PTF1A – Permanent Neonatal Diabetes Mellitus

PTF1A encodes a pancreas-specific helix–loop–helix transcription factor essential for early pancreatic development and beta-cell differentiation. Loss-of-function mutations, including noncoding enhancer deletions and hypomorphic missense alleles, disrupt both endocrine and exocrine pancreas formation, leading to permanent neonatal diabetes mellitus (PNDM). Permanent neonatal diabetes mellitus manifests within the first six months of life and requires lifelong insulin therapy. The autosomal recessive inheritance of PTF1A-related PNDM is supported by consanguinity and familial segregation. Genetic testing for PTF1A coding and regulatory regions is therefore critical to establish a molecular diagnosis and guide management.

In a cohort from the Emirate of Abu Dhabi, two unrelated PNDM patients were found to harbor homozygous deletions of a distal PTF1A enhancer, presenting with diabetes at birth and exocrine pancreatic insufficiency in some cases (PMID:26463504). Similarly, in Qatar, PTF1A enhancer deletions represent the most frequent genetic cause of PNDM in a consanguineous population, underscoring the gene’s autosomal recessive inheritance pattern (PMID:31441606).

A novel hypomorphic missense variant, c.571C>A (p.Pro191Thr), was identified homozygously in two siblings from one consanguineous family and in two additional affected sibs from a second family, totaling four individuals with permanent neonatal diabetes and variable exocrine phenotypes but intact cerebellar function (PMID:27284104).

Segregation analysis across the two families demonstrated cosegregation of PTF1A variants with disease in two additional affected siblings, confirming recessive transmission (PMID:27284104). No PTF1A variants were observed in unaffected relatives.

Functional assays in pancreatic progenitor cells showed that the p.Pro191Thr protein exhibited a ~75% reduction in transactivation activity compared to wild type, consistent with a loss-of-function mechanism and haploinsufficiency (PMID:27284104). Enhancer deletions likely abolish PTF1A expression during critical windows of pancreatic organogenesis.

Together, genetic and functional data support a moderate level of clinical validity for PTF1A in permanent neonatal diabetes. Genetic testing for PTF1A coding and enhancer variants enables precise diagnosis, informs prognosis, and guides family planning and therapeutic decisions. Key take-home: PTF1A variants account for a significant proportion of autosomal recessive PNDM and should be included in neonatal diabetes gene panels.

References

• American journal of medical genetics. Part A • 2016 • Genetic characteristics, clinical spectrum, and incidence of neonatal diabetes in the Emirate of AbuDhabi, United Arab Emirates. PMID:26463504
• Molecular genetics & genomic medicine • 2019 • The clinical and genetic characteristics of permanent neonatal diabetes (PNDM) in the state of Qatar. PMID:31441606
• Diabetes • 2016 • Isolated Pancreatic Aplasia Due to a Hypomorphic PTF1A Mutation. PMID:27284104

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