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We identified a childhood obesity locus on chromosome 6q16.3-q24.2 1 that includes 2.4 Mb common to eight genome scans for Type 2 diabetes (T2D) or obesity 1-8 . Analysis of the ENPP1 (PC-1) gene, a candidate for insulin resistance 9,10 in 6,147 subjects revealed association between a three allele risk haplotype (K121Q/IVS20 delT-11/A>G +1044 TGA, QdelTG) and childhood obesity (OR=1.69, p=0.0006), and in adults with morbid or moderate obesity (OR= 1.50, p= 0.006, OR= 1.37, p= 0.02) and also with T2D (OR=1.56, p=0.00002). The Genotype IBD Sharing Test suggested a contribution of this obesity-associated ENPP1 risk haplotype to the observed chromosome 6q linkage with childhood obesity. The haplotype confers a higher risk of glucose intolerance and T2D to obese children and to their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesityassociated A>G +1044 TGA SNP, was found to be specific for pancreatic islet beta-cells, adipocytes and liver. These findings suggest a primary role for several variants of ENPP1 in mediating insulinresistance, in the development of both obesity and type 2 diabetes, suggesting an underlying molecular mechanism common to both widespread afflictions. Competing interests statementThe authors declare that they have no competing financial interests. NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2007 October 4. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptInitially, the phenotypic characteristics of 62 "6q-evidence" families (defined by an individual pedigree Zscore > 1.0 in the 2-LOD drop interval flanked by markers D6S434 and D6S1704) were compared with the remaining 35 families from our previously published genome scan for childhood obesity 1 . The "6q-evidence" obese children have a trend towards higher area under the glycemia curve after glucose administration and a significantly lower insulinogenic index (Supplementary Table 1). Compared to none of the other families, 3.1% of the "6q-evidence" obese children are glucose intolerant or diabetic and 13.8% of 6q linked obese children parents have type 2 diabetes mellitus (T2D) compared to 3.2% of parents in other families (p=0.018). Thus, the obesity susceptibility gene(s) on chromosome 6q may be also involved in glucose homeostasis.The "6q-evidence" 2-LOD drop interval 1 covers 41.4 Mb and includes 166 referenced genes. This was narrowed to a 2.4 Mb interval between markers D6S1656 and D6S270 using overlapping published linkage results on chromosome 6q16.1-q27 with either obesity 2 , insulin secretion 3,4 or T2D 5-8 . Within this interval, the best candidate was ectonucleotide pyrophosphatase phosphodiesterase ENPP1 (also known as the Plasma Cell glycoprotein-1 PC-1). ENPP1 is believed to directly inhibit insulin-induced conformational changes of the insulin receptor, thereby affecting its activation and downstream signaling 9,11 .The microsatellite marker D6S1656 in...

ObjectivePro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1–5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency.MethodsWe studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial. We annotated the functional status of 369 published MC4R variants.ResultsIn cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants. Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond. In a 28-day Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers. Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls.ConclusionsSetmelanotide led to weight loss in obese people with MC4R deficiency; however, further studies are justified to establish whether Setmelanotide can elicit clinically meaningful weight loss in a subset of the MC4R deficient obese population.

The melanocortin-4 receptor (MC4R) gene pathogenic mutations are the most prevalent forms of monogenic obesity, responsible for approximately 2% of obesity cases, but its role in common obesity is still elusive. We analyzed the contribution of non-synonymous mutations V103I (rs2229616, c.307G > A) and I251L (no rs, c.751A > C) to obesity in 16 797 individuals of European origin from nine independent case-control, population-based and familial cohorts. We observed a consistent negative association of I251L variant (prevalence ranging 0.41-1.21%) with both childhood and adult class III obesity [odds ratio (OR) ranging from 0.25 to 0.76, 0.001 < P-value < 0.05] and with modulation of body mass index (BMI) in general populations, in eight out of nine studies, whereas only one study showed an association between V103I and BMI. Meta-analyses of previous published data with the current ones provided strong evidence of the protective effect of I251L toward obesity (OR = 0.52, P = 3.58 10-5), together with a modest negative association between V103I and obesity (OR = 0.80, P = 0.002). Taken together, gain-of-function mutations I251L and V103I may be responsible for a preventive fraction of obesity of 2%, which mirrors the prevalence of monogenic obesity due to MC4R haploinsufficiency. These results also emphasize the importance of the MC4R signalling tonus to prevent obesity, even in the context of our current obesogenic environment.

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Congenital tufting enteropathy (CTE) is a rare and severe enteropathy recently ascribed to mutations in the epcam gene. Here we establish SPINT2, previously ascribed to congenital sodium diarrhea, as a second gene associated with CTE and report molecular and immunohistochemistry data in 57 CTE patients. Inclusion criteria were early onset diarrhea and intestinal insufficiency with the typical histological CTE abnormalities. The clinical phenotype was registered, the entire coding regions of epcam and SPINT2 sequenced, and immunostaining of EpCAM and SPINT2 performed on intestinal biopsies. An epcam mutation was involved in 41 patients (73 %) who mainly displayed isolated digestive symptoms. Mutations severely affected gene expression since the EpCAM signal on intestinal tissues was either undetectable or low and irregular. Twelve other patients (21 %) carried mutations in SPINT2, and were phenotypically characterized by systematic association with keratitis (p < 10(-4)) and, for half of them, with choanal atresia (p < 10(-4)). Dependency on parenteral nutrition (PN) was comparable in patients with epcam or SPINT2 mutations, but the frequent epcam mutation c.556-14A>G (abnormal splicing) was significantly associated with a better outcome (p = 0.032) with milder PN dependency to weaning in some cases. Finally, four patients (7 %) with isolated digestive symptoms had no detectable epcam or SPINT2 mutation. Two candidate genes, Elf3 and Claudin7, were excluded from this population. Our study allows us to separate CTE patients into at least three genetic classes, each with specific phenotypes. The genetics approach raises the question of the distinction between two congenital enteropathies. Our findings should help improve the diagnosis of CTE, guide toward strategies of long-term PN management, and limit indications for intestinal transplantation to life-threatening PN complications.

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