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

Abstract

The expression of X-linked genes is equalized between males and females in mammalian species through X-Chromosome inactivation (XCI). Every cell in a female mammalian embryo randomly chooses one X Chromosome for epigenetic silencing at the 8–16 cell stage, resulting in a Gaussian distribution of XCI ratios with a peak at 50:50. At the tail extremes of this distribution, X-linked recessive mutations can manifest in disease in female carriers if the mutant allele is disproportionately active. The role of XCI skewing, if any, in X-linked retinal disease is still unknown, although many have speculated that such skewing accounts for phenotypic variation in female carriers of X-linked retinitis pigmentosa (XlRP). Some investigators have used clinical findings such as tapetal-like reflex, pigmentary changes, and multifocal ERG parameters to approximate XCI patches in the retina. These studies are limited by small cohorts and the relative inaccessibility of retinal tissue for genetic and epigenetic analysis. Although blood has been used as a proxy for other tissues in determining XCI ratios, blood XCI skews with age out of proportion to other tissues and may not accurately reflect retinal XCI ratios. Future investigations in determining retinal XCI ratios and the contribution of XCI to phenotype could potentially impact prognosis for female carriers of X-linked retinal disease.

Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing Their Potential for Retinal Gene Therapy

“…Either the maternal or paternal X chromosome is chosen at random and is passed down to daughter cells. A 50:50 ratio of the maternal and paternal X chromosome is expected [6]. Xist , located on the long arm of chromosome X, is a non-translated region of RNA in the X-inactivation centre (XIC).…”

“…Despite the X-linked inheritance of RPGR , the severe phenotype can also be seen in female carriers [5] and is caused by the preferential inactivation of the normal X chromosome [6]. X-linked RP can, therefore, be mistakenly characterised as autosomal dominant with every generation, including females, showing typical disease characteristics [7].…”

Coroideremia familiar: reporte de caso con énfasis en la evolución clínica y adquisición de discapacidad visual

“…La coroideremia es una enfermedad ligada al sexo, que se transmite genéticamente a través del cromosoma X. Las mujeres tienen dos cromosomas X, y pueden llevar el gen afectado en uno de ellos, sin embargo tienen una versión sana de este gen y por lo tanto se comportan como portadoras 26,27 . Esto se ve reflejado en el paciente y familia aquí reportadas, donde hay mujeres portadoras, dos hombres afectados y un primo materno posiblemente afectado.…”

A novel small deletion in the NHS gene associated with Nance-Horan syndrome

“…Like many other X-linked inherited ocular diseases, such as X-linked retinitis pigmentosa and choroideremia 37 , 38 , female carriers of Nance-Horan syndrome can have variable mild phenotypes. It’s mainly due to skewed X inactivation 39 . II3 experienced declined vision, with a BCVA of 0.15 OD and 0.4 OS.…”