Molecular pathogenetic mechanism of Leber's hereditary optic neuropathy

Abstract

Leber's hereditary optic neuropathy (LHON) is the most common hereditary optic atrophies. The disease causes the bilateral loss of central vision. The importance of LHON lies in it ability to cause such severe and usually permanent vision loss in young adults who are about to start or have recently begun employrent or higher education, and the ramification of diagnosing an inherited disease to other members of the patient's family. The maternal transmission of visual dysfunction in families with LHON suggested the mutations in mitochondrial DNA (mtDNA) are the molecular bases of this disorder. Up to date, 35 LHON-associated mtDNA mutations have been identified in many pedigrees worldwide. Of these, three primary mutations: ND1 G3460A, ND4 G11778A and ND6 T14484C, which involve genes encoding the subunits of respiratory chain complex I, aocounts for more than 50% of LHON pedigrees in different ethnic origins. In particular,the G11778A mutation is the most common LHON-associated mtDNA mutation. Strikingly, matrilineal relatives within families or among families carrying the same LHON-associated mtDNA mutations exhibited variable penetrance and expressivity including the severity, age-of-onset and progression in vision loss. Incomplete and variable penetrance of vision loss as well as mild biochemical defects associated with these mtDNA mutations indicated that the LHON-associated mtDNA mutation(s) itself is not sufficient to produce the clinical phenotype. Therefore, other modifier factors including environmental factors, nuclear modifier genes and mitochondrial haplotypes are required for the phenotypic expression of vision loss associated with these mtDNA mutations, Most eye diseases are tmulti-factorial in etiology. These diseases are caused by complex and interactive effects of personal factors, environmental conditions and gene aberrations. Some of these disorders are known to have a genetic etiology or predisposition with autosomal dominant, autosomal recessive, X-linked or maternally-transmitted pattern of inheritance. Recently, these have rapidly been defined at the molecular levels. In some cases, the maternal transmission of visual dysfunctions suggested the mitochondrial involvement. In fact, mtDNA mutations fiequently manifest with neuro-ophthalmoligcal symptoms. Of these,acute-onset and bilateral optic atrophy is the primary clinical sign of LHON, which is caused by missense mutations in mtDNA[1 -15]. Key words: Leber's hereditary opitc neuropathy; mitochondrial DNA; pathogenetic