Russ-Silsby James, Patel Kashyap A, Laver Thomas W, Hawkes Gareth, Johnson Matthew B, Wakeling Matthew N, Patil Prashant P, Hattersley Andrew T, Flanagan Sarah E, Weedon Michael N, De Franco Elisa
Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, U.K.
The Society for the Rehabilitation of Crippled Children Narayana Health Children's Hospital, Mumbai, India.
Diabetes. 2023 Nov 1;72(11):1729-1734. doi: 10.2337/db23-0498.
ONECUT1 (also known as HNF6) is a transcription factor involved in pancreatic development and β-cell function. Recently, biallelic variants in ONECUT1 were reported as a cause of neonatal diabetes mellitus (NDM) in two subjects, and missense monoallelic variants were associated with type 2 diabetes and possibly maturity-onset diabetes of the young (MODY). Here we examine the role of ONECUT1 variants in NDM, MODY, and type 2 diabetes in large international cohorts of subjects with monogenic diabetes and >400,000 subjects from UK Biobank. We identified a biallelic frameshift ONECUT1 variant as the cause of NDM in one individual. However, we found no enrichment of missense or null ONECUT1 variants among 484 individuals clinically suspected of MODY, in whom all known genes had been excluded. Finally, using a rare variant burden test in the UK Biobank European cohort, we identified a significant association between heterozygous ONECUT1 null variants and type 2 diabetes (P = 0.006) but did not find an association between missense variants and type 2 diabetes. Our results confirm biallelic ONECUT1 variants as a cause of NDM and highlight monoallelic null variants as a risk factor for type 2 diabetes. These findings confirm the critical role of ONECUT1 in human β-cell function.
ONECUT1（也称为HNF6）是一种参与胰腺发育和β细胞功能的转录因子。最近，有报道称ONECUT1的双等位基因变异是两名受试者新生儿糖尿病（NDM）的病因，错义单等位基因变异与2型糖尿病以及可能的青年成年发病型糖尿病（MODY）相关。在此，我们在患有单基因糖尿病的大型国际队列受试者以及来自英国生物银行的40多万名受试者中，研究了ONECUT1变异在NDM、MODY和2型糖尿病中的作用。我们鉴定出一种双等位基因移码ONECUT1变异是一名个体患NDM的病因。然而，我们在484名临床疑似MODY且所有已知基因均已排除的个体中，未发现错义或无效ONECUT1变异的富集。最后，在英国生物银行欧洲队列中使用罕见变异负担测试，我们鉴定出杂合性ONECUT1无效变异与2型糖尿病之间存在显著关联（P = 0.006），但未发现错义变异与2型糖尿病之间存在关联。我们的结果证实双等位基因ONECUT1变异是NDM的病因，并强调单等位基因无效变异是2型糖尿病的一个风险因素。这些发现证实了ONECUT1在人类β细胞功能中的关键作用。
