MODY types 1 to 11 (Maturity Onset Diabetes of the Young) - Genes HNF4A, GCK, HNF1A, PDX1, TCF2, NEUROD1, KLF11, CEL, PAX4, INS, BLK

Diabetes MODY (Maturity Onset Diabetes of the Young), named according to the old classification of juvenile - onset diabetes or in adulthood (maturity-onset) is a form of diabetes autosomal dominant inheritance usually happens before 25 years, but also they are finding cases of later onset, so it has been proposed to abandon the name of MODY. This type of diabetes, is caused by defects in insulin secretion, and thus, currently, the MODY are included in the group of genetic defects function of beta cells and is heterogeneous from the point of view genetic, metabolic and clinical.

They have identified five major diagnostic criteria for MODY, generally accepted:

1. Hyperglycemia usually diagnosed before age 25 years in at least one, and preferably two, family members.
2. Autosomal dominant inheritance, with a vertical transmission for at least 3 generations, and a similar phenotype shared by diabetics family.
3. Absence of insulin therapy at least 5 years after diagnosis, or significant concentrations of C - peptide, even in a patient being treated with insulin.
4. Insulin concentrations that are usually in the normal range.
5. There is often overweight or obese.  

Genetic heterogeneity of MODY

MODY diabetes are subclassified into types 1 to 11, according to the affected genes.

• MODY 1 - Due to mutations HNF4A gene (Hepatocyte nuclear factor-4-alpha), located on the long arm of chromosome 20 (20q13.12). This gene encodes a protein nuclear transcription factor binds to DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor that regulates the expression of several hepatic genes. This gene may play a role in the development of liver, kidneys and intestines.

• MODY 2 - due to mutations in the gene GCK (Glucokinase), located on the short arm of chromosome 7 (7p15.3-p15.1). This gene, catalyzes the initial step in glucose utilization by the beta cells and liver with a physiological glucose concentration. Glucokinase has a high Km for glucose, so it is only effective when glucose is abundant. The role of GCK is to provide glucose 6-phosphate (G6P) for glycogen synthesis. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps facilitate the absorption and conversion of glucose to act as an insulin - sensitive hepatic glucose use determinant.

• MODY 3 - due to mutations in the HNF1A (Hepatocyte Nuclear Factor-1-alpha) gene, located on the long arm of chromosome 12 (12q24.2). The protein encoded by this gene is a transcription factor required for the expression of several liver - specific genes. The encoded protein acts as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3 '. Defects in this gene are a cause of type MODY type 3 (MODY3) Diabetes and can also cause the occurrence of hepatic adenomas.

• MODY 4 - due to mutations in the PDX1 gene (IPF1) (Pancreas / duodenum Homebox Protein-1), located on the long arm of chromosome 13 (13q12.1). The protein encoded by this gene is a transcriptional activator of several genes, including insulin, somatostatin, glucokinase, islet amyloid polypeptide, and glucose transporter type 2 protein encoded in the nucleus is involved in the early development of the pancreas and plays an important role in regulation of glucose-dependent insulin gene expression.

• MODY 5 - due to mutations in the gene TCF2 (HNF1B) (Hepatic Transcription Factor-2), located on the long arm of chromosome 17 (17q12). This gene encodes a protein that binds DNA either as a homodimer or a heterodimer with the hepatocyte related protein nuclear factor 1-alpha. It has been shown that the gene acts in the development of the nephron, and regulates embryonic development of the pancreas.

• MODY 6 - due to mutations in the gene NEUROD1, located on the long arm of chromosome 2 (2q32). This gene encodes a member of the family of basic transcription factors NeuroD basic helix-loop-helix (bHLH). Protein forms heterodimers with other bHLH proteins and activates transcription of genes that contain a specific DNA sequence known as the E-box. Regulates expression of the insulin gene.

• MODY 7 - due to mutations in the gene KLF11, located on the short arm of chromosome 2 (2p25). The protein encoded by this gene is a transcription factor that activates the promoters of genes epsilon and gamma-globin and in a much lesser degree, the beta-globin gene. This binding inhibits cell growth and causes apoptosis.

• MODY 8 - due to mutations in the CEL gene, located on the long arm of chromosome 9 (9q34.3). The protein encoded by this gene is a glycoprotein secreted by the pancreas in the digestive tract and mammary gland infant. The physiological role of this protein hydrolysis and absorption of cholesterol and fat - soluble vitamins. This protein promotes the production of chylomicrons in the intestine. Also its presence in plasma suggests their interactions with cholesterol and oxidized lipoproteins to modulate the progression of atherosclerosis.

• MODY 9 - due to mutations in the Pax4 gene, located on the long arm of chromosome 7 (7q32). This gene plays an important role in the development and differentiation of the beta cells of pancreatic islets. It is a transcriptional repressor that binds to a common element in the promoters of glucagon, insulin and somatostatin.

• MODY 10 - due to mutations in the gene INS (Insulin), located on the short arm of chromosome 11 (11p15.5). The INS gene encoding the hormone insulin, necessary to control glucose levels in blood. Insulin is produced in a precursor form called proinsulin, consisting of a single amino acid chain. Proinsulin chain is cleaved to form individual units (the A and B chains) which are joined together by disulfide bonds to form insulin.

• MODY 11 - due to mutations in the gene BLK, located on the short arm of chromosome 8 (8p23-p22). This gene encodes a non - receptor tyrosine kinase involved in the development, differentiation and cell signaling B. The signaling B cell receptor (BCR) requires strict regulation of various protein tyrosine kinases and phosphatases, and coreceptors associated. Antigen binding receptor B cell antigen (BCR) signaling triggers which eventually leads to the activation of B cells through BLK signaling plays an important role in signal transmission through surface immunoglobulin and validates transition pro-B pre-B and signaling for growth arrest and apoptosis.

This disease is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient for the disease to be expressed.

Tests performed in IVAMI: in IVAMI we perform mutation detection either type of MODY (1 to 11), by complete PCR amplification of the exons of HNF4A, GCK, HNF1A, PDX1, TCF2, NEUROD1 genes, KLF11, CEL, PAX4, and BLK INS, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).