This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. One of the topics supported by this grant has been a study of some human mutations in the CART gene. A leu34phe mutation results in early onset obesity in an Italian family and this mutation is therefore of interest. After constructing a cDNA for CART with the mutation, it was transfected into cells and the peptide products of the gene were studied. The non mutated cDNA was used as control. First we found that in some cell lines, the mutation resulted in a reduction in peptide expression. This provided cellular evidence that the mutation had a cellular effect on peptide levels. Next we showed that introduction of the mutation prevented normal processing and trafficking within the cells, resulting in a different peptide shunted to the constitutive pathway instead of the usual regulated pathway. These findings are important evidence that the CART gene is important for feeding and body weight in humans and that the mutation results in disrupted CART expression and trafficking.
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