HYPOPARATHYROIDISM AND DEAFNESS ASSOCIATED WITH PLEIOPLASMIC LARGE-SCALE REARRANGEMENTS OF THE MITOCHONDRIAL-DNA - A CLINICAL AND MOLECULAR-GENETIC STUDY OF 4 CHILDREN WITH KEARNS-SAYRE-SYNDROME

In four children with hypoparathyroidism and deafness as initial major manifestations of Kearns-Sayre syndrome, a unique pattern of mitochon drial DNA rearrangements was observed. Hypocalcemic tetany caused by P TH deficiency started between age of 6-13 y and was well controlled by small amounts of 1,25-(OH)(2)-cholecalciferol. Rearranged mitochondri al genomes were present in blood cells of all patients and consisted o f partially duplicated and deleted molecules, created by the loss of 7 813, 8348, 8587, and 9485 bp, respectively. The deletions were localiz ed between the origins of replication of heavy and light strands and e ncompassed at least eight polypeptide-encoding genes and six tRNA gene s. Sequence analysis revealed imperfect direct repeats present in all rearrangements flanking the breakpoints. The duplicated population acc ounted for 25-53% of the mitochondrial genome and was predominant to t he deleted DNA (5-30%) in all cases. The proportions of the mutant pop ulation (30-75%) correlated with the age at onset of the disease. We c onclude that, unlike heteroplasmic deletions, pleioplasmic rearrangeme nts may escape selection in rapid-dividing cells, distribute widely ov er many tissues, and thus cause multisystem involvement. Hypoparathyro idism and deafness might be the result of altered signaling pathway ca used by selective ATP deficiency.