WOLFRAM-SYNDROME - A MITOCHONDRIAL-MEDIATED DISORDER

Mitochondrial DNA mutations cause several human diseases, (eg, Leber's hereditary optic neuropathy). Wolfram syndrome (characterised by diab etes insipidus, diabetes mellitus, optic atrophy, and deafness) also h as, in some cases, a mitochondrial origin. The disease, often familial , has been well documented as an autosomal recessive disorder, and mos t of the clinical phenotypes are consistent with an ATP supply defect that is often seen in mitochondrial-mediated disorders. We propose a d ual genome defect model for Wolfram syndrome in which nuclear genetic defects or mitochondrial genetic defects can independently lead to the disease. This model suggests that besides a mitochondrial gene defect alone, a nuclear gene defect, which interferes with the normal functi on of mitochondria (probably with a normal mitochondrial genome), can also be the underlying explanation for the pleiotropic features of Wol fram syndrome. This hypothesis explains how an autosomal recessive dis order can result in mitochondrial dysfunction, and has a general appli cation in the identification of candidate genes for the various import ant phenotypes (eg, deafness and diabetes mellitus) seen in mitochondr ial disorders.