ANovel UnstableMutation in Mitochondrial DNA Responsible for Maternally Inherited Diabetes and Deafness

OBJECTIVEdThe m.3243A.Gmutation in mitochondrial DNA (mtDNA) is responsible for maternally inherited diabetes and deafness (MIDD). Other mtDNAmutations are extremely rare. RESEARCHDESIGNANDMETHODSdWe studied a patient presenting with diabetes and deafness who does not carry the m.3243A.G mutation. RESULTSdWe identified a deficiency of respiratory chain complex I in the patient’s fibro-blasts. mtDNA sequencing revealed a novel mutation that corresponds to an insertion of one or two cytosine residues in the coding region of the MT-ND6 gene (m.14535_14536insC or CC), leading to premature stop codons. This heteroplasmic mutation is unstable in the patient’s somatic tissues. CONCLUSIONSdWe describe for the first time an unstable mutation in a mitochondrial gene coding for a complex I subunit, which is responsible for the MIDD phenotype. This mu-tation is likely favored by the m.14530T.C polymorphism, which is homoplasmic and leads to the formation of an 8-bp polyC tract responsible for genetic instability. Diabetes Care 34:2591–2593, 2011 The most common form of maternallyinherited diabetes and deafness(MIDD) is associated with the m.3243A.G mutation in mitochondrial DNA (mtDNA), which is located in the tRNALeu gene (1). The mutation that af-fects up to 1 % of diabetic patients leads to both impaired glucose-induced insulin secretion (2) and progressive b-cell loss (3). However, in some rare cases charac-terized by a highly suggestive phenotype but without m.3243A.G mutation, ge-neticists should look for other diabetes-prone variants (4). Here, we describe a patient presenting an MIDD phenotype who carries a novel unstable mutation in the mitochondrial MT-ND6 gene respon-sible for a deficiency in the respiratory chain complex I