X-linked neurological disorders

Abstract

Many X-linked genes in mammals are involved in intellectual disability (XLID). In this lecture, I study some of these genes, such as Mecp2, whose absence is highly deleterious (lethality in males; Rett syndrome in females), but the double dose is also deleterious in boys with Mecp2 duplication. This illustrates just how important precise dosage is.

I'm also analyzing the selective advantages linked to dose differences in X-linked genes for specific brain functions in males and females. Although hormones have dominated theories of the origins of sex differences, over the past two decades, the sex imbalance of X and Y chromosome effects has been clearly demonstrated to cause sex differences in non-gonadal tissues that are not mediated by gonadal hormones. Specific X-linked genes are prime candidates for these effects.

I describe how random XCI and variable gene escape result in a cellular mosaic within and between XX individuals. Each female is a unique mosaic for X-linked gene expression: the outcome will depend on the interaction of all alleles between the two (active) Xs, as well as the inherent variation in the initiation of "random" inactivation, also in mixing and cell migration. In this lecture, I explore the advantages of random XCI over single heterozygosity in the brain and how functional possibilities increase by combining cellular phenotypes. I also analyze certain situations in which, conversely, there is incompatibility between cells expressing one or other allele of an X-linked gene (the ephrin receptor and its ligand EFNB1). This can lead to certain craniofacial disorders and a form of epilepsy specific to women.

Genes that escape X inactivation are particularly present in the context of female-specific diseases. Some genes always escape inactivation, while others vary from one individual to another and within the same individual. Genes that are constitutively excluded are conserved (e.g. Jarid1c, Utx). Genes that are variable are less conserved. The time and place of escape also appear to be important: dosage can vary during development and in adults. Several of these genes are implicated in autoimmune diseases.