Motheaten mice and the protein tyrosine phosphatase gene

Mice homozygous for the recessive allele 'motheaten' [me), and its milder variant 'viable motheaten' (mev) express multiple hematopoietic and immunologic abnormalities, including developmental or functional defects in macrophages, granulocytes, T cells, B cells and natural killer (NK) cells. These mice develop systemic autoimmunity with hypergammaglobulinemia and antinuclear autoantibodies, and the majority of B cells are of the B1 type (Ly-1 + ). The me mutation was initially mapped to the distal end of chromosome 6. Subsequent linkage analysis positioned the me locus at the same site on chromosome 6 to which the protein tyrosine phosphatase 1C (PTP1C) gene (hematopoietic cell protein tyrosine phosphatase (Hcph) gene) had been previously mapped. Cloning and sequencing of the PTP1C gene from me" mice revealed two types of transcripts that differed from the wild-type catalytic domain by a 15 bp in-frame deletion or a 69 bp in-frame insertion. In contrast, the PTP1C catalytic domains from me and wild-type mice were identical in sequence. On the other hand, the majority of me PTP1C transcripts have a 101 bp frameshift deletion within the signal transducing SH2 (src homology 2) domain. There is also a second, minor transcript that instead has a single C nucleotide deletion in the SH2 domain. In contrast, no abnormalities were detected in the SH2 domain of the mev PTP1C transcripts. These transcript changes, the result of single-point mutations and modification in the splicing process, lead to absence of PTP1C expression in the more clinically-severe me mutation (but not the less severe mev mutation) and reduced catalytic activity in both mutations. How these hematopoiesis-affecting PTP1C mutations lead to autoantibody production is not clear. Recently, however, PTP1C was found to associate with FcyRIIBl and CD22 and to inhibit B cell receptor (BCR) signaling. Thus, the lack of PTP1C could, upon BCR engagement, result in the uninhibited activation of Lyn and Syk kinases. B cell activation would be promoted, resulting in hypergammaglobulinemia and apoptosis primarily of B1 cells (Ly-I ) because of the normally poor response of B1 cells to BCR signaling.

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