title: A novel mutation MT-COIII m.9267G>C and MT-COI m.5913G>A mutation in mitochondrial genes in a Tunisian family with maternally inherited diabetes and deafness (MIDD) associated with severe nephropathy.
abstract: Mitochondrial diabetes (MD) is a heterogeneous disorder characterized by a chronic hyperglycemia, maternal transmission and its association with a bilateral hearing impairment. Several studies reported mutations in mitochondrial genes as potentially pathogenic for diabetes, since mitochondrial oxidative phosphorylation plays an important role in glucose-stimulated insulin secretion from beta cells. In the present report, we studied a Tunisian family with mitochondrial diabetes (MD) and deafness associated with nephropathy. The mutational analysis screening revealed the presence of a novel heteroplasmic mutation m.9276G>C in the mitochondrial COIII gene, detected in mtDNA extracted from leukocytes of a mother and her two daughters indicating that this mutation is maternally transmitted and suggest its implication in the observed phenotype. Bioinformatic tools showed that m.9267G>C mutation (p.A21P) is « deleterious » and it can modify the function and the stability of the MT-COIII protein by affecting the assembly of mitochondrial COX subunits and the translocation of protons then reducing the activity of the respective OXPHOS complexes of ATP synthesis. The nonsynonymous mutation (p.A21P) has not been reported before, it is the first mutation described in the COXIII gene which is related to insulin dependent mitochondrial diabetes and deafness and could be specific to the Tunisian population. The m.9267G>C mutation was present with a nonsynonymous inherited mitochondrial homoplasmic variation MT-COI m.5913 G>A (D4N) responsible of high blood pressure, a clinical feature detected in all explored patients.
authors.affiliation: Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Université de Sfax, Tunisia. Electronic address: mouna.biologiste@yahoo.com.
authors.forename: Mouna
authors.initials: M
authors.lastname: Tabebi
authors.affiliation: Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Université de Sfax, Tunisia.
authors.forename: Emna
authors.initials: E
authors.lastname: Mkaouar-Rebai
authors.affiliation: Service d'endocrinologie, C.H.U. Habib Bourguiba de Sfax, Tunisia.
authors.forename: Mouna
authors.initials: M
authors.lastname: Mnif
authors.affiliation: Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Université de Sfax, Tunisia.
authors.forename: Fakhri
authors.initials: F
authors.lastname: Kallabi
authors.affiliation: Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Université de Sfax, Tunisia.
authors.forename: Afif
authors.initials: A
authors.lastname: Ben Mahmoud
authors.affiliation: Service d'endocrinologie, C.H.U. Habib Bourguiba de Sfax, Tunisia.
authors.forename: Wafa
authors.initials: W
authors.lastname: Ben Saad
authors.affiliation: Service d'endocrinologie, C.H.U. Habib Bourguiba de Sfax, Tunisia.
authors.forename: Nadia
authors.initials: N
authors.lastname: Charfi
authors.affiliation: Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Université de Sfax, Tunisia.
authors.forename: Leila
authors.initials: L
authors.lastname: Keskes-Ammar
authors.affiliation: Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Université de Sfax, Tunisia.
authors.forename: Hassen
authors.initials: H
authors.lastname: Kamoun
authors.affiliation: Service d'endocrinologie, C.H.U. Habib Bourguiba de Sfax, Tunisia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abid
authors.affiliation: Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Université de Sfax, Tunisia. Electronic address: faiza.fakhfakh@gmail.com.
authors.forename: Faiza
authors.initials: F
authors.lastname: Fakhfakh
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D016022:Case-Control Studies; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics; D003638:Deafness / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000737:chemistry / Q000235:genetics*; D005260:Female; D050259:Genes, Mitochondrial; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000201:enzymology / Q000235:genetics; D007674:Kidney Diseases / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D014416:Tunisia; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV; C581860:cytochrome c oxidase subunit I, human
keywords: Deafness; MT-COI m.5913 G>A; MT-COIII m.9267G>C; Mitochondrial diabetes; Nephropathy