PLEIOTROPY IN MICRODELETION SYNDROMES - NEUROLOGIC AND SPERMATOGENIC ABNORMALITIES IN MICE HOMOZYGOUS FOR THE P(6H) DELETION ARE LIKELY DUE TO DYSFUNCTION OF A SINGLE-GENE

Variability and complexity of phenotypes observed in microdeletion syndromes can be due to deletion of a single gene whose product participates in several aspects of development or can be due to the deletion of a number of tightly linked genes, each adding its own effect to the syndrome. The p(6H) deletion in mouse chromosome 7 presents a good model with which to address this question of multigene vs. single-gene pleiotropy. Mice homozygous for the p(6H) deletion are diluted in pigmentation, are smaller than their littermates, and manifest a nervous jerk-gait phenotype. Male homozygotes are sterile and exhibit profound abnormalities in spermiogenesis, By using N-ethyl-N-nitrosourea (EtNU) mutagenesis and a breeding protocol designed to recover recessive mutations expressed hemizygously opposite a large p-locus deletion, we have generated three noncomplementing mutations that map to the p(6H) deletion, Each of these EtNU-induced mutations has adverse effects on the size, nervous behavior, and progression of spermiogenesis that characterize P-6H deletion homozygotes. Because EtNU is thought to induce primarily intragenic (point) mutations in mouse stem-cell spermatogonia, we propose that the trio of phenotypes (runtiness, nervous jerky gait, and male sterility) expressed in p(6H) deletion homozygotes is the result of deletion of a single highly pleiotropic gene, We also predict that a homologous single locus, quite possibly tightly linked and distal to the D15S12 (P) locus in human chromosome 15q11q13, may be associated with similar developmental abnormalities in humans.