medwireNews: Mutations in the ONECUT1 gene can underlie neonatal diabetes and contribute to the risk for early-onset type 2 diabetes, research shows.
“Our findings add ONECUT1 to a small list of genes (for example, GCK) involved in monogenic recessive (severe neonatal syndromic) diabetes and monogenic dominant (adult- and juvenile-onset) diabetes, and with common regulatory variants associated with multifactorial diabetes,” say Alexander Kleger (Ulm University, Germany) and co-workers.
Their discovery, published in Nature Medicine, arose from two cases, both born to consanguineous parents, who had homozygous ONECUT1 mutations and were diagnosed with diabetes at 1 day of age and at 14 months. Both children had intrauterine growth restriction, anemia, and various other abnormalities.
The patient diagnosed at day 1 was more severely affected than the other, including with marked neurologic impairment, and died at the age of 60 days.
In addition, both patients’ mothers, plus another affected female relative, had experienced “repeated miscarriages and/or neonatal child mortality, suggesting that homozygous ONECUT1 mutations are generally lethal or result in early mortality,” say the researchers.
Both index patients had hypotrophic pancreas and gallbladder, again markedly more severe in the younger case in whom the gallbladder was entirely absent. Experiments in cultured cells revealed that the absence of ONECUT1 resulted in impaired formation of pancreatic progenitors and beta-like cell formation.
Pancreatic progenitor “numbers are known to determine pancreas size, which is consistent with pancreatic hypoplasia in patients with homozygous mutations,” write Kleger and team.
Further examination of the cases’ families revealed a high rate of altered glucose metabolism in heterozygous ONECUT1 mutation carriers, manifesting as type 2 diabetes, gestational diabetes, elevated fasting glucose, or impaired glucose tolerance.
Moreover, the researchers identified 13 incidences of heterozygous ONECUT1 mutations in a cohort of 2165 German people with presumed type 2 diabetes, but none in 397 healthy controls. And the median age at diabetes diagnosis was 29 years in these people, compared with 46 years in the rest of the cohort.
In a larger multi-ethnic cohort of 19,852 people with type 2 diabetes and 23,273 controls they found a trend toward increased likelihood of type 2 diabetes with the presence of ONECUT1 missense variants, which achieved statistical significance (odds ratio=1.31) in people of European ancestry. However, they note that the risk varied with the specific variant, with some being potentially “neutral or even protective.”
The association with younger age at onset was also reproducible in this larger cohort.
“Our data suggest that monogenetic profiles may underlie part of the clinical heterogeneity of [type 2 diabetes],” say Kleger and colleagues.
They add: “Most patients heterozygous for rare ONECUT1 coding variants had [glycated hemoglobin] values close to the normal range upon treatment, suggesting that they […] respond generally well to diabetes treatment,” similar to patients with monogenic diabetes.
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