X chromosome inactivation and X-linked mental retardation

Abstract

The expression of X‐linked genes in females heterozygous for X‐linked defects can be modulated by epigenetic control mechanisms that constitute the X chromosome inactivation pathway. At least four different effects have been found to influence, in females, the phenotypic expression of genes responsible for X‐linked mental retardation (XLMR). First, non‐random X inactivation, due either to stochastic or genetic factors, can result in tissues in which one cell type (for example, that in which the X chromosome carrying a mutant XLMR gene is active) dominates, instead of the normal mosaic cell population expected as a result of random X inactivation. Second, skewed inactivation of the normal X in individuals carrying a deletion of part of the X chromosome has been documented in a number of mentally retarded females. Third, functional disomy of X‐linked genes that are expressed inappropriately due to the absence of X inactivation has been found in mentally retarded females with structurally abnormal X chromosomes that do not contain the X inactivation center. And fourth, dose‐dependent overexpression of X‐linked genes that normally “escape” X inactivation may account for the mental and developmental delay associated with increasing numbers of otherwise inactive X chromosomes in individuals with X chromosome aneuploidy. © 1996 Wiley‐Liss, Inc.

ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal

“…The observation that she appears to have completely skewed X inactivation with expression from her inverted X chromosome helps explain why this female patient has phenotypic expression of mental retardation rather than remaining an asymptomatic carrier. Complete skewing of X chromosome inactivation has been documented in a number of mentally retarded females 19 , 20. However, we now also recognise that some genes on the X chromosome can be partially expressed from an otherwise inactive X chromosome 21.…”

Gene expression analysis in lymphoblasts derived from patients with autism spectrum disorder

“…However, no significant difference of NLGN3 gene expression normalized by β-actin or TBP was observed with regard to gender in healthy controls or individuals with ASD ( P > 0.05). This might be due to inactivation of one X chromosome in females [41]. There are several possibilities that might explain the reduced expression of the NLGN3 and SHANK3 genes in ASD.…”

Skewed X chromosome inactivation in carriers is not a constant finding in FG syndrome

“…13 There were three manifesting carriers in three different families (20246, 21826 and 28438): X-inactivation may be correlated with the phenotype in blood cells if the parental origin of alleles would reveal preferential inactivation of the maternal chromosome in the asymptomatic females and preferential inactivation of the paternal chromosome in the symptomatic ones. Other tissues like brain would be more relevant to the phenotypic expression.…”