Novel Mitochondrial DNA Length Variants and Genetic Instability in a Family with Diabetes and Deafness

Abstract

We have identified two locations with novel multiplasmic length variants in the mitochondrial DNA of a family with diabetes and deafness. At nt568 in the D-loop, the 6-bp polycytidine tract was found to be variable in length up to a total of 12 residues. A second region with length variants was found at nt8281 in the intergenic COII-tRNA(Lys) region, which consists of two copies of the 9-bp repeat CCCCCTCTA. Only the second repeat occurs in a heteroplasmic C(9-14)A form with both T residues largely deleted. In addition, the mtDNA contained a number of new homoplasmic point mutations. Both length variants are stably inherited in a maternal way with no major changes in their length distribution. In contrast, during culture of fibroblasts from the proband the average length of the polycytidine tracts is increased at both locations indicating a fibroblast-specific genetic instability. Cybrid cells containing mtDNA from the proband proliferate less efficient than cybrids with wild-type mtDNA in co-culture experiments, suggesting functional consequences of the mtDNA length variants or the additional homoplasmic point mutations. Since oxygen consumption was not severely affected, these mutation seem less detrimental for mitochondrial function than the A3243G diabetogenic mutation and most other pathogenic mtDNA mutations. The contribution of mtDNA length variants to the phenotype of members of this family is discussed.

Recurrent Tissue-Specific mtDNA Mutations Are Common in Humans

“…G94A has recently been reported in two Chinese pedigrees transmitting Lebers Hereditary Optic Neuropathy but in these families this variant was an inherited fixed polymorphism, not a heteroplasmic somatic mutation [36]. Despite the rarity of G203A in the global population (estimated as 0.3% in a survey of human mtDNA sequences deposited in GenBank) [8] it has been identified as a fixed variant in patients with deafness in two independent studies in different ethnicities [37], [38].…”

Mitochondrial tRNALeu(CUN) A12307G variant may not be associated pancreatic cancer

“…The common T16189C variant in the D-loop region has been found to play an important role in the development of metabolic syndrome (Palmieri et al, 2011). Moreover, the homoplasmic CYTB T15287C mutation has been reported to increase the penetrance and expressivity of aminoglycoside-induced and non-syndromic hearing loss (Janssen et al, 2006). Finally, the A11467G and G12372A mutations identified have been shown to alter brain pH (Rollins et al, 2009).…”

A Novel Unstable Mutation in Mitochondrial DNA Responsible for Maternally Inherited Diabetes and Deafness

“…Several polyC repeats are found in the D-loop or in intergenic regions of mtDNA (11,12) and are unstable by a genetic standpoint. In the MIDD family, Janssen et al (13) have shown that two repeats, a 6-bp polycytidine tract at nucleotide 568 in the D-loop and a 9-bp CCCCCTCTA sequence in the intergenic COII-tRNA Lys region, are variable in length. Both repeats are stably inherited in a maternal way, but in proband’s fibroblasts, the average length of the polycytidine tracts is increased at both locations, indicating a fibroblast-specific instability.…”