Evidence that mutations in the X-linked DDP gene cause incompletely penetrant and variable skewed X inactivation.
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.
1Department of Genetics, Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland; OH 44106-4955, USA.
R M
RM
Plenge
L
L
Tranebjaerg
P K
PK
Jensen
C
C
Schwartz
H F
HF
Willard
D000328:Adult; D000368:Aged; D000483:Alleles; D004303:Dosage Compensation, Genetic; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008126:Lod Score; D008875:Middle Aged; D010375:Pedigree; D019683:Penetrance; D011506:Proteins / Q000235:genetics*; D011944:Receptors, Androgen / Q000032:analysis; D014960:X Chromosome / Q000235:genetics
D011506:Proteins; D011944:Receptors, Androgen