PAX4 – MODY9 (Maturity-Onset Diabetes of the Young, Type 9)

PAX4, a paired-homeodomain transcription factor critical for pancreatic β-cell development, has been implicated in autosomal dominant maturity-onset diabetes of the young type 9 ([MODY9]) via rare heterozygous variants. MODY9 is characterized by early-onset hyperglycemia, polyuria, and polydipsia, requiring tailored therapeutic strategies ([PMID:36595822]).

Genetic evidence includes at least 4 unrelated probands with heterozygous PAX4 variants: one Chinese infant with c.487C>T ([PMID:36595822]), two Thai probands carrying R164W and IVS7-1G>A ([PMID:17426099]), and a Japanese patient harboring c.385C>T (p.Arg129Trp) with familial segregation ([PMID:21263211]). The mode of inheritance is autosomal dominant, and R164W segregated with diabetes in multiple affected family members (3 relatives) ([PMID:17426099]).

The variant spectrum comprises missense changes (e.g., c.385C>T (p.Arg129Trp)), splice-site disruptions (c.772-1G>A leading to p.Gln250del), and frameshift or nonsense alleles. No recurrent or founder variants have been described to date, and population frequencies are absent, underscoring rarity in MODY9.

Functional studies demonstrate that splicing mutation IVS7-1G>A disrupts the PAX4 acceptor site, yielding a p.Gln250del protein with impaired repression of insulin and glucagon promoters and increased β-cell apoptosis under hyperglycemic stress ([PMID:25951767]). R164W and p.Arg192His alleles also exhibit reduced transcriptional repressor activity on β-cell target promoters in luciferase assays, consistent with a loss-of-function mechanism ([PMID:17426099]; [PMID:22521316]). Human iPSC-derived islet models with p.Arg192His and p.Tyr186Ter show aberrant endocrine differentiation and diminished insulin content, reversible by gene correction ([PMID:37777536]).

Although PAX4 p.Arg192His is a common East Asian risk allele for type 2 diabetes, its modest effect contrasts with the highly penetrant loss-of-function mutations in MODY9, emphasizing distinct clinical contexts ([PMID:29941447]).

Integration of genetic segregation and robust functional data supports a Strong gene–disease association for PAX4 and MODY9. Genetic testing for PAX4 should be considered in early-onset, nonautoimmune diabetes to guide precision therapy and prognosis.

References

• Medicine • 2022 • C.487C>T mutation in PAX4 gene causes MODY9: A case report and literature review. PMID:36595822
• 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
• 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
• Nature Communications • 2023 • PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development. PMID:37777536

Evidence Based Scoring (AI generated)