Masters Theses

Date of Award

12-2005

Degree Type

Thesis

Degree Name

Master of Science

Major

Life Sciences

Major Professor

Edward J. Michaud

Committee Members

Dabney Johnson, Bruce D. McKee, Brynn Voy, Carla Sommardahl

Abstract

Single-gene mutations in the mouse serve as useful models for understanding the pathophysiology and molecular mechanisms of human diseases. Three dominant autosomal mutations affecting skin, hair and eye development in the mouse were recovered in mutagenesis experiments at the Oak Ridge National Laboratory. Previous work demonstrated that these mutations constitute an allelic series at the mouse Furloss (Frl) locus, and they were given the symbols Frla, Frlb and Frlc. The heterozygous phenotypes of all three mutants are similar; the mice appear normal at birth but gradually lose their hair until the hair follicles and sebaceous glands are completely absent. Mice also develop corneal opacities at about six months of age. Homozygous mice exhibit the same skin, hair and eye abnormalities, but Frla and Frlb homozygotes have reduced viability. The phenotype of Frl mice closely resembles seven other dominant mouse mutations (Bareskin, Bsk; Rex denuded, Reden; Recombination-induced mutation 3, Rim3; Defolliculated, Dfl; Reduced Coat 2, Rco2; Finnegan, Fgn; and Hairloss), which all map to the distal portion of chromosome 11. Genetic linkage analysis with Frl and Rex (Re) demonstrated that Frl also maps to this same region. Recent work by others demonstrated that Rim3 mice have a mutation in the Gasdermin 3 (Gsdm3) gene. Due to the striking similarity of phenotypes between Rim3 mice and Frl mice, as well as the Frl mapping data, the Gsdm3 gene was sequenced in the Frl mice, and through collaboration, in Bsk mice. The mutations for all three Frl alleles were identified in exon 12, and the mutation for Bsk was identified in exon 10, of Gsdm3. In addition to Rim3, Frla, Frlb, Frlc and Bsk, other groups have recently determined that Bsk, Reden, Rco2, Dfl, Fgn and Hairloss (unpublished) are all the result of mutations in Gdm3, bringing the allelic series of unique mouse mutations in the Gasdermin 3 gene to nine. Histological analysis revealed acanthosis, hyperkeratosis and hypergranulosis in the epidermis of the skin and the cornea of the eye. In addition, it also showed a prolonged catagen stage, which resulted in abnormally long hair follicles during the next anagen stage, and the eventual complete destruction of hair follicles. Gsdm3 does not have an ortholog in humans or rats, and is believed to be the result of a unique duplication event of Gasdermin1 in the genus Mus. The Furloss mice will serve as useful models for studying related sebaceous gland defects and scarring alopecia in humans. The allelic series of nine mutations in Gsdm3 will be valuable for studying the structure and function of the Gsdm3 protein.

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