title: 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.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden, The Netherlands. g.m.c.janssen@lumc.nl
authors.forename: G M C
authors.initials: GM
authors.lastname: Janssen
authors.forename: A
authors.initials: A
authors.lastname: Neu
authors.forename: L M
authors.initials: LM
authors.lastname: 't Hart
authors.forename: C M T
authors.initials: CM
authors.lastname: van de Sande
authors.forename: J
authors.initials: J
authors.lastname: Antonie Maassen
mesh_terms: D000328:Adult; D004272:DNA, Mitochondrial / Q000235:genetics*; D003638:Deafness / Q000150:complications / Q000235:genetics*; D048909:Diabetes Complications / Q000235:genetics*; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D008297:Male; D018598:Minisatellite Repeats / Q000235:genetics*; D009154:Mutation; D010375:Pedigree
chemical_list: D004272:DNA, Mitochondrial