👤 Ramiro Hector Cerviño

Loss-of-function mutations in melanocortin-4 receptor (MC4R) are the most common cause of monogenic obesity, a severe type of early-onset obesity. Our aim was to determine the prevalence of MC4R mutations in a cohort of 97 Argentinian children with early-onset obesity. We found two novel mutations (p.V52E and p.G233S) and estimated a prevalence of 2.1%. We investigated the pathogenicity of mutations in HEK293T cells expressing wild-type or mutant MC4R and found that both mutants exhibited reduced plasma membrane expression and altered agonist-induced cAMP responses, with no changes in basal activity. Besides, MC4R G233S mutant demonstrated an altered agonist-dependent inhibition of voltage-gated calcium channels type 2.2. Results using a Gα Show less

Mammalian heterochromatin protein 1 (HP1) alpha, HP1beta and HP1gamma are closely related non-histone chromosomal proteins that function in gene silencing, presumably by organizing higher order chromatin structures. Here, we show by co-immunoprecipitation that HP1alpha, but neither HP1beta nor HP1gamma, forms a complex with the BRG1 chromatin-remodeling factor in HeLa cells. In vitro, BRG1 interacts directly and preferentially with HP1alpha. The region conferring this preferential binding has been mapped to residues 106-180 of the HP1alpha C-terminal chromoshadow domain. Using site-directed mutagenesis, we have identified three amino acid residues I113, A114 and C133 in HP1alpha (K, P and S in HP1beta and HP1gamma) that are essential for the selective interaction of HP1alpha with BRG1. Interestingly, these residues were also shown to be critical for the silencing activity of HP1alpha. Taken together, these results demonstrate that mammalian HP1 proteins are biochemically distinct and suggest an entirely novel function for BRG1 in modulating HP1alpha-containing heterochromatic structures. Show less