Case Report: Neonatal Diabetes Mellitus Caused by a Novel GLIS3 Mutation in Twins.

Background: Mutations in GLIS3 cause a rare syndrome characterized by neonatal diabetes mellitus (NDM), congenital hypothyroidism, congenital glaucoma and cystic kidneys. To date, 14 mutations in GLIS3 have been reported, inherited in an autosomal recessive manner. GLIS3 is a key transcription factor involved in ß-cell development, insulin expression, and development of the thyroid, eyes, liver and kidneys. Cases: We describe non-identical twins born to consanguineous parents presenting with NDM, congenital hypothyroidism, congenital glaucoma, hepatic cholestasis, cystic kidney and delayed psychomotor development. Sequence analysis of GLIS3 identified a novel homozygous nonsense mutation, c.2392C>T, p.Gln798Ter (p.Q798*), which results in an early stop codon. The diabetes was treated with a continuous subcutaneous insulin infusion pump and continuous glucose monitoring. Fluctuating blood glucose and intermittent hypoglycemia were observed on follow-up. Conclusions: This report highlights the importance of early molecular diagnosis for appropriate management of NDM. We describe a novel nonsense mutation of GLIS3 causing NDM, extend the phenotype, and discuss the challenges in clinical management. Our findings provide new areas for further investigation into the roles of GLIS3 in the pathophysiology of diabetes mellitus.

Rectal potential difference and the functional expression of CFTR in the gastrointestinal epithelia in cystic fibrosis mouse models.

Cystic fibrosis (CF) is an autosomal recessive disease that results from mutations in the CF transmembrane conductance regulator (CFTR) gene. The effect of interventions aimed at correcting the CF electrophysiologic phenotype has been primarily measured using in vitro methods in gastrointestinal and respiratory epithelia. A reliable in vivo assay of CFTR function would be of great value in the investigation of pharmacologic interventions for CF mouse models. We performed the in vivo rectal potential difference (RPD) assay on three different mouse models. We then compared the in vivo data with the results obtained using the in vitro Ussing chamber method. The results from the in vitro method correlated closely with the results acquired using the in vivo method and were reproducible. The data suggest that the in vivo RPD assay is a reliable assay of functional CFTR expression in CF mouse models.

Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects.

Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, DeltaF508, results in the production of a misfolded CFTR protein that is retained in the endoplasmic reticulum and targeted for degradation. Curcumin is a nontoxic Ca-adenosine triphosphatase pump inhibitor that can be administered to humans safely. Oral administration of curcumin to homozygous DeltaF508 CFTR mice in doses comparable, on a weight-per-weight basis, to those well tolerated by humans corrected these animals' characteristic nasal potential difference defect. These effects were not observed in mice homozygous for a complete knockout of the CFTR gene. Curcumin also induced the functional appearance of DeltaF508 CFTR protein in the plasma membranes of transfected baby hamster kidney cells. Thus, curcumin treatment may be able to correct defects associated with the homozygous expression of DeltaF508 CFTR.