinate-CoA Ligases; C518788:SUCLA2 protein, human