PAX4 – Monogenic Diabetes

PAX4 (HGNC:8618) encodes a paired-box homeodomain transcription factor essential for pancreatic β-cell development and maintenance. Heterozygous variants in PAX4 have been implicated in maturity-onset diabetes of the young (MODY) and other nonautoimmune, early-onset diabetes phenotypes (MONDO:0015967). Genetic testing for PAX4 complements existing MODY gene panels to guide diagnosis and personalized therapy.

Autosomal dominant inheritance of PAX4-MODY has been demonstrated in at least three unrelated families with co-segregation of rare variants. A large Brazilian kindred harbored c.491G>A (p.Gly164Asp) segregating with early-onset diabetes and polyneuropathy in multiple affected relatives (PMID:32801813). In Thai MODY probands, a missense R164W and the splice-site IVS7-1G>A variant co-segregated with diabetes in kindreds absent from 342 controls (PMID:17426099). A Japanese family exhibited a novel 39-bp deletion (exon 3 c.374-412del39) leading to a frameshift and premature stop, segregating with MODY in father and son (PMID:21263211).

The PAX4 variant spectrum includes multiple missense changes within the homeodomain (e.g., p.Gly164Asp, p.Arg172Trp, p.Arg129Trp, p.His329Pro) and canonical splice-site mutations (IVS7-1G>A). These alleles are absent or extremely rare in population databases and cluster in functional domains critical for DNA binding and repression. No clear founder variants have been reported; age at diagnosis spans 15–50 years. Polyneuropathy (HP:0001271) is reported in some carriers.

Functional studies consistently demonstrate loss of repressor activity and β-cell dysfunction. In vitro assays show R164W, R172W, and R129W mutants fail to repress insulin and glucagon promoters (PMID:17426099; PMID:21263211). Minigene analyses of IVS7-1G>A reveal aberrant splicing with deletion of Gln250, impaired nuclear repression, and increased β-cell apoptosis under hyperglycemia (PMID:25951767). Human iPSC-derived β-like cells carrying p.Arg192His or p.Tyr186X alleles exhibit reduced insulin content and dysregulated endocrine specification, reversible by gene correction (PMID:37777536).

A common PAX4 polymorphism, p.Arg192His, confers modest type 2 diabetes risk in East Asians but lacks segregation with monogenic diabetes and is functionally hypomorphic rather than pathogenic for MODY (PMID:22521316). No studies have refuted the PAX4-MODY association.

Collectively, PAX4 meets ClinGen criteria for a Strong gene-disease association based on multiple segregating families (n=3) with concordant functional data. Genetic testing of PAX4 variants informs diagnosis of autosomal dominant MODY, enables targeted treatment, and guides genetic counseling.

References

• Diabetes, metabolic syndrome and obesity : targets and therapy • 2020 • Identification of the First PAX4-MODY Family Reported in Brazil. PMID:32801813
• The Journal of clinical endocrinology and metabolism • 2007 • PAX4 mutations in Thais with maturity onset diabetes of the young. PMID:17426099
• The Tohoku journal of experimental medicine • 2011 • A novel PAX4 mutation in a Japanese patient with maturity-onset diabetes of the young. PMID:21263211
• Acta diabetologica • 2016 • Aberrant mRNA splicing of paired box 4 (PAX4) IVS7-1G>A mutation causing maturity-onset diabetes of the young, type 9. PMID:25951767
• Journal of diabetes and its complications • 2012 • Defective PAX4 R192H transcriptional repressor activities associated with maturity onset diabetes of the young and early onset-age of type 2 diabetes. PMID:22521316
• Nature communications • 2023 • PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development. PMID:37777536

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