Identical mitochondrial DNA deletion in a woman with ocular myopathy and in her son with pearson syndrome

Abstract

Single deletions of mitochondrial DNA (mtDNA) are associated with three major clinical conditions: Kearns-Sayre syndrome, a multisystem disorder; Pearson syndrome (PS), a disorder of the hematopoietic system; and progressive external ophthalmoplegia (PEO), primarily affecting the ocular muscles. Typically, single mtDNA deletions are sporadic events, since the mothers, siblings, and offspring of affected individuals are unaffected. We studied a woman who presented with PEO, ptosis, and weakness of pharyngeal, facial, neck, and limb muscles. She had two unaffected children, but another of her children, an infant son, had sideroblastic anemia, was diagnosed with PS, and died at age 1 year. Morphological analysis of a muscle biopsy sample from the mother showed cytochrome c oxidase-negative ragged-red fibers-a typical pattern in patients with mtDNA deletions. Southern blot analysis using multiple restriction endonucleases and probed with multiple mtDNA fragments showed that both the mother and her infant son harbored an identical 5,355-bp single deletion in mtDNA, without flanking direct repeats. The deletion was the only abnormal species of mtDNA identified in both patients, and there was no evidence for duplications. We conclude that, although the vast majority of single large-scale deletions in mtDNA are sporadic, in rare cases, single deletions can be transmitted through the germline.

Figure 1

A, Maps of mtDNA species—namely, monomeric and dimeric Δ-mtDNA and WT-mtDNA. The protruding, pie-shaped section on the Δ-mtDNA denotes the deleted region. Only the genes involved in the rearrangement are shown—namely, cytochrome c oxidase subunit III (blackened box) and cytochrome b (unblackened box). A dashed line indicates the breakpoint. Also shown are the D-loop and the locations of the PvuII (P), BamHI (B), and SnaBI (S) restriction sites. Cyt b = cytochrome b. B, Southern blot analysis of mtDNA from muscle and blood from the patients whom we studied. DNA was digested with PvuII (P), BamHI (B), or SnaBI (S), and the blot was hybridized sequentially with probes 1 and 2 (see text). The identity of each hybridizing fragment and its size (in kb) are indicated at left. C, Sequence around the deletion breakpoints.