Genetic Mutation Linked to New Form of Diabetes

Finding the genetic cause of rare familial diabetes (monogenic diabetes) provides new biological insights into human pancreas development and function, as well as potentially novel therapeutic targets with important treatment implications.

Maturity-onset diabetes of the young (MODY) is a type of monogenic diabetes that develops as a result of beta-cell dysfunction and generally presents itself in affected patients before they are 25 years old. Individuals with MODY also tend to be non-obese, non-insulin-dependent and have an autosomal dominant inheritance of diabetes.


An international team of scientists working with those at the University of Exeter Medical School, (Exeter, UK) studied different cohorts comprised of a discovery cohort comprises 38 European probands with strong MODY-like phenotype who did not have mutations in the three most common MODY genes; a replication cohort was derived from 469 non-Finnish European routine MODY diagnostic referrals; a Finnish-European replication MODY cohort, that consisted of 80 patients who were routinely referred for MODY diagnostic testing; and two other cohorts.

Plasma glucose was analyzed using the Hemocue Glucose System. Serum insulin was measured by an AutoDelfia fluoroimmunometric assay and serum C-peptide by Cobas e411 electrochemiluminometric immunoanalysis. Serum gastric inhibitory polypeptide (GIP) was analyzed using Millipore’s Human GIP Total ELISA. They sequenced MODY cases with unknown etiology and compared variant frequencies to large public databases. Amplicons were sequenced and reactions were analyzed on an ABI 3730 Capillary sequencer.

The investigators found that from 36 European patients, they identify two probands with novel Regulatory Factor X6 (RFX6) heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population. They found similar results in 348 non-Finnish Europeans and 80 Finnish replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common MODY mutations. The hyperglycemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Of 27 patients who expressed RFX6-MODY, 81% were female and most patients were around 32 years old at the time of diagnosis.

Michael L. Weedon, PhD, the lead author of the study, said, “There has been limited recent success in finding new MODY genes. The reason for this limited success is the difficulty of distinguishing monogenic diabetes patients from those with type 1 diabetes, or from the increasing number of patients with early-onset type 2 diabetes due to rising rates of obesity.” The study was published on October 12, 2017, in the journal Nature Communications.

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University of Exeter Medical School