No abstract

Red hair in humans is associated with variant alleles of the alphaMSH receptor gene, MC1R. Loss of MC1R function in other mammals results in red or yellow hair pigmentation. We show that a mouse bacterial artificial chromosome (BAC) which contains Mc1r will efficiently rescue loss of Mc1r in transgenic mice, and that overexpression of the receptor suppresses the effect of the endogenous antagonist, agouti protein. We engineered the BAC to replace the mouse coding region with the human MC1R sequence and used this in the transgenic assay. The human receptor also efficiently rescued Mc1r deficiency, and in addition, appeared to be completely resistant to the effects of agouti, suggesting agouti protein may not play a role in human pigmentary variation. Three human variant alleles account for 60% of all cases of red hair. We engineered each of these in turn into the BAC and find that they have reduced, but not completely absent, function in transgenic mice. Comparison of the phenotypes of alphaMSH-deficient mice and humans in conjunction with this data suggests that red hair may not be the null phenotype of MC1R.

Two hundred and nineteen cases of Ph+ve CML and 15 Ph-ve, BCR+ve CML cases have been analysed to determine the breakpoint site and its relationship to clinical features, cytogenetic response, duration of chronic phase and survival. 119 cases have had RNA analysis performed to determine the type of BCR/ABL transcript and have also been analysed in a similar way. Presenting features at diagnosis including age, sex, white-cell count and platelet count showed no significant difference for those with 5' and 3' breakpoints and those with either b2a2 or b3a2 BCR/ABL transcripts. However, in a subgroup of patients whose presenting white-cell count was < 100 x 10(9)/l, those with b3a2 transcript did have a significantly higher platelet count. Analysis by Sokal risk grouping showed no difference for 5' or 3' breakpoints but a trend for lower stage among those with b2a2 transcripts. No correlation was found either for genomic breakpoint site or BCR/ABL RNA transcript in terms of duration of chronic phase or survival. When stratified by randomized therapy, either interferon-alpha or standard chemotherapy, no difference was noted in relation to genomic breakpoint site or BCR/ABL transcript. Cytogenetic response was not related to the molecular findings.

Cer1 is the mouse homologue of the Xenopus Cerberus gene whose product is able to induce development of head structures during embryonic development. The Cer1 protein is a member of the cysteine knot superfamily and is expressed in anterior regions of the mouse gastrula. A segmental pattern of expression with nascent and newly formed somites is also seen. This suggests an additional role in development of the axial skeleton, musculature, or peripheral nervous system. Xenopus animal cap assays and mouse germ-layer explant recombination experiments indicate that the mouse protein can act as a patterning molecule for anterior development in Xenopus, including induction of Otx2 expression, and suggest it may have a similar role in mouse development. However, we present here genetic data that demonstrate that Cer1 is not necessary for anterior patterning, Otx2 expression, somite formation, or even normal mouse morphogenesis.