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Am J Physiol Cell Physiol 276: C788-C795, 1999;
0363-6143/99 $5.00
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Vol. 276, Issue 4, C788-C795, April 1999

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

Sheila M. Bell1, Claire M. Schreiner1, Patrick J. Schultheis2, Marian L. Miller3, Richard L. Evans4, Charles V. Vorhees1, Gary E. Shull2, and William J. Scott1

1 Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati 45229; 2 Department of Molecular Genetics, Biochemistry, and Microbiology and 3 Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; and 4 Center for Oral Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

In most cells, the ubiquitously expressed Na+/H+ exchanger isoform 1 (NHE1) is thought to be a primary regulator of pH homeostasis, cell volume regulation, and the proliferative response to growth factor stimulation. To study the function of NHE1 during embryogenesis when these cellular processes are very active, we targeted the Nhe1 gene by replacing the sequence encoding transmembrane domains 6 and 7 with the neomycin resistance gene. NHE activity assays on isolated acinar cells indicated that the targeted allele is functionally null. Although the absence of NHE1 is compatible with embryogenesis, Nhe1 homozygous mutants (-/-) exhibit a decreased rate of postnatal growth 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, around the eyes and chin, and on the ventral surface of the paws. Histological analysis of adult tissues revealed a thickening of the lamina propria and a slightly atrophic glandular mucosa in the stomach.

sodium/hydrogen exchanger; gene targeting; stomach; skin


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