MODY (Maturity Onset Diabetes of the Young) Maturity-onset of diabetes of the young, or MODY, is a form of diabetes that is caused by mutations in a number of different genes. Maturity onset diabetes of the young (MODY) [1] refers to any of several hereditary forms of diabetes caused by mutations in an autosomal dominant gene [2] (sex independent, i.e. MODY is an autosomal, dominantly inherited form of diabetes that is characterized by an early age of onset (at least one affected family member with an onset before 25 years of age) and pancreatic beta-cell dysfunction. Linkage between microsatellite markers and disease was described in French and UK pedigrees and the first mutation was reported in 1992. MODY has been associated with defects in several genes; glucokinase (GCK) was the first MODY gene to be identified. The prevalence of GCK-MODY is difficult to assess, as the mild hyperglycemia and the absence of symptoms means that patients are frequently not diagnosed. In the Caucasian population, approximately 2% of the population will be diagnosed with gestational diabetes; of these, ~2-5% will have a GCK mutation. Neonatal diabetes mellitus (NDM), caused by homozygous inactivating mutation, is a rare disorder with an estimated incidence of 1:400,000 live births.
The glucokinase (GCK) gene encodes a 465 amino acid protein with a MW of 52 kDa, which is expressed in the pancreas, liver, and brain.
The two isoforms of glucokinase differ by 13-15 amino acids at the N-terminal end of the molecule, which produces only a minimal difference in structure. In liver, glucokinase acts as the gateway for the "bulk processing" of available glucose, while in the neuroendocrine cells, it acts as a sensor, triggering cell responses that affect body-wide carbohydrate metabolism.
The presence of tissue-specific promoters allows differential regulation and transcription of different transcripts. Heterozygous inactivating mutations are associated with mild hyperglycemia in children or gestational DM in women which are often subclinical and can be treated with diet alone.
Homozygous inactivating mutation results in permanent neonatal diabetes and requires insulin treatment within the first month. Over 190 mutations of the GCK gene have been identified in many populations, with the majority in France and Italy. Slideshare uses cookies to improve functionality and performance, and to provide you with relevant advertising.
Description Human PDX-1 is a protein of 283 amino acids with a calculated molecular weight of 30.64 kDa.
Function Pancreatic and duodenal homeobox-1 (PDX-1) is a homeodomain-containing transcription factor essential for pancreatic development, beta-cell differentiation and the maintenance of mature beta cell function through regulating the expression of key endocrine beta-cell-specific genes such as insulin, glucokinase, islet amyloid polypeptide and the glucose transporter type 2. Homology Human PDX-1 shares a 90% amino acid homology with hamster, 88% with rat, 87% with mouse and 68% with Xenopus. Somatic Pro63fsdelC: a frameshift mutation resulting from a single nucleotide deletion within codon 63 in exon 1 of the coding sequence of PDX-1.
Prognosis Elevated expression of PDX-1 is found in a number of human cancers, including pancreatic, breast, prostate cancer, colorectal cancer, colon cancer, kidney, gastric, paediatric solid pseudopapillary tumors (SPT) and intestinal-type ovarian mucinous neoplasm (OMN). Prognosis Maturity-onset diabetes of young 4 (MODY4) is a form of early-onset type-II diabetes mellitus in which expression of diabetes occurs later than that observed for MODY1, MODY2 and MODY3.
Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence.
Insulin promoter factor-1 gene mutation linked to early-onset type 2 diabetes mellitus directs expression of a dominant negative isoprotein.

Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus. Identification of a nuclear localization signal, RRMKWKK, in the homeodomain transcription factor PDX-1. Macfarlane WM, Frayling TM, Ellard S, Evans JC, Allen LI, Bulman MP, Ayers S, Shepherd M, Clark P, Millward A, Demaine A, Wilken T, Docherty K, Hattersley AT. Functional consequences of mutations in the MODY4 gene (IPF1) and coexistence with MODY3 mutations. Weng J, Macfarlane WM, Lehto M, Gu HF, Shepherd LM, Ivarsson SA, Wibell L, Smith T, Groop LC. PDX-1 protein containing its own antennapedia-like protein transduction domain can transduce pancreatic duct and islet cells. Insulin promoter factor-1 mutations and diabetes in Trinidad: identification of a novel diabetes-associated mutation (E224K) in an Indo-Trinidadian family.
Cockburn BN, Bermano G, Boodram LL, Teelucksingh S, Tsuchiya T, Mahabir D, Allan AB, Stein R, Docherty K, Bell GI.
Sakai H, Eishi Y, Li XL, Akiyama Y, Miyake S, Takizawa T, Konishi N, Tatematsu M, Koike M, Yuasa Y. Crucial role of PDX-1 in pancreas development, beta-cell differentiation, and induction of surrogate beta-cells. Transcription factors involved in pancreas development are expressed in paediatric solid pseudopapillary tumours. Expression of PDX-1 in prostate cancer, prostatic intraepithelial neoplasia and benign prostatic tissue.
Intestinal type and endocervical-like ovarian mucinous neoplasms are immunophenotypically distinct entities.
Ma J, Chen M, Wang J, Xia HH, Zhu S, Liang Y, Gu Q, Qiao L, Dai Y, Zou B, Li Z, Zhang Y, Lan H, Wong BC.
PDX1 deficiency causes mitochondrial dysfunction and defective insulin secretion through TFAM suppression. Gauthier BR, Wiederkehr A, Baquie M, Dai C, Powers AC, Kerr-Conte J, Pattou F, MacDonald RJ, Ferrer J, Wollheim CB. The expression pattern of PDX-1, SHH, Patched and Gli-1 is associated with pathological and clinical features in human pancreatic cancer. Quint K, Stintzing S, Alinger B, Hauser-Kronberger C, Dietze O, Gahr S, Hahn EG, Ocker M, Neureiter D. Pancreatic and duodenal homeobox 1 (PDX1) phosphorylation at serine-269 is HIPK2-dependent and affects PDX1 subnuclear localization.
An R, da Silva Xavier G, Semplici F, Vakhshouri S, Hao HX, Rutter J, Pagano MA, Meggio F, Pinna LA, Rutter GA. Glucose regulates steady-state levels of PDX1 via the reciprocal actions of GSK3 and AKT kinases. Liu SH, Patel S, Gingras MC, Nemunaitis J, Zhou G, Chen C, Li M, Fisher W, Gibbs R, Brunicardi FC. A novel hypomorphic PDX1 mutation responsible for permanent neonatal diabetes with subclinical exocrine deficiency. However, endogenous PDX-1 is usually detected as a protein with molecular mass of 46 kDa, likely due to posttranslational modifications such as phosphorylation and sumoylation.

In solid pseudopapillary tumors (SPT), however, PDX-1 only exists in the cytoplasm, but not in the nucleus. The point deletion causes a frame shift resulting in the translation of 59 novel codons before termination and the production of a prematurely terminated truncated protein of 16 kDa. Elevated expression level of PDX-1 in pancreatic cancer is significantly correlated with lymph node metastasis, TNM grading, pathological grading and tumor cell proliferation. Pro63fsdelC of PDX-1 contributes to the development of MODY4 when the mutation is heterozygous. In the promoter region of PDX-1, there are three highly conserved regions, termed "Area I-II-III" which are located between -2800 and -1600 base pairs (bp), and a forth distal enhancer element, termed "Area IV" which is located between -6500 and -6045 bp.
The numbers indicate the positions of phosphorylation sites and functional domains on the polypeptide chain of human PDX-1. PDX-1 expression becomes restricted to beta cells and a small subpopulation of delta and PP cells in adult.
PDX-1 is functionally involved in mitochondrial signal generation in the moment-to-moment control of insulin release by regulating mitochondrial transcription factor A (TFAM). PDX-1 expression in pancreatic cancer is an independent survival factor since the patients with positive PDX-1 have a significantly worse prognosis than those patients with negative PDX-1. These enhancer elements harbor binding sites for multiple transcription factors and transcriptional regulators such as HNF-1alpha, HNF-3beta, HNF-6, Foxa1, Foxa2, Pax6, MafA and PDX-1 itself.
The middle region contains a homeodomain, which is essential for DNA binding and protein-protein interactions.
In colorectal cancer, PDX-1 is highly expressed in hepatic metastasis of colorectal cancer, while lower expression of PDX-1 is found in primary colorectal tumor. Within the homeodomain, there is an antennapedia-like protein transduction domain (PTD) which allows PDX-1 to permeate into cells and a nuclear localization signal (NLS) motif, RRMKWKK(197-203aa), which is sufficient for the nuclear import of PDX-1.
Area IV is capable of independently directing pancreatic beta-cell-specific reporter gene expression and potentiating the proximal enhancer activity.
There is a conserved motif in the C-terminus of PDX-1 that mediates the PDX-1-PCIF1 interaction resulting in the inhibition of PDX-1 transcriptional activity.
PDX-1 expression also correlates with histological type and depth of invasion of gastric carcinomas. Several C-terminal residues such as Gly 212, Glu 224 and Pro 239 are essential for full transactivation of PDX-1 as evidenced by the association of their missense mutations with diabetes (Fig.
Aberrant overexpression of PDX-1 is observed in a number of human cancers such as pancreatic, gastric, colon, breast, prostate, colorectal, kidney cancer and paediatric solid pseudopapillary tumors. Up-regulated PDX-1 expression is also observed in premalignant metaplastic ductal epithelium during transforming growth factor (TGF)-alpha-induced pancreatic ductal metaplasia and neoplasia. Several potential phosphorylation sites within PDX-1 have been identified, such as Thr 11 by DNA-PK, Ser 61 and 66 by GSK3beta, Thr 152 by PASK, Thr 231 and Ser 232 by CK2 and Ser 268 by AKT-GSK and HIPK2.
PDX-1 expression is subject to regulation by glucose, glucagon-like peptide 1 (GLP-1), palmitic acid, peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARgamma, epidermal growth factor (EGF) and high fat diet.

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