Evidence That Mutations in the X-linked DDP Gene Cause Incompletely Penetrant and Variable Skewed X Inactivation

• Published in: American journal of human genetics Vol. 64; no. 3; pp. 759 - 767
• Main Authors: Plenge, Robert M., Tranebjaerg, Lisbeth, Jensen, Peter K.A., Schwartz, Charles, Willard, Huntington F.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.03.1999; University of Chicago Press
• Subjects: Adult; Aged; Alleles; Biological and medical sciences; Complex syndromes; Dosage Compensation, Genetic; Dystonia-deafness peptide ( DDP) gene; Female; Genetic Linkage; Genotype; Heterozygote; Humans; Lod Score; Medical genetics; Medical sciences; Middle Aged; Pedigree; Penetrance; Proteins - genetics; Receptors, Androgen - analysis; X activation; X Chromosome - genetics; X-linked mental retardation; X-linked mental retardation; Dystonia-deafness peptide ( DDP) gene; X activation; Sex linked character; Nervous system diseases; Linkage; Family study; Pathogenesis; Auditory disorder; Inactivation; Genetic determinism; Involuntary movement; Heterozygosity; Hearing loss; Striated muscle disease; Association; Gene penetrance; Genetics; ENT disease; Female; X-Chromosome; Dystonia; Mutation; Complex syndrome; Neurological disorder; Extrapyramidal syndrome
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/302286

X chromosome inactivation results in the random transcriptional silencing of one of the two X chromosomes early in female development. After random inactivation, certain deleterious X-linked mutations can create a selective disadvantage for cells in which the mutation is on the active X chromosome, leading to X inactivation patterns with the mutation on the inactive X chromosome in nearly 100% of the individual's cells. In contrast to the homogeneous patterns of complete skewed inactivation noted for many X-linked disorders, here we describe a family segregating a mutation in the dystonia-deafness peptide ( DDP) gene, in which female carriers show incompletely penetrant and variable X inactivation patterns in peripheral blood leukocytes, ranging between 50:50 and >95:5. To address the genetic basis for the unusual pattern of skewing in this family, we first mapped the locus responsible for the variable skewing to the proximal long arm (Xq12-q22) of the X chromosome ( Z=5.7, P=.002, LOD score 3.57), a region that includes both the DDP and the XIST genes. Examination of multiple cell types from women carrying a DDP mutation and of peripheral blood leukocytes from women from two unrelated families who carry different mutations in the DDP gene suggests that the skewed X inactivation is the result of selection against cells containing the mutant DDP gene on the active X chromosome, although skewing is apparently not as severe as that seen for many other deleterious X-linked mutations. Thus, DDP is an example of an X-linked gene for which mutations cause partial cell selection and thus incompletely skewed X inactivation in peripheral blood leukocytes.