X‐inactivation pattern in multiple tissues from two leber's hereditary optic neuropathy (LHON) patients

Abstract

The more frequent manifestation of ophthalmological abnormalities in males, relative to females, is an unexplained feature of Leber's hereditary optic neuropathy (LHON) that suggests an X-linked modifying gene acting in concert with the pathogenic LHON mitochondrial DNA (mtDNA) mutation. In addition, segregation analysis of the optic neuropathy in LHON pedigrees was compatible with the presence of a recessive-modifying gene on chromosome X. According to this two-locus model, females would be affected only if homozygous or if they were susceptible to skewed X-inactivation. Attempts both to localize the putative LHON-modifying gene by linkage analysis and to find an excess of skewed X-inactivation in affected females were unsuccessful, although the inactivation pattern was only studied in DNA isolated from blood cells. We had the opportunity to analyze a wide range of tissues at autopsy, including the optic nerves and the retina, from two LHON female patients. We found no evidence of skewed X-inactivation in the affected tissues, thus weakening further the hypothesized involvement of a specific X chromosome locus in the pathophysiological expression of LHON.

Danon disease: A focus on processing of the novel LAMP2 mutation and comments on the beneficial use of peripheral white blood cells in the diagnosis of LAMP2 deficiency

“…The most common biological sample and method used to test XCI skewing ratios are peripheral blood and HUMARA assay (Kubota et al, 1999), respectively. Studies comparing individual tissues in terms of their XCI-skewing are limited (Bittel et al, 2008;Pegoraro et al, 2003), similar to the data on the applicability of XCI values established in WBCs to other tissues. Unfortunately HUMARA assay may be uninformative, as in the case of the female patient III/2.…”

Identification of an X-Chromosomal Locus and Haplotype Modulating the Phenotype of a Mitochondrial DNA Disorder

“…Epigenetic mechanisms provide an alternative explanation for the reduced penetrance and sex bias in LHON. Although two studies failed to find skewed X inactivation in the blood (Pegoraro et al 1996) and ocular tissue (Pegoraro et al 2003) from women affected with LHON, many imprinted disease genes do not show X skewing (Renieri et al 2003). In families with no known disease, the failure to fully correct a maternal imprint leads to the preferential transmission of grandpaternal chromosomes to male offspring (Naumova et al 1998).…”

The Role of X-Chromosome Inactivation in Retinal Development and Disease

“…In one study that examined multiple tissues at autopsy from a female affected with Leber's Hereditary Optic Neuropathy, the XCI ratio in retina was 43:57, compared to 65:35 in blood and 56:44 in optic nerve (Pegoraro et al 2003). Not only was the ratio more skewed in blood than in retina, but it was also skewed in the opposite direction.…”