Carboxyl-ester lipase is a digestive pancreatic enzyme encoded by the highly polymorphic CEL gene1. Mutations in CEL cause maturity-onset diabetes of the young (MODY) with pancreatic exocrine dysfunction2. Here we identified a hybrid allele (CEL-HYB), originating from a crossover between CEL and its neighboring pseudogene CELP. In a discovery cohort of familial chronic pancreatitis cases, the carrier frequency of CEL-HYB was 14.1% (10/71) compared with 1.0% (5/478) in controls (odds ratio [OR] = 15.5, 95% confidence interval [CI] = 5.1-46.9, P = 1.3 × 10−6). Three replication studies in non-alcoholic chronic pancreatitis cohorts identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2, 95% CI = 3.2-8.5, P = 1.2 × 10−11; formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models revealed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. The hybrid variant of CEL is the first chronic pancreatitis gene identified outside the protease/antiprotease system of pancreatic acinar cells.

Double-stranded RNA (dsRNA) is produced during the replication cycle of most viruses and triggers antiviral immune responses through Toll-like receptor 3 (TLR3). However, the molecular mechanisms and subcellular compartments associated with dsRNA-TLR3-mediated signaling are largely unknown. Here we show that c-Src tyrosine kinase is activated by dsRNA in human monocyte-derived dendritic cells, and is recruited to TLR3 in a dsRNAdependent manner. DsRNA-induced activation of interferon-regulatory factor 3 and signal transducer and activator of transcription 1 was abolished in Src kinase-deficient cells, and restored by adding back c-Src, suggesting a central role of c-Src in antiviral immunity. We also provide evidence that TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA, and colocalizes with c-Src on endosomes containing dsRNA in the lumen. These results provide novel insight into the molecular mechanisms of TLR3-mediated signaling, which may contribute to the understanding of innate immune responses during viral infections.

OBJECTIVE-Mutations in the insulin (INS) gene can cause neonatal diabetes. We hypothesized that mutations in INS could also cause maturity-onset diabetes of the young (MODY) and autoantibody-negative type 1 diabetes.RESEARCH DESIGN AND METHODS-We screened INS in 62 probands with MODY, 30 probands with suspected MODY, and 223 subjects from the Norwegian Childhood Diabetes Registry selected on the basis of autoantibody negativity or family history of diabetes.RESULTS-Among the MODY patients, we identified the INS mutation c.137GϾA (R46Q) in a proband, his diabetic father, and a paternal aunt. They were diagnosed with diabetes at 20, 18, and 17 years of age, respectively, and are treated with small doses of insulin or diet only. In type 1 diabetic patients, we found the INS mutation c.163CϾT (R55C) in a girl who at 10 years of age presented with ketoacidosis and insulindependent, GAD, and insulinoma-associated antigen-2 (IA-2) antibody-negative diabetes. Her mother had a de novo R55C mutation and was diagnosed with ketoacidosis and insulindependent diabetes at 13 years of age. Both had residual ␤-cell function. The R46Q substitution changes an invariant arginine residue in position B22, which forms a hydrogen bond with the glutamate at A17, stabilizing the insulin molecule. The R55C substitution involves the first of the two arginine residues localized at the site of proteolytic processing between the B-chain and the C-peptide. M olecular genetic studies of monogenic forms of diabetes such as maturity-onset diabetes of the young (MODY) and neonatal diabetes have provided important insight into the pathophysiology and have led to improved diagnosis and treatment (1-7). In type 1 diabetes, immune-mediated destruction of the pancreatic ␤-cells plays an important role in the pathogenesis (8). However, some type 1 diabetic children do not present with signs of autoimmunity and are classified as having autoantibody-negative type 1 diabetes, also denoted idiopathic or type 1b diabetes (9 -11). Recently, we observed that heterozygous missense mutations in the insulin gene (INS) can cause permanent neonatal diabetes (12). The majority of these mutations occurred de novo. Moreover, this phenomenon has been noted in previous studies of KCNJ11 and ABCC8 in patients with neonatal diabetes and is in accordance with the sporadic nature of permanent neonatal diabetes. CONCLUSIONS-OurWe hypothesized that INS mutations might also cause MODY and could explain some cases of apparent type 1 diabetes. The aim of the present study was therefore to search for INS mutations in patients with MODY of unknown etiology as well as in selected patients from the Norwegian Childhood Diabetes Registry. RESEARCH DESIGN AND METHODSPhysicians refer subjects to the Norwegian MODY Registry based on at least two of the following criteria: first-degree relative with diabetes, onset of diabetes before 25 years of age in at least one family member, insulin level Ͻ0.5 units ⅐ kg Ϫ1 ⅐ day Ϫ1 , diabetes diagnosed between age 25 and 40 years of age, or unusual ...