Hypoparathyroidism and deafness associated with pleioplasmic large scale rearrangements of the mitochondrial DNA: A clinical and molecular genetic study of four children with Kearns-Sayre syndrome

Abstract

In four children with hypoparathyroidism amid deafness as initial major manifestations of Kearns-Sayre syndrome, a unique pattern of mitochondrial DNA rearrangements was observed. Hypocalcemic tetany caused by PTH deficiency started between age of 6-13 y and was well controlled by small amounts of 1.25-(OH)2-cholecalciferol. Rearranged mitochondrial genomes were present in blood cells of all patients and consisted of partially duplicated and deleted molecules, created by the loss of 7813, 8348, 8587, and 9485 bp, respectively. The deletions were localized between the origins of replication of heavy and light strands and encompassed at least eight polypeptide encoding genes and six tRNA genes. Sequence analysis revealed imperfect direct repeats present in all rearrangements flanking the break points. The duplicated population accounted for 25-53% of the mitochondrial genome and was predominant to the deleted DNA (5-30%) in all cases. The proportions of the mutant population (30-75%) correlated with the age at onset of the disease. We conclude that, unlike heteroplasmic deletions, pleioplasmic rearrangements may escape selection in rapid dividing cells, distribute widely over many tissues, and thus cause multisystem involvement. Hypoparathyroidism and deafness might be the result of altered signaling pathway caused by selective ATP deficiency.