Skewed X-chromosome inactivation is a common feature of X-linked mental retardation disorders.
Some deleterious X-linked mutations may result in a growth disadvantage for those cells in which the mutation, when on the active X chromosome, affects cell proliferation or viability. To explore the relationship between skewed X-chromosome inactivation and X-linked mental retardation (XLMR) disorders, we used the androgen receptor X-inactivation assay to determine X-inactivation patterns in 155 female subjects from 24 families segregating 20 distinct XLMR disorders. Among XLMR carriers, approximately 50% demonstrate markedly skewed X inactivation (i.e., patterns > or =80:20), compared with only approximately 10% of female control subjects (P<.001). Thus, skewed X inactivation is a relatively common feature of XLMR disorders. Of the 20 distinct XLMR disorders, 4 demonstrate a strong association with skewed X inactivation, since all carriers of these mutations demonstrate X-inactivation patterns > or =80:20. The XLMR mutations are present on the preferentially inactive X chromosome in all 20 informative female subjects from these families, indicating that skewing is due to selection against those cells in which the XLMR mutation is on the active X chromosome.
Plenge
Robert M
RM
Department of Genetics, Case Western Reserve University School of Medicine, and Center for Human Genetics and Research Institute, University Hospitals of Cleveland, OH 44106, USA.
Stevenson
Roger A
RA
Lubs
Herbert A
HA
Schwartz
Charles E
CE
Willard
Huntington F
HF
D016022:Case-Control Studies; D004303:Dosage Compensation, Genetic; D005260:Female; D008040:Genetic Linkage; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D011944:Receptors, Androgen / Q000235:genetics
D011944:Receptors, Androgen