MODY in Iceland is associated with mutations in HNF -1? and a novel mutation in NeuroD1

Kristinsson, S. Y.; Thorolfsdottir, E. T.; Talseth, Bente A.; Steingrímsson, Eiríkur; Þórsson, Árni V.; Helgason, Tómas; Hreiðarsson, Ástráður B.; Arngrı́msson, Reynir

doi:10.1007/s001250100016

Cited by 95 publications

(64 citation statements)

References 14 publications

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“…Mice deficient in these transcription factors revealed these factors to be indispensable for islet cell development and insulin gene expression [46][47][48][49]. In addition, mutations in the BETA2 and PDX1 genes were found in some patients with maturity-onset diabetes of the young (MODY) [50,51]. The RIPE3b has also been shown to be involved in b-cell-specific insulin gene transcription as well as in its glucose-regulated expression.…”

Section: Discussionmentioning

confidence: 99%

Mouse MafA, homologue of zebrafish somite Maf 1, contributes to the specific transcriptional activity through the insulin promoter

Kajihara

Sone

Amemiya

et al. 2003

Biochemical and Biophysical Research Communications

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Large Maf transcription factors, which are members of the basic leucine zipper (b-Zip) superfamily, have been reported to be involved in embryonic development and cell differentiation. Previously, we isolated a novel zebrafish large Maf cDNA, somite Maf1 (SMaf1), which possesses transactivational activity within its N-terminus domain. To elucidate SMaf1 function in mammals, we tried to isolate the mouse homologue of zebrafish SMaf1. We isolated the mouse homologue of zebrafish SMaf1, which is the same molecule as the recently reported MafA. MafA mRNA was detected in formed somites, head neural tube, and liver cells in the embryos. In the adult mouse, MafA transcript was amplified in the brain, lung, spleen, and kidney by RT-PCR. MafA mRNA was also detectable in b-cell line. Next, we analyzed the transcriptional activity of MafA using rat insulin promoters I and II (RIPI and II), since a part of RIP sequence was similar to the Maf recognition element (MARE) and MafA was expressed in pancreatic b-cells. MafA was able to activate transcription from RIPII, but not RIPI, in a dose dependent manner and the activity was dependent on RIPE3b/C1 sequences. In addition, the amount of MafA protein was regulated by glucose concentration. These results indicate that MafA is the homologue of zebrafish SMaf1 and acts as a transcriptional activator of the insulin gene promoter through the RIPE3b element.

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Section: Discussionmentioning

confidence: 99%

Mouse MafA, homologue of zebrafish somite Maf 1, contributes to the specific transcriptional activity through the insulin promoter

Kajihara

Sone

Amemiya

et al. 2003

Biochemical and Biophysical Research Communications

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“…Lastly, chromosome 11 had a single region of maximum LOD score at 11p15.4: 5.8-8.7 cM. Cataloguing the genes under each of these linkage peaks led to the identification of NEU-ROD1 at chromosome 2q31.3, which previously had been implicated as a maturity-onset diabetes of the young (MODY6) gene (11,12), and INS at chromosome 11p15 as possible candidate genes. There were no mutations in the coding region of NEUROD1.…”

Section: Identification Of Insulin Gene Mutations In Ndmentioning

confidence: 99%

Insulin gene mutations as a cause of permanent neonatal diabetes

Støy

Edghill

Flanagan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

508

478

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We report 10 heterozygous mutations in the human insulin gene in 16 probands with neonatal diabetes. A combination of linkage and a candidate gene approach in a family with four diabetic members led to the identification of the initial INS gene mutation. The mutations are inherited in an autosomal dominant manner in this and two other small families whereas the mutations in the other 13 patients are de novo. Diabetes presented in probands at a median age of 9 weeks, usually with diabetic ketoacidosis or marked hyperglycemia, was not associated with ␤ cell autoantibodies, and was treated from diagnosis with insulin. The mutations are in critical regions of the preproinsulin molecule, and we predict that they prevent normal folding and progression of proinsulin in the insulin secretory pathway. The abnormally folded proinsulin molecule may induce the unfolded protein response and undergo degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum stress and potentially ␤ cell death by apoptosis. This process has been described in both the Akita and Munich mouse models that have dominant-acting missense mutations in the Ins2 gene, leading to loss of ␤ cell function and mass. One of the human mutations we report here is identical to that in the Akita mouse. The identification of insulin mutations as a cause of neonatal diabetes will facilitate the diagnosis and possibly, in time, treatment of this disorder.endoplasmic reticulum stress ͉ insulin biosynthesis ͉ disulfide bonds ͉ unfolded protein response

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“…The reduced ␤-cell mass leads to diabetes with a variable penetrance, and on certain genetic backgrounds, this phenotype does not manifest at all. As with several genes of the core endodermal program that operate in islets, mutations in NeuroD are associated with MODY (MODY6; Kristinsson et al, 2001). NeuroD mutations also associate with human type II diabetes.…”

Section: Neurodmentioning

confidence: 99%

Gene regulatory factors in pancreatic development

Jensen

2003

Developmental Dynamics

347

289

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The intensity of research on pancreatic development has increased markedly in the past 5 years, primarily for two reasons: we now know that the insulin-producing ␤-cells normally arise from an endodermally derived, pancreasspecified precursor cell, and successful transplants of islet cells have been performed, relieving patients with type I diabetes of symptoms for extended periods after transplantation. Combining in vitro ␤-cell formation from a pancreatic biopsy of a diabetic patient or from other stem-cell sources followed by endocrine cell transplantation may be the most beneficial route for a future diabetes therapy. However, to achieve this, a thorough understanding of the genetic components regulating the development of ␤-cells is required. The following review discusses our current understanding of the transcription factor networks necessary for pancreatic development and how several genetic interactions coming into play at the earliest stages of endodermal development gradually help to build the pancreatic organ.

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MODY in Iceland is associated with mutations in HNF -1? and a novel mutation in NeuroD1

Cited by 95 publications

References 14 publications

Mouse MafA, homologue of zebrafish somite Maf 1, contributes to the specific transcriptional activity through the insulin promoter

Mouse MafA, homologue of zebrafish somite Maf 1, contributes to the specific transcriptional activity through the insulin promoter

Insulin gene mutations as a cause of permanent neonatal diabetes

Gene regulatory factors in pancreatic development

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