ONECUT1 – Neonatal Diabetes Mellitus

Biallelic loss-of-function variants in ONECUT1 have been established as a cause of autosomal recessive neonatal diabetes mellitus (NDM). Initially, two unrelated individuals presenting with intrauterine growth restriction, pancreas hypoplasia and early-onset diabetes were shown to harbor recessive ONECUT1 mutations ([PMID:34663987]). A subsequent analysis of large monogenic diabetes cohorts and UK Biobank data identified an additional individual with a homozygous frameshift variant causing NDM ([PMID:37639628]).

Genetic evidence supports an autosomal recessive inheritance mode with at least three probands carrying biallelic null variants. Reported variants include c.693G>T (p.Glu231Asp) observed in functional screening and mutational analyses of ONECUT1 ([PMID:37639628]). No significant enrichment of missense or null ONECUT1 alleles was detected among 484 suspected MODY cases, underscoring specificity for neonatal-onset disease ([PMID:37639628]).

Segregation data are limited, with no additional affected family members beyond the probands described. However, the recurrence of loss-of-function alleles in distinct populations and ethnicities strengthens the genetic association.

Functional studies demonstrate that loss of ONECUT1 disrupts pancreatic progenitor formation and the subsequent endocrine differentiation program. Directed differentiation of human pluripotent stem cells lacking ONECUT1 revealed reduced NKX2.2 and NKX6.1 expression in pancreatic progenitors ([PMID:34663987]). A CRISPR interference screen further identified a distal enhancer (ONECUT1e-664kb) whose deletion abolished ONECUT1 expression and impaired pancreatic lineage commitment ([PMID:39163202]).

There is no conflicting evidence disputing the role of ONECUT1 in NDM. Although monoallelic variants confer risk for later-onset diabetes, only biallelic loss-of-function alleles are causative for neonatal-onset disease.

In summary, genetic and experimental data converge to define ONECUT1 as a key regulator of human β-cell development. Identification of biallelic null variants informs molecular diagnosis and enables precision management of neonatal diabetes.

Key take-home: ONECUT1 loss-of-function underlies autosomal recessive neonatal diabetes, supporting its inclusion in early genetic testing panels.

References

• Nature Medicine • 2021 • Mutations and variants of ONECUT1 in diabetes. PMID:34663987
• Diabetes • 2023 • The Role of ONECUT1 Variants in Monogenic and Type 2 Diabetes Mellitus. PMID:37639628
• Cell Reports • 2024 • CRISPR screening uncovers a long-range enhancer for ONECUT1 in pancreatic differentiation and links a diabetes risk variant. PMID:39163202

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