International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

I12 Gaping Lids, A Recessive Mutation Causing Nonsyndromic Open-Eyelids-at-Birth, Maps to Centromeric Mouse Chromosome 11

Muriel J. Harris, Kathleen G. Banks, Diana M. Juriloff. Department of Medical Genetics, University of British Columbia, Vancouver, B.C., Canada

Open-eyelids-at-birth can occur as an isolated, nonsyndromic birth defect in mice. We study the etiology of the open-eyelids defect as a model of genetically complex developmental threshold traits. As one strategy to discover the genes involved in nonsyndromic open-eyelids with multigenic cause (such as lidgap-Stein and lidgap-Miller), we are mapping the nonsyndromic open-eyelids with single locus cause (such as gaping lids, gp) as potential candidate loci for involvement in the genetically more complex etiologies.

Gaping lids, gp, is a spontaneous recessive mutation that occurred in 1961 on the C57BL/6-ax strain in the laboratory of Diane Kelton at the University of Massachusetts. It was imported to UBC in 1971, was outcrossed to SM/Ml, made homozygous, and inbred to form the GP/Bc strain (F60) with 100% open-eyelids-at-birth. It has not previously been mapped. After outcrosses of GP/Bc to normal strains, segregation in the BC1 and F2 generations supports single autosomal recessive gene inheritance of gp (with modifiers of penetrance): 0% open-eyelids (0/43) in F1, 19% (47/249) in F2, 50% (67/135) in BC1 after the cross to CBA/J; 0% (0/32) in F1, 11% (31/282) in F2 after the cross to ICR/Bc. As is common in mutants with open-eyelids-at-birth, the adult eyes of gp homozygotes show signs of apparent damage, including opaque corneas. The fetal defect is a failure of the eyelids to grow across the eye and fuse on days 15 and 16 of gestation. There are no other gross morphological defects. Homozygotes are viable and fertile.

We had previously excluded linkage with approximately 30% of the genome, using isozyme and phenotypic loci as linkage markers. In this study, we tested for linkage with three candidate regions containing known open-eyelid mutations: lgGa on distal Chr 13, wa1 (Tgfa) on mid Chr 6, and wa2 (Egfr) on proximal Chr 11, using informative SSLPs in the F2 generation after an outcross between GP/Bc (gp/gp) and CBA/J. We found linkage to SSLPs on proximal Chr 11, with gp mapping centromeric to D11Mit62 and D11Mit226 (3/40 recombinants among open-eyelid F2 newborns). To refine the map position, we made a second cross, between GP/Bc and ICR/Bc. Among 23 open-eyelid F2 newborns, we found one recombinant between gp and D11Mit71 (at 1.1 cM from the centromere in MGD), and no recombinants between gp and the more centromeric markers, D11Mit74 (at 0 cM), D11Mit72 or D11Mcg1 (at 0.25 cM).

As we had looked for gp on proximal Chr 11 because of the candidacy of Egfr, we tested for allelism between gp and Egfr- (the Egfr-null allele from D.Threadgill). We found that gp and Egfr-null complemented each other completely. All 15 newborn compound heterozygotes had normal, fused-closed, eyelids. They also, like gp/gp, had normal straight vibrissae, whereas the vibrissae in Egfr mutants (wa2/wa2) are curled. We also mapped Egfr against some of the same SSLPs that we used to map gp, and found that gp maps proximal and Egfr maps distal to D11Mit62 and D11Mit226. In sum, gp appears not to be a mutation at the Egfr locus, but at an unidentified locus in the approximately 1 cM region between D11Mit71 and the centromere of Chr 11.

(Research funded by the Medical Research Council of Canada.)

 


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