MUTATIONS AT THE MURINE MOTH-EATEN LOCUS ARE WITHIN THE HEMATOPOIETIC-CELL PROTEIN-TYROSINE-PHOSPHATASE (HCPH) GENE

Mice homozygous for the recessive allelic mutation motheaten (me) or v iable motheaten (me(v)) on chromosome 6 develop severe defects in hema topoiesis. In this paper we present the findings that the me and me(v) mutations are within the hematopoietic cell protein-tyrosine phosphat ase (Hcph) gene. High resolution mapping localized me to an area tight ly linked to Hcph on chromosome 6. Abnormalities of the Hcph protein p roduct were demonstrated by Western blot analysis and by activity assa ys in both me/me and me(v)/me(v) mice. Molecular analysis of the Hcph cDNA identified abnormal transcripts in both mutants. DNA sequence ana lyses of cDNA and genomic clones revealed that both the me and me(v) m utations are point mutations that result in aberrant splicing of the H cph transcript. These findings provide the first available animal mode ls for a specific protein-tyrosine phosphatase deficiency, thus facili tating determination of the precise role of this signaling molecule in hematopoiesis.