Molecular analysis of 36 mutations at the mouse pink-eyed dilution (p) locus.

Abstract

Thirty-six radiation- or chemically induced homozygous-lethal mutations at the p locus in mouse chromosome 7 have been analyzed at 17 loci defined by molecular probes to determine the types of lesions, numbers of p-region markers deleted or rearranged, regions of overlap of deletion mutations, and genetic distances between loci. A linear deletion map of the [Myod1, Ldh3]-[Snrpn, Znf127] region has been constructed from the molecular analyses of the p-locus deletions. The utility of these deletions as tools for the isolation and characterization of the genes specifying the neurological, reproductive, and developmental phenotypes genetically mapped to this region will grow as more detailed molecular analyses continue.

Complementation analyses for 45 mutations encompassing the pink-eyed dilution (p) locus of the mouse.

“…For 35 of the mutations listed in Table 1, kidney and liver homogenates of heterozygotes were tested for LDH (lactate dehydrogenase) activity; only one mutation, p461"20n, exhibited reduced activity (MENDEL 1987). Similar results were obtained for 30 plethal mutations tested with a probe for Ldhl; again p46nF'" was the only mutation in which this locus was found to be deleted (JOHNSON 1990;JOHNSON et al 1995). Analyses of offspring of a cross to M. spretus indicated that the serum amyloid A (Sua) gene complex is also missing in p46DF'"f' (MENDEL 1987;JOHNSON et al 1995), whereas sequences corre-tations, p46lWiOLl…”

“…Similar results were obtained for 30 plethal mutations tested with a probe for Ldhl; again p46nF'" was the only mutation in which this locus was found to be deleted (JOHNSON 1990;JOHNSON et al 1995). Analyses of offspring of a cross to M. spretus indicated that the serum amyloid A (Sua) gene complex is also missing in p46DF'"f' (MENDEL 1987;JOHNSON et al 1995), whereas sequences corre-tations, p46lWiOLl…”

“…ENU-induced point mutations mapping to this region indicate that the complex phenotype (which also includes male sterility) can result from deletion of a single highly pleiotropic gene (RNCHIK et al 1995) Because pWFt0", a preimplantation lethal, fully complements all other plocus lethals, the pl-2 unit is not associated with the plocus region. This mutation has also been found not to be deleted for any pregion probes (JOHNSON et al 1995). Our finding that p""" is an inversion leads us to conclude that the lethal is associated with the distal breakpoint, and results of genetic tests strongly suggest that this breakpoint lies within the cdeletion complex.…”

“…Complementation map: Only one of the mutations, 1993NICHOLLS et aZ. 1993;JOHNSON et al 1995). Because p4'H"", a neonatally lethal mutation, fully complements (except for the pigment phenotype) a large number of prenatally lethal mutations, pl and nl functional units can be localized on opposite sides of p. The functional units pl-1 and nl must lie proximal and distal to p, respectively, because 1s among the prenatally lethal mutations that are complemented by p"' "".…”

Hypopigmentation in the Prader-Willi syndrome correlates withP gene deletion but not with haplotype of the hemizygousP allele

“…1), large enough to include several undiscovered genes. Arguing against this explanation, however, several large deletions that include the p gene do not result in hypopigmentation in heterozygous mice [Johnson et al, 1995]; thus, a putative unknown pigmentation gene would have to have been introduced into this region in the human lineage subsequent to the mammalian radiation. Third, and we believe most likely, hypopigmentation in PWS and AS may result from reduced expression of the intact P allele in the specific context of large proximal 15q deletions.…”