PAX6 – Diabetes Mellitus

Heterozygous mutations in the paired box gene PAX6 (HGNC:8620) are a well‐established cause of congenital aniridia and have been increasingly implicated in endocrine pancreas dysfunction leading to diabetes mellitus (MONDO:0005015). PAX6 encodes a transcription factor critical for ocular and islet development; loss‐of‐function alleles result in haploinsufficiency affecting both tissues.

Genetic evidence includes four unrelated aniridia patients with truncating PAX6 mutations who all exhibited glucose intolerance and impaired insulin secretion (PMID:11756345), a de novo heterozygous 2-bp deletion c.402_404del (p.Ser136del) in a 27-year-old with early-onset diabetes diagnosed at 15 (PMID:15842522), and a three-member family in which a 484–630 kb deletion distal to PAX6 cosegregated dominantly with aniridia and diabetes (PMID:30572005). A recent case described a heterozygous Gln135Ter mutation impairing insulin promoter transactivation in β-cells (PMID:35979842).

Inheritance is autosomal dominant with evidence of segregation in affected relatives (three members cosegregating) and no reported unaffected carriers. The spectrum of PAX6 alleles includes frameshift and nonsense mutations in both DNA-binding and transactivation domains, as well as regulatory deletions affecting PAX6 expression.

Functional studies demonstrate that PAX6 deficiency impairs prohormone convertase 1/3 (PC1/3) expression and proinsulin processing, leading to defective insulin maturation. Heterozygous R240Stop human patients and Pax6 R266Stop mice show decreased PC1/3 levels and abnormal glucose tolerance (PMID:19034419). The Gln135Ter mutant fails to activate insulin gene transcription in vitro, confirming a loss‐of‐function mechanism.

No conflicting evidence has been reported to date. The concordance between genetic segregation, multiple unrelated case reports, and mechanistic functional assays supports a pathogenic role for PAX6 haploinsufficiency in monogenic diabetes associated with aniridia.

Key Take-home: Heterozygous PAX6 mutations confer a clinically actionable risk for diabetes mellitus via impaired insulin processing; glucose monitoring is advised in PAX6 mutation carriers.

References

• Diabetic Medicine • 2005 • A case of novel de novo paired box gene 6 (PAX6) mutation with early-onset diabetes mellitus and aniridia. PMID:15842522
• Diabetes • 2002 • PAX6 mutation as a genetic factor common to aniridia and glucose intolerance. PMID:11756345
• Diabetologia • 2009 • Paired box 6 (PAX6) regulates glucose metabolism via proinsulin processing mediated by prohormone convertase 1/3 (PC1/3). PMID:19034419
• Diabetes Research and Clinical Practice • 2019 • Deletion distal to the PAX6 coding region reveals a novel basis for familial cosegregation of aniridia and diabetes mellitus. PMID:30572005
• Endocrinology, Diabetes & Metabolism Case Reports • 2022 • A case of early-onset diabetes with impaired insulin secretion carrying a PAX6 gene Gln135 mutation.* PMID:35979842

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