Male CD81 knockout genotype disrupts Mendelian distribution of offspring

CD81 is an integral membrane protein in the tetraspanin superfamily that serves as an adaptor protein. CD81 is also a maternally imprinted gene that is found in a regulated cluster of genes on mouse chromosome 7. Among offspring produced from heterozygous breeding pairs, CD81(null/null) mice grew at the same rate as CD81(+/+) and CD81(+/null) mice. Because of an inhibition in sperm-egg fusion, CD81(null/null) female mice are much less fertile than CD81(+/+) and CD81(+/null) mice. However, no published study has detailed the effect of the male CD81 genotype on the genotype and sex distribution of offspring. We set up breeding pairs of heterozygotic (C.129-Cd81(tm1) N7) female mice and male mice with CD81(+/null), CD81(+/+), or CD81(null/null) genotypes. The survival and development of CD81(+/null), CD81(+/+), and CD81(null/null) offspring were monitored and compared. Compared with those of heterozygous male breeders, CD81(null/null) pups were born at a less-than-expected ratio from CD81(null/null) males. Sex distribution did not differ among pups sired by CD81(null/null) compared with CD81(+/null) mice. The data suggest that the effect of the CD81(null/null) paternal genotype on offspring is manifested early in development or in utero.