@article {435, title = {FOXP3 mutations causing early-onset insulin-requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.}, journal = {Pediatr Diabetes}, volume = {19}, year = {2018}, month = {2018 05}, pages = {388-392}, abstract = {

Diabetes occurs in 1/90 000 to 1/160 000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory cell function and mutations are known to cause "immune dysregulation, polyendocrinopathy (including insulin-requiring diabetes), enteropathy, X-linked" (IPEX) syndrome. This condition is often fatal unless patients receive a bone-marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin-requiring diabetes without other features of IPEX syndrome and were found to have mutations in FOXP3. Whole-exome or next generation sequencing of genes of interest was carried out in subjects with isolated neonatal diabetes without a known genetic cause. RT-PCR was carried out to investigate the effects on RNA splicing of a novel intronic splice-site variant. Four male subjects were found to have FOXP3 variants in the hemizygous state: p.Arg114Trp, p.Arg347His, p.Lys393Met, and c.1044+5G>A which was detected in 2 unrelated probands and in a brother diagnosed with diabetes at 2.1 years of age. Of these, p.Arg114Trp is likely a benign rare variant found in individuals of Ashkenazi Jewish ancestry and p.Arg347His has been previously described in patients with classic IPEX syndrome. The p.Lys393Met and c.1044+5G>A variants are novel to this study. RT-PCR studies of the c.1044+5G>A splice variant confirmed it affected RNA splicing by generating both a wild type and truncated transcript. We conclude that FOXP3 mutations can cause early-onset insulin-requiring diabetes with or without other features of IPEX syndrome.

}, keywords = {Diabetes Mellitus, Diabetes Mellitus, Type 1, Diarrhea, Forkhead Transcription Factors, Genetic Diseases, X-Linked, Humans, Immune System Diseases, Infant, Infant, Newborn, Male, Registries}, issn = {1399-5448}, doi = {10.1111/pedi.12612}, author = {Hwang, Jessica L and Park, Soo-Young and Ye, Honggang and Sanyoura, May and Pastore, Ashley N and Carmody, David and Del Gaudio, Daniela and Wilson, Janna F and Hanis, Craig L and Liu, Xiaoming and Atzmon, Gil and Glaser, Benjamin and Philipson, Louis H and Greeley, Siri Atma W} } @article {153, title = {Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism.}, journal = {J Med Genet}, volume = {52}, year = {2015}, month = {2015 Sep}, pages = {612-6}, abstract = {

BACKGROUND: Diabetes in neonates usually has a monogenic aetiology; however, the cause remains unknown in 20-30\%. Heterozygous INS mutations represent one of the most common gene causes of neonatal diabetes mellitus.

METHODS: Clinical and functional characterisation of a novel homozygous intronic mutation (c.187+241G>A) in the insulin gene in a child identified through the Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu).

RESULTS: The proband had insulin-requiring diabetes from birth. Ultrasonography revealed a structurally normal pancreas and C-peptide was undetectable despite readily detectable amylin, suggesting the presence of dysfunctional β cells. Whole-exome sequencing revealed the novel mutation. In silico analysis predicted a mutant mRNA product resulting from preferential recognition of a newly created splice site. Wild-type and mutant human insulin gene constructs were derived and transiently expressed in INS-1 cells. We confirmed the predicted transcript and found an additional transcript created via an ectopic splice acceptor site.

CONCLUSIONS: Dominant INS mutations cause diabetes via a mutated translational product causing endoplasmic reticulum stress. We describe a novel mechanism of diabetes, without β cell death, due to creation of two unstable mutant transcripts predicted to undergo nonsense and non-stop-mediated decay, respectively. Our discovery may have broader implications for those with insulin deficiency later in life.

}, keywords = {Diabetes Mellitus, Humans, Infant, Insulin, Regular, Human, Introns, Mutation, Sequence Analysis, DNA}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2015-103220}, author = {Carmody, David and Park, Soo-Young and Ye, Honggang and Perrone, Marie E and Alkorta-Aranburu, G and Highland, Heather M and Hanis, Craig L and Philipson, Louis H and Bell, Graeme I and Greeley, Siri Atma W} }