Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures

In most cells, the ubiquitously expressed Na+/H+ exchanger isoform 1 (NHE1) is thought to be a primary regulator of pH homeostasis, cell volume regula tion, and the proliferative response to growth factor stimulation. To study the function of NHE1 during embryogenesis when these cellular processes ar e very active, we targeted the Nhe1 gene by replacing the sequence encoding transmembrane domains 6 and 7 with the neomycin resistance gene. NHE activ ity assays on isolated acinar cells indicated that the targeted allele is f unctionally null. Although the absence of NHE1 is compatible with embryogen esis, Nhe1 homozygous mutants (-/-) exhibit a decreased rate of postnatal g rowth that is first evident at 2 wk of age. At this time, Nhe1 -/- animals also begin to exhibit ataxia and epileptic-like seizures. Approximately 67% of the -/- mutants die before weaning. Postmortem examinations frequently revealed an accumulation of a waxy particulate material inside the ears, ar ound the eyes and chin, and on the ventral surface of the paws. Histologica l analysis of adult tissues revealed a thickening of the lamina propria and a slightly atrophic glandular mucosa in the stomach.