Sequence Analysis of the Mitochondrial Genomes from Dutch Pedigrees with Leber Hereditary Optic Neuropathy

Abstract

The complete mitochondrial DNA (mtDNA) sequences for 63 Dutch pedigrees with Leber hereditary optic neuropathy (LHON) were determined, 56 of which carried one of the classic LHON mutations at nucleotide (nt) 3460, 11778, or 14484. Analysis of these sequences indicated that there were several instances in which the mtDNAs were either identical or related by descent. The most striking example was a haplogroup J mtDNA that carried the 14484 LHON mutation. Four different but related mitochondrial genotypes were identified in seven of the Dutch pedigrees with LHON, including six of those described by van Senus. The control region of the founder sequence for these Dutch pedigrees with LHON matches the control-region sequence that Macmillan and colleagues identified in the founder mtDNA of French Canadian pedigrees with LHON. In addition, we obtained a perfect match between the Dutch 14484 founder sequence and the complete mtDNA sequences of two Canadian pedigrees with LHON. Those results indicate that these Dutch and French Canadian 14484 pedigrees with LHON share a common ancestor, that the single origin of the 14484 mutation in this megalineage occurred before the year 1600, and that there is a 14484/haplogroup J founder effect. We estimate that this lineage--including the 14484 LHON mutation--arose 900-1,800 years ago. Overall, the phylogenetic analyses of these mtDNA sequences conservatively indicate that a LHON mutation has arisen at least 42 times in the Dutch population. Finally, analysis of the mtDNA sequences from those pedigrees that did not carry classic LHON mutations suggested candidate pathogenic mutations at nts 9804, 13051, and 14325.

De novo COX2 mutation in a LHON family of Caucasian origin: implication for the role of mtDNA polymorphism in human pathology

“…Of these, the synonymous 3333T transition in the ND1 gene apparently represented a silent mutation. It was detected in two of our haplogroup H controls, and had been noted in four other haplogroup H-specific mtDNA sequences in extensive European population surveys, two of which also had the 11778A LHON mutation in their mtDNAs (Herrnstadt et al 2002;Howell et al 2003) (Fig. 2).…”

“…Among mtDNAs belonging to haplogroup H, the 3849A transition was unique to the proband's haplotype (Fig. 2), although it had previously been reported in healthy controls whose mtDNAs belonged to haplogroups U2 and R (Herrnstadt et al 2002;Pala- Found in downloaded mtDNA sequences (adapt from Herrnstadt et al 2002;Howell et al 2003), and present in haplogroup H specific background in our sample set c Heteroplasmic appearance; also reported as homoplasies in different phylogenetic branches (see text for details); CRS polymorphism refers to rare polymorphisms present in the original Cambridge sequence (adapt from Anderson et al 1981;Andrews et al 1999) nichamy et al 2004). This mutation modified the third nucleotide of a leucine codon in the ND1 gene and did not create an amino acid substitution, and thus is a silent base change.…”

“…The 7598A mutation has been previously described as a haplogroup-specific marker for East Eurasian haplogroup E, a monophyletic sub-branch of mtDNA haplogroup M9 that appears at minor frequencies in some East Asian populations (Stoneking et al 1990;Ballinger et al 1992;Ingman and Gyllensten 2003). However, it also occur as homoplasmic events in two phylogenetic branches within Caucasian populations (Finnila et al 2001;Howell et al 2003). Interestingly, this mutation has arisen twice in haplogroup H mtDNAs, including the case that is the focus of our study, and, in both instances, was associated with LHON expression, implying that it might have some role in disease etiology.…”

Molecular genetic basis of primary inherited optic neuropathies

“…[16][17][18] The role of the European haplotype J (G15812A, G15257A, G13708A, and T4216C) in disease expression is still unclear. 19 In particular, approximately 75% of patients with the 14484 mutation have this haplotype, while it is only found in B10% of mtDNAs from the general European population. It may be that having a polymorphism within the haplotype J increases the penetrance of the 14484 mutation.…”

Characterization of mtDNA variation in a cohort of South African paediatric patients with mitochondrial disease

“…This variation was initially associated with a rare variety of hypertrophic cardiomyopathy in a 65-year-old Indian patient, 21 but subsequently suggested to be a polymorphism associated with the M5a haplogroup. 22 The second complex I variation, m.4160T4C missense variation in the MTND1 gene, has been reported several times before [23][24][25] and has been associated with LHON and the related neurological abnormalities involved. This variation substitutes a highly conserved amino-acid residue for another with the same polarity (p.Leu285Pro) and in silico analyses predicts it to have a detrimental impact.…”