Table 1.
MODY-Monogenic Diabetes: Gene, Protein, Function, Treatment, and Inheritance
| Gene (OMIM) | Protein | Function | Treatment | Inheritance | References |
|---|---|---|---|---|---|
| HNF4A (600281) – Formerly MODY1 | Hepatocyte nuclear factor 4α | Beta-cell transcription factor | First-line treatment: Sulfonylurea | Autosomal dominant | (3, 6, 8, 9) |
| Second-line treatments: GLP-1 RA (10), insulin | |||||
| GCK (138079) – Formerly MODY2 | Glucokinase | Glucose-sensor, first rate-limiting enzyme in glycolysis | No medication or diet, unless pregnancy (see Tables 2A and 2B) | Autosomal dominant | (6, 7, 11) |
| OR | |||||
| Neonatal diabetes: Autosomal recessive (neonatal cases) | |||||
| HNF1A (142410) – Formerly MODY3 | Hepatocyte nuclear factor 1α | Beta-cell transcription factor | First-line: Low-dose sulfonylurea or meglitinides | Autosomal dominant | (6, 12–17) |
| Second-line treatments: GLP-1 RA, DPP-4 inhibitors, insulin | |||||
| PDX1 a (606392) – Formerly MODY4 | Pancreas/duodenum homeobox protein 1 | Pancreatic and beta-cell development and function | First-line: OHAs/sulfonylureas | Most are Autosomal recessive | (6, 18, 19) |
| Second-line: Insulin | |||||
| HNF1B (189907) – Formerly MODY5 | Hepatocyte nuclear factor 1β | Beta-cell transcription factor | Minority respond to sulfonylureas, insulin | Autosomal dominant | (6, 20–23) |
| NEUROD1 a (601724) – Formerly MODY6 | Neurogenic differentiation factor 1 | Beta-cell transcription factor | First-line: Diet, OHA/sulfonylureas, | Autosomal dominant | (6, 24, 25) |
| Second-line: Insulin | |||||
| KLF11 a (603301) – Formerly MODY7 | Krueppel-like factor 11 | Zinc finger transcription factor that binds to SP-1-like sequences in epsilon and gamma-globin gene promoters. This binding (when functioning normally) inhibits cell growth and apoptosis | Insulin | Autosomal Dominant | (6, 18, 19) |
| CEL (114840) – Formerly MODY8 | Carboxyl ester lipase | Exocrine pancreas function (if mutated, leads to pancreatic atrophy and exocrine pancreatic insufficiency) Fibrosis and lipomatosis leading to diabetes | First-line: Oral hypoglycemic agents (OHAs)/sulfonylureas | Deletion of variable number of tandem repeat | (6, 26) |
| Second-line: Insulin (the pancreas needs to be damaged/destroyed to necessitate treatment) | |||||
| PAX4 a (167413) – Formerly MODY9 | Paired box 4 | Differentiation of endoderm-derived endocrine pancreas | First-line: Diet, OHAs/sulfonylureas | Autosomal dominant | (6, 18, 19) |
| Second-line: Insulin | |||||
| INS (176730) – Formerly MODY10 | Insulin | Production of insulin or insulin action | Diet, OHAs/sulonfylureas or insulin (may be small doses of insulin) | Autosomal dominant | (6, 27, 28) |
| OR | |||||
| Neonatal diabetes: Dominant, often de novo or recessive | |||||
| BLK a (191305) – Formerly MODY11 | Tyrosine-protein kinase BLK (Nonreceptor tyrosine kinase of the src family of proto-oncogenes) | Expressed in β-cells where it enhances insulin synthesis and secretion in response to glucose by up-regulating transcription factors Pdx1 and Nkx6.1 | First-line: Diet, OHAs/sulfonylureas | Autosomal dominant | (6, 18, 19, 29) |
| Second-line: Insulin | |||||
| ABCC8 (600509) – Formerly MODY12 | Sulfonylurea receptor subunit of β-cell KATP channel | Closure of ATP-sensitive potassium channel leads to beta-cell membrane depolarization, calcium influx and fusion of insulin secretory granules with β-cell membrane | First-line: Sulfonylurea | Autosomal Dominant | (6, 30–32) |
| Second-line: SGLT-2 inhibitors, insulin | |||||
| OR | |||||
| Neonatal diabetes: Dominant, often de novo or recessive | |||||
| KCNJ11 (600937) – Formerly MODY13 | Potassium channel subunit of β-cell KATP channel | Closure of the ATP-sensitive potassium channel leads to beta-cell membrane depolarization, calcium influx and fusion of insulin secretory granules with β-cell membrane | OHAs/sulfonylurea, insulin | Autosomal dominant | (6, 33, 34) |
| OR | |||||
| Neonatal diabetes: Dominant, often de novo | |||||
| APPL1 (604299) - Formerly MODY14 | Adaptor protein, phosphotyrosine interaction, PH domain, and leucine zipper containing 1 | Protein that bind to AKT in the insulin-signaling pathway | First-line: Diet, OHAs/sulfonylureas | Autosomal dominant | (6, 35) |
| Second-line: insulin | |||||
| WSF1 (606201) | Wolframin | Function of the endoplasmic reticulum | Multidisciplinary approach (DI, DM, hypogonadism, psychiatric manifestations, neurologic manifestations) | Autosomal recessive | (18, 36) |
aVariants in APPL1, CEL, BLK, KLF11, NEUROD1, PAX4, and PDX1 have previously been published as variants at population frequencies that are not consistent with clinical significance (6). This is due to variants in BLK, KLF11, NEUROD1, PAX4, and PDX1 being reported in the Human Gene Mutation (HGMD) as pathogenic, but are present in the Exome Aggregation Consortium (ExAC) Database in the Genome Aggregation Database (gnomAD) at population frequencies that are not consistent with their potential clinical significance (6). Additional studies are needed and consultation with an expert is necessary to understand their association with clinical pathogenesis.
Abbreviations: DPP-4, dipeptidyl peptidase-4; GLP-1 RA, glucagon-like peptide-1 receptor agonist; KATP, potassium-sensitive ATP channel; MODY, maturity-onset diabetes of the young; OHA, oral hypoglycemia agent; SGLT-2, sodium–glucose co-transporter-2.