PAX4 – Maturity-onset diabetes of the young

PAX4 encodes a paired-homeodomain transcriptional repressor essential for pancreatic β-cell differentiation. Maturity-onset diabetes of the young (MODY) is an autosomal-dominant monogenic diabetes characterized by early onset (often <25 years) and absence of autoimmunity markers. Multiple case reports and functional studies have implicated PAX4 mutations in MODY9 (MODY subtype 9).

Genetic evidence includes a Japanese family with a heterozygous 39-base deletion predicted to cause exon skipping and premature truncation, identified in the proband and his affected father (c.385C>T (p.Arg129Trp)) ([PMID:21263211]). In Thai families, two novel variants—c.514C>T (p.Arg172Trp) and IVS7-1G>A—co-segregate with diabetes in multiple generations ([PMID:17426099]; [PMID:25951767]). A novel missense variant, c.890G>A (p.Gly297Asp), co-segregated with diabetes or prediabetes across three generations involving 11 affected relatives ([PMID:37621150]).

Segregation analyses demonstrate co-segregation of PAX4 variants with diabetes in three independent pedigrees, totaling 11 affected first- and second-degree relatives. All reported alleles are heterozygous and follow an autosomal-dominant pattern.

Functional assays consistently show loss of PAX4 transcriptional repression on insulin and glucagon promoters. Luciferase reporter experiments for p.Arg129Trp and p.Arg172Trp revealed impaired repressor activity, and minigene splicing assays confirmed cryptic splice-site usage and increased β-cell apoptosis under hyperglycemic conditions ([PMID:21263211]; [PMID:22521316]; [PMID:25951767]).

A French linkage and mutation screening study found no PAX4 variants in MODY or late-onset Type II diabetes cohorts, suggesting ethnic specificity of variant penetrance rather than refutation of pathogenicity ([PMID:10230653]).

In summary, PAX4 meets criteria for a strong clinical validity association with MODY based on four unrelated probands, robust segregation in three families, and concordant functional data. PAX4 mutation screening is recommended in early-onset, autoantibody-negative diabetes for precise diagnosis and management. Key take-home: inclusion of PAX4 in MODY gene panels enables targeted therapy and genetic counseling.

References

• The Tohoku journal of experimental medicine • 2011 • A novel PAX4 mutation in a Japanese patient with maturity-onset diabetes of the young [PMID:21263211]
• The Journal of clinical endocrinology and metabolism • 2007 • PAX4 mutations in Thais with maturity onset diabetes of the young [PMID:17426099]
• 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 pediatric endocrinology & metabolism • 2023 • Novel PAX4 variant in a child and family with diabetes mellitus - case report and review of the literature [PMID:37621150]
• 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]
• Diabetologia • 1999 • No evidence of linkage or diabetes-associated mutations in the transcription factors BETA2/NEUROD1 and PAX4 in Type II diabetes in France [PMID:10230653]

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