Father-to-daughter transmission of focal dermal hypoplasia associated with nonrandom X-inactivation: support for X-linked inheritance and paternal X chromosome mosaicism.
Focal dermal hypoplasia (FDH) is a rare syndrome of severe developmental anomalies of the tissues and organs derived from ectoderm and mesoderm. Though data have suggested that FDH is an X-linked dominant trait associated with male hemizygote lethality, a hypothesis supported by the observation of three unrelated infants with FDH manifestations and de novo chromosome rearrangements involving Xp22, observations of father-to-daughter transmission have suggested possible genetic heterogeneity and autosomal dominant inheritance with sex limitation. We hypothesize that, if FDH is an X-linked disorder, cells expressing an active disease locus might experience a selective disadvantage resulting in a nonrandom pattern of X-inactivation in patient tissue. To test this hypothesis, we studied one of the two previously described families demonstrating father-to-daughter inheritance of FDH. To determine if the affected daughter had a skewed pattern of X-inactivation consistent with X-linked inheritance of FDH, somatic cell hybrids were constructed by fusing hypoxanthine phosphoribosyl transferase (HPRT)-deficient rodent fibroblasts with either patient dermal fibroblasts or peripheral white blood cells (WBCs); hybrid clones retaining an active X chromosome were analyzed to determine the parental origin of the active X chromosome. Analyses of resulting hybrid clones showed that while hybrids constructed from skin fibroblasts contained an active X chromosome inherited from either of the patient's parents, hybrids constructed from WBCs showed a skewed pattern of X-inactivation; 11 of 11 hybrids contained an active maternal X chromosome (chi 2 = 12.2, P = .001).(ABSTRACT TRUNCATED AT 250 WORDS)
Gorski
J L
JL
Department of Pediatrics, University of Michigan Medical Center, Ann Arbor 48109-0688.
D000328:Adult; D002478:Cells, Cultured; D004247:DNA; D004303:Dosage Compensation, Genetic; D005260:Female; D005489:Focal Dermal Hypoplasia / Q000235:genetics*; D005799:Genes, Dominant; D008040:Genetic Linkage; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D010290:Parents; D012867:Skin / Q000473:pathology; D014960:X Chromosome
D004247:DNA