PTF1A – Neonatal Diabetes Mellitus

Multiple independent studies have demonstrated a strong association between mutations in PTF1A (HGNC:23734) and neonatal diabetes mellitus (MONDO_0016391). In particular, case reports and series have identified homozygous enhancer mutations and compound heterozygous variants that segregate with early‐onset diabetes, with affected individuals often presenting with pancreatic agenesis or hypoplasia. For instance, two siblings with a PTF1A enhancer mutation had variable phenotypes, with one presenting with typical neonatal diabetes (PMID:26184423). Additional families have shown segregation of both truncating and enhancer mutations, supporting an autosomal recessive inheritance pattern. Genetic evidence is bolstered by recurrent reports of the mutation c.571C>A (p.Pro191Thr) in unrelated families (PMID:27284104). These findings are complemented by case series where detailed molecular analyses uncovered compound heterozygosity or homozygosity in affected individuals, further supporting the link between PTF1A disruption and neonatal diabetes (PMID:28663161).

Functional assessments have provided mechanistic insight into the role of PTF1A in pancreatic development. In vitro transient transfection assays demonstrated that the p.Pro191Thr variant reduces transactivation activity by approximately 75%, corroborating the clinical findings (PMID:27284104). Such functional data support the hypothesis of a haploinsufficiency or hypomorphic mechanism underlying pancreatic agenesis and subsequent diabetes. The integration of molecular genetics with functional studies strengthens the clinical validity of this gene–disease association.

Several studies have also noted phenotypic variability among patients harboring PTF1A mutations aside from neonatal diabetes. While some present with isolated endocrine deficiencies, others exhibit exocrine pancreatic insufficiency without cerebellar involvement. This variability emphasizes the need for comprehensive genetic testing when evaluating neonatal diabetes, as the presence of additional phenotypes may modify management strategies. Furthermore, identification of recurrent variants such as c.571C>A (p.Pro191Thr) has prognostic implications and influences targeted clinical intervention.

The aggregation of genetic, segregation, and functional evidence across multiple cohorts places this association in the strong category. The overall strength is derived from several unrelated probands (e.g. 2 siblings in one report and compound heterozygotes in others (PMID:26184423, PMID:28663161) and consistent experimental findings (PMID:27284104).

In summary, the integration of genetic findings and robust functional data supports a strong link between PTF1A mutations and neonatal diabetes mellitus. This association not only aids in diagnostic decision‑making but also facilitates targeted patient management and informed genetic counseling. The collective evidence underlines the clinical utility of genetic testing in early-onset diabetes and highlights the importance of considering PTF1A in patients with pancreatic developmental anomalies.

Key Take‑home Message: PTF1A mutations represent a clinically actionable determinant in neonatal diabetes mellitus, where early genetic diagnosis can significantly influence therapeutic strategies.

References

• Hormone research in paediatrics • 2015 • Variable Phenotype of Diabetes Mellitus in Siblings with a Homozygous PTF1A Enhancer Mutation PMID:26184423
• Journal of clinical research in pediatric endocrinology • 2017 • Pancreatic Agenesis due to Compound Heterozygosity for a Novel Enhancer and Truncating Mutation in the PTF1A Gene PMID:28663161
• Diabetes • 2016 • Isolated Pancreatic Aplasia Due to a Hypomorphic PTF1A Mutation PMID:27284104

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