A non-functioning vitamin D receptor predisposes to leukaemoid reactions in mice

in Hematological Oncology (2010), 28(4), 185-191

The vitamin D hormone 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the biologically active form of vitamin D, is not only essential for mineral metabolism but may have important functions beyond calcium ... [more ▼]

The vitamin D hormone 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the biologically active form of vitamin D, is not only essential for mineral metabolism but may have important functions beyond calcium homoeostasis. By gene targeting, we have recently generated mice expressing a functionally inactive mutant vitamin D receptor (VDR). After a change in environmental conditions from specific pathogen free (SPF) conditions to a modified barrier system, a high percentage of aged mutant, but not wild-type, mice developed a haematological disorder characterized by splenomegaly, granulocytosis, thrombocytosis and dysplastic changes with displacement of erythropoiesis in bone marrow during the following months. All cases were associated with very high serum levels of the acute phase reaction protein serum amyloid A (SAA). Serological testing of affected mice revealed antibodies against murine hepatitis virus (MHV). However, electron microscopy of spleen and bone marrow cells did not reveal virus particles, and clinical signs of infectious diseases were absent. We hypothesize that a non-functioning VDR is associated with a latent defect in the regulation of myeloid cell differentiation and proliferation. Under the conditions of environmental stress, this latent defect may predispose to a deregulation of myelopoiesis in the form of a leukaemoid reaction accompanied by dysplastic changes. Thus, 1,25(OH)(2)D(3) may be an important inhibitory factor in the onset and progression of myeloproliferative and myelodysplastic diseases [less ▲]

Interaction between undulated and Patch leads to an extreme form of spina bifida in double-mutant mice.

in Nature Genetics (1995), 11(1), 60-3

The aetiology of spina bifida involves genetic and environmental factors, which may be why major genes contributing to pathogenesis have not been identified. Here we report that undulated-Patch double ... [more ▼]

The aetiology of spina bifida involves genetic and environmental factors, which may be why major genes contributing to pathogenesis have not been identified. Here we report that undulated-Patch double-mutant mice have a phenotype reminiscent of an extreme form of spina bifida occulta in humans. This unexpected phenotype in double-mutant but not single-mutant mice shows that novel congenital anomalies such as spina bifida can result from interaction between products of independently segregating loci. This example of digenic inheritance may explain the often sporadic nature of spina bifida in humans. [less ▲]