@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} } @article {284, title = {Microcephaly, epilepsy, and neonatal diabetes due to compound heterozygous mutations in IER3IP1: insights into the natural history of a rare disorder.}, journal = {Pediatr Diabetes}, volume = {15}, year = {2014}, month = {2014 May}, pages = {252-6}, abstract = {

Neonatal diabetes mellitus is known to have over 20 different monogenic causes. A syndrome of permanent neonatal diabetes along with primary microcephaly with simplified gyral pattern associated with severe infantile epileptic encephalopathy was recently described in two independent reports in which disease-causing homozygous mutations were identified in the immediate early response-3 interacting protein-1 (IER3IP1) gene. We report here an affected male born to a non-consanguineous couple who was noted to have insulin-requiring permanent neonatal diabetes, microcephaly, and generalized seizures. He was also found to have cortical blindness, severe developmental delay and numerous dysmorphic features. He experienced a slow improvement but not abrogation of seizure frequency and severity on numerous anti-epileptic agents. His clinical course was further complicated by recurrent respiratory tract infections and he died at 8 years of age. Whole exome sequencing was performed on DNA from the proband and parents. He was found to be a compound heterozygote with two different mutations in IER3IP1: p.Val21Gly (V21G) and a novel frameshift mutation p.Phe27fsSer*25. IER3IP1 is a highly conserved protein with marked expression in the cerebral cortex and in beta cells. This is the first reported case of compound heterozygous mutations within IER3IP1 resulting in neonatal diabetes. The triad of microcephaly, generalized seizures, and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. As mutations in genes such as NEUROD1 and PTF1A could cause a similar phenotype, next-generation sequencing approaches-such as exome sequencing reported here-may be an efficient means of uncovering a diagnosis in future cases.

}, keywords = {Amino Acid Substitution, Blindness, Cortical, Carrier Proteins, Developmental Disabilities, Diabetes Mellitus, Epilepsy, Generalized, Fatal Outcome, Frameshift Mutation, Heterozygote, Humans, Infant, Newborn, Infant, Newborn, Diseases, Male, Membrane Proteins, Microcephaly, Neurologic Manifestations, Point Mutation, Severity of Illness Index}, issn = {1399-5448}, doi = {10.1111/pedi.12086}, author = {Shalev, Stavit A and Tenenbaum-Rakover, Yardena and Horovitz, Yoseph and Paz, Veronica P and Ye, Honggang and Carmody, David and Highland, Heather M and Boerwinkle, Eric and Hanis, Craig L and Muzny, Donna M and Gibbs, Richard A and Bell, Graeme I and Philipson, Louis H and Greeley, Siri Atma W} } @article {292, title = {Neonatal diabetes, gallbladder agenesis, duodenal atresia, and intestinal malrotation caused by a novel homozygous mutation in RFX6.}, journal = {Pediatr Diabetes}, volume = {15}, year = {2014}, month = {2014 Feb}, pages = {67-72}, abstract = {

Recently, bi-allelic mutations in the transcription factor RFX6 were described as the cause of a rare condition characterized by neonatal diabetes with pancreatic and biliary hypoplasia and duodenal/jejunal atresia. A male infant developed severe hyperglycemia (446 mg/dL) within 24 h of birth. Acute abdominal concerns by day five necessitated exploratory surgery that revealed duodenal atresia, gallbladder agenesis, annular pancreas and intestinal malrotation. He also exhibited chronic diarrhea and feeding intolerance, cholestatic jaundice, and subsequent liver failure. He died of sepsis at four months old while awaiting liver transplantation. The phenotype of neonatal diabetes with intestinal atresia and biliary agenesis clearly pointed to RFX6 as the causative gene; indeed, whole exome sequencing revealed a novel homozygous RFX6 mutation c.779A>C; p.Lys260Thr (K260T). This missense mutation also changes the consensus 5{\textquoteright} splice donor site before intron 7 and is thus predicted to cause disruption in splicing. Both parents, who were not known to be related, were heterozygous carriers. Targeted genetic testing based on consideration of phenotypic features may reveal a cause among the many genes now associated with heterogeneous forms of monogenic neonatal diabetes. Our study demonstrates the feasibility of using modern sequencing technology to identify one such rare cause. Continued research is needed to determine the possible cost-effectiveness of this approach, especially when clear phenotypic clues are absent. Further study of patients with RFX6 mutations should clarify its role in pancreatic, intestinal and enteroendocrine cellular development and explain features such as the diarrhea exhibited in our case.

}, keywords = {Abnormalities, Multiple, Congenital Abnormalities, Diabetes Mellitus, Type 1, Digestive System Abnormalities, DNA-Binding Proteins, Duodenal Obstruction, Fatal Outcome, Gallbladder, Humans, Infant, Infant, Newborn, Infant, Newborn, Diseases, Intestinal Atresia, Intestinal Volvulus, Male, Pancreas, Pancreatic Diseases, Regulatory Factor X Transcription Factors, Transcription Factors}, issn = {1399-5448}, doi = {10.1111/pedi.12063}, author = {Concepcion, Jennifer P and Reh, Christina S and Daniels, Mark and Liu, Xiaoming and Paz, Veronica P and Ye, Honggang and Highland, Heather M and Hanis, Craig L and Greeley, Siri Atma W} }