Diabetes caused by insulin gene (INS) deletion: clinical characteristics of homozygous and heterozygous individuals

Raile, Klemens; O’Connell, Michele A; Galler, Angela; Werther, George A.; Kühnen, Peter; Krude, Heiko; Blankenstein, Oliver

doi:10.1530/eje-11-0208

Cited by 37 publications

(28 citation statements)

References 20 publications

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“…Haploinsufficiency of insulin has been suggested to contribute to the risk for diabetes in heterozygous individuals 19. Thus, our discovery extends the current understanding of how diabetes occurring in neonates may have broader implications for those with insulin deficiency leading to diabetes later in life.…”

Section: Resultsmentioning

confidence: 54%

“…Most other insulin gene mutations, including the only other known intronic mutation (heterozygous c.188-31G>A), lead to misfolded proteins that increase ER stress and β cell death 5 15. Deletions and recessive mutations that lead to reduced insulin biosynthesis have also been described as rare causes of neonatal diabetes 18 19. We describe the first deep intronic homozygous mutation leading to altered splicing and creation of two unstable mutant transcripts.…”

Section: Discussionmentioning

confidence: 96%

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Continued lessons from theINSgene: an intronic mutation causing diabetes through a novel mechanism

Carmody

Park

et al. 2015

J Med Genet

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Background Diabetes in neonates usually has a monogenic etiology; 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 characterization 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 beta 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. Conclusion Dominant INS mutations cause diabetes via a mutated translational product causing ER stress. We describe a novel mechanism of diabetes, without beta 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.

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Section: Resultsmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 96%

Continued lessons from theINSgene: an intronic mutation causing diabetes through a novel mechanism

Carmody

Park

et al. 2015

J Med Genet

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“…Recessive INS gene mutations are “loss-of-function” mutations, which affect insulin biosynthesis at transcriptional and/or translational levels through different mechanisms including insulin gene deletion or truncation with failure of insulin transcription; instability of insulin mRNA; or defective translational initiation due to loss of the natural start codon (Garin et al, 2010; Raile et al, 2011). Such mutations may result in a >80% decrease of insulin production from the mutant allele.…”

Section: Diabetogenic Ins-gene Mutations: Recessive Vs Dominant Amentioning

confidence: 99%

INS-gene mutations: From genetics and beta cell biology to clinical disease

Liu

Sun

Cui

et al. 2015

Molecular Aspects of Medicine

111

137

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A growing list of insulin gene mutations causing a new form of monogenic diabetes has drawn increasing attention over the past seven years. The mutations have been identified in the untranslated regions of the insulin gene as well as the coding sequence of preproinsulin including within the signal peptide, insulin B-chain, C-peptide, insulin A-chain, and the proteolytic cleavage sites both for signal peptidase and the prohormone convertases. These mutations affect a variety of different steps of insulin biosynthesis in pancreatic beta cells. Importantly, although many of these mutations cause proinsulin misfolding with early onset autosomal dominant diabetes, some of the mutant alleles appear to engage different cellular and molecular mechanisms that underlie beta cell failure and diabetes. In this article, we review the most recent advances in the field and discuss challenges as well as potential strategies to prevent/delay the development and progression of autosomal dominant diabetes caused by INS-gene mutations. It is worth noting that although diabetes caused by INS gene mutations is rare, increasing evidence suggests that defects in the pathway of insulin biosynthesis may also be involved in the progression of more common types of diabetes. Collectively, the (pre)proinsulin mutants provide insightful molecular models to better understand the pathogenesis of all forms of diabetes in which preproinsulin processing defects, proinsulin misfolding, and ER stress are involved.

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“…Before sequencing GATA6 , up-to-date candidate genes known to cause monogenic diabetes and pancreas developmental abnormalities were sequenced ( GCK, HNF1A, HNF1B , HNF4A , INS, ABCC8, KCNJ11, PDX1, PTF1A, ONECUT2, FGF10, SOX17, HLXB9 and HNF6 ). The genotyping methodology was conventional [20]. The 7 exons and neighboring intronic regions of human GATA6 were sequenced in both directions using 11 primer pairs (online suppl.…”

Section: Methodsmentioning

confidence: 99%

Two Novel GATA6 Mutations Cause Childhood-Onset Diabetes Mellitus, Pancreas Malformation and Congenital Heart Disease

Gong

Šimaitė²,

Kühnen³

et al. 2013

Horm Res Paediatr

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Background:GATA6 mutations are the most frequent cause of pancreatic agenesis and diabetes in human sporadic cases. In families, dominantly inherited mutations show a variable phenotype also in terms of endocrine and exocrine pancreatic disease. We report two novel GATA6 mutations in an independent cohort of 8 children with pancreas aplasia or hypoplasia and diabetes. Methods: We sequenced GATA6 in 8 children with diabetes and inborn pancreas abnormalities, i.e. hypoplasia or aplasia in which other known candidate genes causing monogenic diabetes and pancreatic defects had been excluded. Results: We found two novel heterozygous GATA6 mutations (c.951_954dup and c.754_904del) in 2 patients with sporadic pancreas hypoplasia, diabetes and severe cardiac defects (common truncus arteriosus and tetralogy of Fallot), but not in the remaining 6 patients. GATA6 mutations in carriers exhibited hypoplastic pancreas with absent head in 1 patient and with increased echogenicity and decreasing exocrine function in the other patient. Additionally, hepatobiliary malformations and brain atrophy were found in 1 patient. Conclusion: Our 2 cases with novel GATA6 mutations add more phenotype characteristics of GATA6 haploinsufficiency. In agreement with an increasing number of published cases, the wide phenotypic spectrum of GATA6 diabetes syndrome should draw the attention of both pediatric endocrinologists and geneticists.

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Diabetes caused by insulin gene (INS) deletion: clinical characteristics of homozygous and heterozygous individuals

Cited by 37 publications

References 20 publications

Continued lessons from theINSgene: an intronic mutation causing diabetes through a novel mechanism

Continued lessons from theINSgene: an intronic mutation causing diabetes through a novel mechanism

INS-gene mutations: From genetics and beta cell biology to clinical disease

Two Novel GATA6 Mutations Cause Childhood-Onset Diabetes Mellitus, Pancreas Malformation and Congenital Heart Disease

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