A proposal is made for the training of a pediatric geneticist in molecular genetics. This project will provide the candidate with the resources and support necessary to develop the technical and investigative skills to pursue a productive, independent research career in human molecular genetics. The quality and expertise of the involved faculty ensure a supportive, stimulating scientific environment, providing an excellent opportunity for clinical scientist training. The research proposed is the positional cloning and analysis of a human genetic locus necessary for neuroectodermal development, fetal viability, and responsible for congenital birth defects. Incontinentia pigmenti (IP) is an X-linked dominant, male hemizygote lethal disorder characterized by specific diagnostic congenital anomalies of the neural crest derivatives in the skin, central nervous system, and eye. A constructed YAC and cosmid contig maps two IP1 disease-specific X;autosomal translocation breakpoints to a 120 kb interval within Xp11.21. Cosmid 3B2 crosses the X;9 translocation breakpoint and cosmid 4H2 crosses the X;l3 translocation breakpoint. FISH analysis shows that the translocations are reciprocal and not associated with discernible deletions. These findings suggest that these de novo X;autosome translocations disrupt a single genetic locus thus causing the IP phenotype. A potential IP1 mouse model, the lined (Li ) mutation, maps to the homologous region of the mouse X chromosome.
The specific aims of the proposal include the isolation and characterization of the IP1 cDNA; the demonstration that it is disrupted by IP1 X;autosome translocations and the characterization of disease- specific mutations in additional IP1 females. The sequence and genomic organization of the IP1 gene will be determined and the mouse homologue will be isolated. RNA in situ hybridization and immunocytochemical analyses will be performed to elucidate the temporal and spatial pattern of expression of the IP1 gene during embryogenesis. These studies will provide a means to characterize, clone, and authenticate a genetic locus involved in neural crest differentiation and responsible for fetal death and congenital birth defects.
| McDonald, M T; Flejter, W; Sheldon, S et al. (1997) XY sex reversal and gonadal dysgenesis due to 9p24 monosomy. Am J Med Genet 73:321-6 |
