International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

A19. Anomaly of External Genitalia - A Mouse Model for Hypospadias in Humans

Hideki Katoh1 2, Kaori Muguruma2, Mich Ebukuro2, Yuka Watanabe2
1Hamamatsu Univeristy School of Medicine, Hamamatsu, Japan
2Central Institute for Experimental Animals, Kawasaki, Japan

We found mice with an anomaly of the external genitalia in the AQ strain (tentatively named) derived from a cross of BALB/cA and an inbred strain originated from a ICR closed colony. In this paper, the results of a morphological study, growth and reproduction, genetic crosses carried out to reveal the cause and inheritance of the anomaly and mapping of the gene by genetic crosses are described.

Morphological study: External genital areas of normal and abnormal mice in both sexes were observed in detail. Abnormal mice were characterized as follows: (1) a significantly short distance between penis (or clitoris) and anus in both sexes with the anomaly, (2) a severe opening of scrotal and vaginal areas along the midline, and (3) a significantly small glans penis and glans clitoris. The anomaly in both sexes was developmentally caused by hypoplasia in the genital area, because these characteristics were observed in the new born mice at birth. This trait was very similar to hypospadias in humans based on some references. Therefore, gene name and gene symbol were registered as hypospadias and hys, respectively.

Growth and Reproduction: Mice with the anomaly were completely sterile in males and showed very poor reproduction in females when natural mating with normal mice was carried out. Sperm was normal in activity and number. Development of testis and ovary was morphologically normal.

Genetic crosses: Since this anomaly was thought to be governed by recessive gene(s) according to the family records, mating experiments were carried out using in vitro fertilization. Incrosses of abnormal AQ males and AQ females produced abnormal mice (homozygotes) and crosses of abnormal AQ males and normal C57BL/6 females produced only normal mice (F1 hybrids=heterozygotes). In F2 obtained by mating between F1 females and F1 males, normal and abnormal mice were segregated at a ratio of about 6:1. These results showed that the anomaly is governed by an autosomal recessive gene.

Mapping of the hys gene: Mapping studies of the hypospadias (hys) gene using F2 and BC mice revealed that the hys gene was mapped on Chr 1 and a gene order was centromere-//-D1Mit7-5cM-D1Mit83-9cM-hys-5cM-D1Mit187-2cM-D1Mit90.

In conclusion, it was strongly suggested that the anomaly of external genitalia observed in the AQ strain could be the same as hypospadias reported in human and might be a novel model for comparative medicine in man and animals.

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