The mouse continues to play a vital role in the deciphering of mammalian gene function and the modelling of human neurological disease. Advances in gene targeting technologies have facilitated the efficiency of generating new mouse mutants, although this valuable resource has rapidly expanded in recent years due to a number of major random mutagenesis programmes. The phenotype-driven mutagenesi...

Hemojuvelin (HJV) positively modulates the iron regulator hepcidin, and its mutations are the major cause of juvenile hemochromatosis (JH), a recessive disease leading to iron overload. Defective HJV reduces hepcidin up-regulation both in humans and in Hjv-deficient mice. To investigate the JH pathogenesis and the functional properties of human HJV we studied the biosynthesis and maturation of ...

Prion protein (PrP) inhibits the activation of proapoptotic Bax in primary human neurons and MCF-7 cells. Because neuronal apoptosis occurs in human prion diseases, here we examine the anti-Bax function of familial PrP mutants. All Creutzfeldt-Jakob disease and fatal familial insomnia-associated prion protein mutations partially or completely lose the anti-Bax function in human neurons and, exc...

Pax6 and Gli3 are dorsally expressed genes that are known to antagonize sonic hedgehog (Shh) activity. We have previously shown that dorsoventral patterning defects seen in Shh(-/-) mutants are rescued in Shh(-/-);Gli3(-/-) compound mutants. Here we investigate if the loss of Pax6 can also ameliorate defects seen in Shh(-/-) mutants. In support of this notion, we observe that the fusion of the ...

Hemojuvelin (HJV) positively modulates the iron regulator hepcidin, and its mutations are the major cause of juvenile hemochromatosis (JH), a recessive disease leading to iron overload. Defective HJV reduces hepcidin up-regulation both in humans and in Hjv-deficient mice. To investigate the JH pathogenesis and the functional properties of human HJV we studied the biosynthesis and maturation of ...

Two inherent challenges in the mechanistic interpretation of protease-deficient phenotypes are defining specific substrate cleavages whose reduction generates and determining whether result from loss function, accumulation, or a function(s) embodied fragments. Hence, recapitulation phenotype by cleavage-resistant would stringently validate importance proteolytic event clarify underlying mechani...

Analysis of genetic mutations is one of the most effective ways to investigate gene function. We now have methods that allow for mass production of mutant lines and cells in a variety of model species. Recently, large numbers of mutant lines have been generated by both 'loss-of-function' and 'gain-of-function' techniques. In parallel, phenotypic information covering various mutant resources has...