International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

A21. Genetic Mapping and Characterization of an Autosomal Recessive Mouse Mutation Resulting in Skeletal Defects and Male Infertility

K.N.Bromfield1, I.J.Karolyi1, A.M.Wenglikowski 1, D.Dolan2, G.Dootz2, A.A.Finnegan3, L.D.Siracusa3, S.A. Camper
1Department of 1Human Genetics and 2Otolaryngology, University of Michigan Medical School, Ann Arbor, MI 48109-0618
3Department of Microbiology and Immunology, Kimmel Cancer Center, Jefferson Medical College, Philadelphia, PA 19107-5541.

A spontaneous mutation resulting in growth insufficiency appeared in the progeny of a female DBA.B6-Ahvy/a and her father, a DBA/2J male, at the N3 backcross generation. Further breeding demonstrated that the growth impairment was genetic and consistent with recessive inheritance. Mutant males are sterile, but mutant females are semi-fertile. There are no obvious neurological problems in the mutants but they exhibit hind leg clasping when held by the tail.

At birth mutants are the same size as their littermates, but the growth impairment is detectable by weaning. Both adult male and female mutants weigh approximately 75% of their normal littermates. Thyroid hormone levels are normal. Alcian blue and alizarin red staining reveals skeletal abnormalities in the mutant mice, including shortened skull, reduced vertebral bodies, flattened iliac crests, shortened fore and hind limbs, curvature of the spine and enlarged joints. The number of vertebrae and ribs is normal. These results suggest that the growth insufficiency is due to a developmental defect of bone or cartilage.

The mutant testis are only 25% the size of normal adult testis, although the seminal vesicles are normal. Histology reveals small seminiferous tubules, no evidence of sperm maturation, reductions in germ cells and Sertoli cells, and Leydig cell abnormalities.

The karyotype of mutants is normal. To determine the genetic map location of the mutant locus, mutant females were crossed to Mus castaneus and 100 F1 intercross progeny were collected. Although the growth insufficiency is less obvious among the intercross progeny, it is fully penetrant. In addition, all of the growth insufficient males are hypogonadal. Pools of DNA from either mutant mice or their normal littermates were composed, and a genome scan with polymorphic markers is in progress. Knowledge of the chromosomal location of the mutant gene may suggest evaluation of allelism with existing mouse mutations. Comparison of the mouse and human linkage maps may reveal a corresponding human skeletal dysplasia or infertility syndrome.

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