Selection against mutant alleles in blood leukocytes is a consistent feature in Incontinentia Pigmenti type 2.
Incontinentia Pigmenti 2 (IP2) is an X-linked dominant disorder with male lethality. Affected females display a characteristic skin eruption that evolves through four classic stages, frequently accompanied by dental and retinal abnormalities. Non-random (skewed) X-inactivation in peripheral blood leukocytes and in fibroblasts has been observed in females with IP2; however, sample sizes have been small and methods of analysis varied. We have examined X-inactivation in a large group of multigenerational IP2 families, in smaller families, and in isolated cases. Ninety-eight percent of affected females in multigenerational IP2 pedigrees show completely skewed patterns of X-inactivation, while only approximately 10% of a normal control population is skewed. Results both in small families and in new mutation cases with subsequent segregation consistent with Xq28 linkage are similar. Isolated cases show a lower percentage (85%) of skewed affected individuals; this difference may be due to inaccurate clinical ascertainment. The parent of origin of new mutations could be determined in 15 families; paternal new mutations were twice as common as maternal. Fibroblast subclones from a biopsy at the boundary of a skin lesion in a newborn IP2 patient were isolated, and clones with either one or the other X active were identified, demonstrating that cells with the active disease-bearing X chromosome are still present in stage I skin lesions.
Parrish
J E
JE
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Scheuerle
A E
AE
Lewis
R A
RA
Levy
M L
ML
Nelson
D L
DL
D000328:Adult; D000483:Alleles; D002460:Cell Line; D004303:Dosage Compensation, Genetic; D005260:Female; D005347:Fibroblasts; D008040:Genetic Linkage; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics; D006801:Humans; D007184:Incontinentia Pigmenti / Q000235:genetics*; D007231:Infant, Newborn; D008214:Lymphocytes; D008297:Male; D009154:Mutation; D010375:Pedigree; D012867:Skin / Q000166:cytology; D014960:X Chromosome / Q000235:genetics
D005954:Glucosephosphate Dehydrogenase