Leber's遗传性视神经病变分子致病机制研究

摘要

Leber's遗传性视神经病变(Leber's hereditary optic neuropathy,LHON)是一种较常见的引起视神经萎缩的遗传性疾病.该病主要引起双侧中心视力丧失,造成永久性的严重视觉障碍,常常发生在一些即将或已工作或上学的年轻人身上,以及在对该病患者家系中其他成员进行遗传病检查时发现.在一些LHON家系中,视觉障碍的患者呈现母系遗传方式,这表明线粒体DNA(mitochondrial DNA,mtDNA)是该病的分子遗传基础.至今为止,在世界各地不同家系报道中已经发现大约有35个与LHON相关的灾变位点,其中ND1 G3460A、ND4 G11778A、ND6 T14484C为三个公认的原发突变位点,均参与呼吸链复合体I的亚基编码.在不同种族发病统计中,其中大约50%的LHON由三个原发致病突变中的一个所致,尤为G11778A突变为主.引人注意的是,LHON家系携带相同突变的母系成员表现出不同的外显率、表现度(如发病严重程度、发病年龄、视力丧失进展程度).不完全和不同的外显率以及轻度的生化影响说明mtDNA突变本身不足以产生临床表型,其他因素(如环境、核修饰基因、线粒体单体型等)可能影响LHON的外显率和表型表达.%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].