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

Variability and complexity of phenotypes observed in microdeletion syn dromes can be due to deletion of a single gene whose product participa tes 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 s yndrome. The p(6H) deletion in mouse chromosome 7 presents a good mode l with which to address this question of multigene vs. single-gene ple iotropy. Mice homozygous for the p(6H) deletion are diluted in pigment ation, are smaller than their littermates, and manifest a nervous jerk -gait phenotype. Male homozygotes are sterile and exhibit profound abn ormalities in spermiogenesis, By using N-ethyl-N-nitrosourea (EtNU) mu tagenesis and a breeding protocol designed to recover recessive mutati ons expressed hemizygously opposite a large p-locus deletion, we have generated three noncomplementing mutations that map to the p(6H) delet ion, Each of these EtNU-induced mutations has adverse effects on the s ize, nervous behavior, and progression of spermiogenesis that characte rize P-6H deletion homozygotes. Because EtNU is thought to induce prim arily intragenic (point) mutations in mouse stem-cell spermatogonia, w e propose that the trio of phenotypes (runtiness, nervous jerky gait, and male sterility) expressed in p(6H) deletion homozygotes is the res ult of deletion of a single highly pleiotropic gene, We also predict t hat a homologous single locus, quite possibly tightly linked and dista l to the D15S12 (P) locus in human chromosome 15q11q13, may be associa ted with similar developmental abnormalities in humans.