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MELAS- and Kearns-Sayre-type co-mutation [corrected] with myopathy and autoimmune polyendocrinopathy
K Ohno1, M Yamamoto, A G Engel
1Department of Neurology and Muscle Research Laboratory, Mayo Clinic, Rochester, MN 55905, USA.
Annals of Neurology
|June 1, 1996
Summary
Mitochondrial DNA (mtDNA) analysis revealed a large deletion and a specific point mutation (A3243G) in a patient with Kearns-Sayre syndrome. This suggests the point mutation may predispose cells to developing large mtDNA deletions, impacting mitochondrial function.
Area of Science:
- Genetics
- Molecular Biology
- Neurology
Background:
- Kearns-Sayre syndrome (KSS) is a rare mitochondrial disorder characterized by progressive external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction defects.
- Autoimmune polyglandular syndrome type II (APS-II) involves autoimmune endocrine failures, including Addison's disease, autoimmune thyroid disease, and type 1 diabetes.
- Co-occurrence of KSS and APS-II is exceptionally rare, suggesting potential shared genetic or molecular underpinnings.
Observation:
- A 35-year-old woman presented with clinical features of KSS and APS-II.
- Genetic analysis of her muscle tissue revealed a large 2,532-bp deletion in mitochondrial DNA (mtDNA), typical of KSS.
- Concurrently, a heteroplasmic A3243G mutation in the tRNA-Leu(UUR) gene, associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes), was identified in her mtDNA.
Findings:
- The patient inherited the A3243G mutation from her mother, who did not have the large mtDNA deletion.
- In the patient's muscle, the mtDNA harboring the large deletion was exclusively found alongside the A3243G mutation.
- The combined mutated mtDNA species constituted 88% of the total muscle mtDNA, strongly suggesting the point mutation predisposes to the large-scale deletion.
Implications:
- This case provides evidence that specific point mutations in mtDNA may play a causal role in the generation of large-scale mtDNA deletions.
- Understanding this relationship could offer new insights into the pathogenesis of mitochondrial disorders like KSS and MELAS.
- Further research into other mtDNA point mutations and their association with large deletions may uncover novel therapeutic targets for mitochondrial diseases.