Role of Actionable Genes in Pursuing a True Approach of Precision Medicine in Monogenic Diabetes
Abstract
:1. Introduction
2. Monogenic Diabetes
3. ABCC8 and KCNJ11
ABCC8/KCNJ11 Actionability
- (a)
- If the mother carries an ABCC8 or KCNJ11 activating mutation, and the fetus has a normal genotype, sulfonylureas therapy can result in excessive insulin secretion that induce macrosomia and neonatal HH in the baby [66,67,68]; when ultrasound monitoring results suggest this possibility, transfer from sulphonylureas to insulin is recommended [69].
- (b)
- If both the mother and the fetus carry an ABCC8 or KCNJ11 activating mutation, babies benefit from early exposure to sulphonylureas treatment which prevents the low birth weight caused by reduced insulin secretion in the uterus [40,59]; sulphonylureas treatment should be, therefore, continued at the lowest dose required to obtain the optimal glycemic control [69].
4. GCK
GCK Actionability
- (a)
- If the mother carries a GCK mutation a non-mutated fetus senses maternal hyperglycemia and consequently increases insulin secretion that, in turn, causes macrosomia (suggested by accelerated fetal growth at ultrasound and resulting in a final birth weight increased by 550–700 g) [83,84]. In these cases, insulin treatment of the pregnant mother is necessary.
- (b)
- If both the mother and the fetus carry a GCK mutation, insulin treatment is not recommended because fetal growth will be normal [72].
- (c)
5. Hepatocyte Nuclear Factors (HNF) Family
5.1. HNF1A
HNF1A Actionability
5.2. HNF4A
HNF4A Actionability
5.3. HNF1B
HNF1B Actionability
6. PPARG
PPARG Actionability
7. GATA4 and GATA6
7.1. GATA4
7.2. GATA6
7.3. GATA4 and GATA6 Actionability
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene | Mutation | Phenotype | Disease Mechanism | Additional Complication | Birth Weight | Actionability |
---|---|---|---|---|---|---|
ABCC8/ KCNJ11 | Heterozygous and Homozygous GOF | Neonatal diabetes MODY Adult-onset diabetes | KATP channel permanently open, K+ efflux/membrane hyperpolarization/defective insulin secretion | Neurodevelopment dysfunction | Normal, as long as maternal hyperglycemia is properly treated Low, when only the fetus is mutated | High dose of sulphonylureas (also in pregnancy, as long as the fetus is mutated; otherwise, insulin should be given) |
GCK | Heterozygous LOF Homozygous/Compound heterozygous LOF | GCK-MODY (moderate fasting hyperglycemia from birth, low risk of chronic complication) Neonatal diabetes | Increased glucose sensor threshold (glucose stimulated insulin secretion begins at higher glucose level) | None | Normal, as long as maternal hyperglycemia is properly treated Low, when only the fetus is mutated | No treatment needed (except during pregnancy when insulin is the treatment of choice) |
HNF1A | Heterozygous and Homozygous LOF | HNF1A-MODY (fasting glycemia increase with age, normoglycemic glycosuria, liver adenomatosis) | Reduced HNF1A expression, reduced β-cell mass, blunted glycolysis and ATP production and eventually defective insulin secretion | Retinopathy, nephropathy and neuropathy are common. Ketoacidosis can develop | Normal, as long as maternal hyperglycemia is properly treated | Low dose of sulphonylureas also in pregnancy for the first two trimesters (when both the mother and the fetus are mutated) |
HNF4A | Heterozygous LOF | HNF4-MODY (fasting glycemia increase with age, liver dysfunction) | Reduced HNF1A expression, reduced β-cell mass, blunted glycolysis and ATP production and eventually defective insulin secretion | Reduced triglycerides and lipoprotein serum concentration | Normal, as long as maternal hyperglycemia is properly treated | |
HNF1B | Heterozygous LOF | HNF1B-MODY (high fasting glycemia, ketoacidosis) | Reduced HNF1B expression, pancreatic hypoplasia, blunted glycolysis and ATP production and eventually defective insulin secretion | Kidney cysts and urinary tract abnormalities, atrophic pancreas, genital abnormalities, hyperuricemia, gout | Normal, as long as maternal hyperglycemia is properly treated Low, when only the fetus is mutated | Systemic screening for renal cysts, exocrine pancreatic function and genital abnormalities (especially in females) |
PPARG | Heterozygous LOF | Severe insulin resistance | Defective adipocyte differentiation due to PPARG haploinsufficiency or dominant negative LOF mutation | Familial partial lipodystrophy type 3 (early-onset diabetes, hypertension, severe insulin resistance and dyslipidemia, hepatic steatosis) | No clear data are available | Thiazolidinediones |
GATA4 | Heterozygous LOF or complete gene deletion | Neonatal diabetes | Dysfunctional transcriptional activity, and altered embryonic organ development | Congenital heart malformation, pancreatic agenesis or hypoplasia | Low | Evaluation and follow up of congenital heart malformation and pancreatic agenesis/hypoplasia |
GATA6 | Heterozygous LOF | Neonatal diabetes Adult-onset diabetes | Dysfunctional transcriptional activity, and altered embryonic organ development | Congenital biliary tract anomalies, gut developmental disorders, neurocognitive abnormalities, additional endocrine abnormalities | Low |
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Marucci, A.; Rutigliano, I.; Fini, G.; Pezzilli, S.; Menzaghi, C.; Di Paola, R.; Trischitta, V. Role of Actionable Genes in Pursuing a True Approach of Precision Medicine in Monogenic Diabetes. Genes 2022, 13, 117. https://doi.org/10.3390/genes13010117
Marucci A, Rutigliano I, Fini G, Pezzilli S, Menzaghi C, Di Paola R, Trischitta V. Role of Actionable Genes in Pursuing a True Approach of Precision Medicine in Monogenic Diabetes. Genes. 2022; 13(1):117. https://doi.org/10.3390/genes13010117
Chicago/Turabian StyleMarucci, Antonella, Irene Rutigliano, Grazia Fini, Serena Pezzilli, Claudia Menzaghi, Rosa Di Paola, and Vincenzo Trischitta. 2022. "Role of Actionable Genes in Pursuing a True Approach of Precision Medicine in Monogenic Diabetes" Genes 13, no. 1: 117. https://doi.org/10.3390/genes13010117
APA StyleMarucci, A., Rutigliano, I., Fini, G., Pezzilli, S., Menzaghi, C., Di Paola, R., & Trischitta, V. (2022). Role of Actionable Genes in Pursuing a True Approach of Precision Medicine in Monogenic Diabetes. Genes, 13(1), 117. https://doi.org/10.3390/genes13010117