Mitochondrial D-loop variation in leber hereditary neuropathy patients harboring primary G11778A, G3460A, T14484C mutations: J and W haplogroups as high-risk factors.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is a maternally inherited form of retinal ganglion cell degeneration leading to optic atrophy in young adults. It is caused by three primary point mutations including G11778A, G3460A, and T14484C in the mitochondrial genome. These three mutations account for the majority of LHON cases and affect genes that encode for different subunits of mitochondrial complex I. Mitochondrial DNA (mtDNA) has a non-coding region at the displacement loop (D-loop) that contains two hypervariable segments (HVS-I and HVS-II) with high polymorphism. METHODS: To investigate any possible association between LHON primary mutations and mtDNA haplogroups (hg), the nucleotide sequence of the HVS-I region of mtDNA was determined in 30 unrelated Iranian patients with LHON harboring one of the primary mutations and 100 normal controls with the same ethnicity. DNA was extracted from the peripheral blood after having obtained informed consent. The nucleotide sequence of HVS-I (np 16,024-16,383) was directly determined. RESULTS: Our analysis revealed a relatively high proportion of haplogroup J in LHON patients (53.3%) compared to normal controls (20%). In addition, a slightly significant increase of normal controls of haplogroup L has been confirmed (14% in normal controls vs. 0% in LHON patients at p = 0.03), whereas other haplogroups did not show contribution to LHON contingency. CONCLUSIONS: The analysis presented here provides evidence that there is an association between G11778A and G3460A with haplogroup J (including J1 and J2) and W, respectively. Therefore, we hypothesize that mtDNA haplogroups J (J1 and J2) and W might act as predisposing haplotypes, increasing penetrance of LHON disease.

Influence of HLA on progression of optic neuritis to multiple sclerosis: results of a four-year follow-up study.

BACKGROUND: Genetic predisposition in multiple sclerosis (MS) has always been a critical concern in aetiology and progress of the disease. The present study looks into the relations between human leukocyte antigen (HLA), optic neuritis (ON) and MS in the Iranian population. METHODS: Patients with potential diagnosis of acute ON underwent a standardized clinical examination for confirming the diagnosis. Selected patients were gathered for HLA typing and clinical follow up. RESULTS: Of the 55 patients, 46 (83.6%) were female. The mean age was 25(+/-7.3) with a range of 12-43. Twenty of the 55 (36%) were confirmed for the diagnosis of clinically definite MS (CDMS). Results show that A23, B21, A11 and B51 alleles were present in 4 (20%), 6 (30%), 2 (10%) and 1 (5%) of the CDMS patients, respectively. Ten (50%) and 17 (85%) CDMS patients were positive for HLA class II alleles, DR2 and DQ1, correspondingly. CONCLUSIONS: The study strongly suggests the association among DR2, A23 and B21 allele and the evolution of ON to MS. High prevalence of A23 and DR2 alleles in CDMS patients compared with the normal population may suggest an important role for these alleles in the development of MS. The study suggests B51 as a protective factor against development of ON in the normal population. In addition, results do not confirm previous studies considering A11 as a predisposing factor. The present study finally evokes that different classes of HLA have different roles in susceptibility to MS and confirms disease heterogeneity as an important emerging concept in MS.