Identification of HNF1A-MODY and HNF4A-MODY in Irish families: Phenotypic characteristics and therapeutic implications

Kyithar, M. P.; Bacon, Siobhán; Pannu, Kamalpreet; Rizvi, Syed R; Colclough, Kevin; Ellard, Sian; Byrne, Maria

doi:10.1016/j.diabet.2011.04.002

Cited by 35 publications

(33 citation statements)

References 36 publications

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“…The Irish HNF1A-MODY cohort investigated in this study has been recently characterized [22]. This study reported on a mutation identification rate of 30.5% among Irish adults clinically selected for HNF1A-MODY from attendees at the diabetes clinic.…”

Section: Discussionmentioning

confidence: 99%

Serum levels of pancreatic stone protein (PSP)/reg1A as an indicator of beta-cell apoptosis suggest an increased apoptosis rate in hepatocyte nuclear factor 1 alpha (HNF1A-MODY) carriers from the third decade of life onward

et al. 2012

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BackgroundMutations in the transcription factor hepatocyte nuclear factor-1-alpha (HNF1A) result in the commonest type of maturity onset diabetes of the young (MODY). HNF1A-MODY carriers have reduced pancreatic beta cell mass, partially due to an increased rate of apoptosis. To date, it has not been possible to determine when apoptosis is occurring in HNF1A-MODY.We have recently demonstrated that beta cell apoptosis stimulates the expression of the pancreatic stone protein/regenerating (PSP/reg) gene in surviving neighbour cells, and that PSP/reg1A protein is subsequently secreted from these cells. The objective of this study was to determine whether serum levels of PSP/reg1A are elevated during disease progression in HNF1A-MODY carriers, and whether it may provide information regarding the onset of beta-cell apoptosis.MethodsWe analysed serum PSP/reg1A levels and correlated with clinical and biochemical parameters in subjects with HNF1A-MODY, glucokinase (GCK-MODY), and type 1 diabetes mellitus. A control group of normoglycaemic subjects was also analysed.ResultsPSP/reg1A serum levels were significantly elevated in HNF1A-MODY (n = 37) subjects compared to controls (n = 60) (median = 12.50 ng/ml, IQR = 10.61-17.87 ng/ml versus median = 10.72 ng/ml, IQR = 8.94-12.54 ng/ml, p = 0.0008). PSP/reg1A correlated negatively with insulin levels during OGTT, (rho = −0.40, p = 0.02). Interestingly we noted a significant positive correlation of PSP/reg1A with age of the HNF1A-MODY carriers (rho = 0.40 p = 0.02) with an age of 25 years separating carriers with low and high PSP/reg1A levels. Patients with type 1 diabetes mellitus also had elevated serum levels of PSP/reg1A compared to controls, however this was independent of the duration of diabetes.ConclusionOur data suggest that beta cell apoptosis contributes increasingly to the pathophysiology of HNF1A-MODY in patients 25 years and over. PSP/reg1A may be developed as a serum marker to detect increased beta-cell apoptosis, or its therapeutic response.

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Section: Discussionmentioning

confidence: 99%

Serum levels of pancreatic stone protein (PSP)/reg1A as an indicator of beta-cell apoptosis suggest an increased apoptosis rate in hepatocyte nuclear factor 1 alpha (HNF1A-MODY) carriers from the third decade of life onward

et al. 2012

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“…A total of 37 (n=12 GCK, n=25 HNF-1α) women participated in the study; these women were identified as part of the MODY cohort screening study in the Mater Hospital (17). The GCK mutations were p.D311fs, A378V, p.I293R, L146fs,D160N and p.Y61X (6 pedigrees).…”

Section: Subjectsmentioning

confidence: 99%

The clinical management of hyperglycemia in pregnancy complicated by maturity-onset diabetes of the young

Bacon

Schmid

McCarthy

et al. 2015

American Journal of Obstetrics and Gynecology

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“…2). The genes are located in chromosomes: 2,7,8,9,11,12,13,17, and 20. The chromosomes-2 and 7 contain two genes, and other chromosomes contain one gene.…”

Section: Resultsmentioning

confidence: 99%

“…Till today, 11 subtype types have been identified that cause mutations. MODY 1, also known as HNF4A-MODY, is caused by mutation in the HNF4A gene on chromosome 20, while MODY 2 is caused by mutations in the GCK gene on chromosome 7 [17]. This gene is responsible for the synthesis of glucokinase (GCK), and this class is also known as GCK-MODY [18].…”

Section: Introductionmentioning

confidence: 98%

Exploring the Genomic Roadmap and Molecular Phylogenetics Associated with MODY Cascades Using Computational Biology

Chakraborty

Bandyopadhyay

Doss

et al. 2014

Cell Biochem Biophys

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Maturity onset diabetes of the young (MODY) is a metabolic and genetic disorder. It is different from type 1 and type 2 diabetes with low occurrence level (1-2%) among all diabetes. This disorder is a consequence of β-cell dysfunction. Till date, 11 subtypes of MODY have been identified, and all of them can cause gene mutations. However, very little is known about the gene mapping, molecular phylogenetics, and co-expression among MODY genes and networking between cascades. This study has used latest servers and software such as VarioWatch, ClustalW, MUSCLE, G Blocks, Phylogeny.fr, iTOL, WebLogo, STRING, and KEGG PATHWAY to perform comprehensive analyses of gene mapping, multiple sequences alignment, molecular phylogenetics, protein-protein network design, co-expression analysis of MODY genes, and pathway development. The MODY genes are located in chromosomes-2, 7, 8, 9, 11, 12, 13, 17, and 20. Highly aligned block shows Pro, Gly, Leu, Arg, and Pro residues are highly aligned in the positions of 296, 386, 437, 455, 456 and 598, respectively. Alignment scores inform us that HNF1A and HNF1B proteins have shown high sequence similarity among MODY proteins. Protein-protein network design shows that HNF1A, HNF1B, HNF4A, NEUROD1, PDX1, PAX4, INS, and GCK are strongly connected, and the co-expression analyses between MODY genes also show distinct association between HNF1A and HNF4A genes. This study has used latest tools of bioinformatics to develop a rapid method to assess the evolutionary relationship, the network development, and the associations among eleven MODY genes and cascades. The prediction of sequence conservation, molecular phylogenetics, protein-protein network and the association between the MODY cascades enhances opportunities to get more insights into the less-known MODY disease.

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Identification of HNF1A-MODY and HNF4A-MODY in Irish families: Phenotypic characteristics and therapeutic implications

Cited by 35 publications

References 36 publications

Serum levels of pancreatic stone protein (PSP)/reg1A as an indicator of beta-cell apoptosis suggest an increased apoptosis rate in hepatocyte nuclear factor 1 alpha (HNF1A-MODY) carriers from the third decade of life onward

Serum levels of pancreatic stone protein (PSP)/reg1A as an indicator of beta-cell apoptosis suggest an increased apoptosis rate in hepatocyte nuclear factor 1 alpha (HNF1A-MODY) carriers from the third decade of life onward

The clinical management of hyperglycemia in pregnancy complicated by maturity-onset diabetes of the young

Exploring the Genomic Roadmap and Molecular Phylogenetics Associated with MODY Cascades Using Computational Biology

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