How a single mutation causes diabetes

Monogenic diabetes is a rare, potentially devastating form, that is usually identified in infants and children under 15 years of age. Unlike the more common type 1 and 2 diabetes, monogenic diabetes is purely hereditary — and only one genetic mutation is needed to trigger the condition. However, the mechanisms by which single-gene mutations induce diabetes symptoms are not well understood.

A team led by Yazeid Alhaidan, who is affiliated with the King Abdullah International Medical Research Center in Riyadh and Odense University Hospital in Denmark, have now identified a gene, EDEM2, behind the diabetes symptoms of two members of a single family. The researchers also showed how changes in EDEM2 cause monogenic diabetes, which may point the way towards therapeutic interventions.

The first person, a lean Caucasian girl, was presumed to have type 1 diabetes at the age of 2.5. The second, her lean father, was presumed to have type 1 diabetes at the age of 11. They were recruited to the study at the age of 23 and 54, respectively. 

Subsequent antibody tests showed that the girl and her father were negative for type 1 diabetes. However, both displayed diabetes symptoms, including high fasting blood sugar levels, low serum insulin levels, low fasting serum C-peptide levels and low fasting serum proinsulin levels.

Whole-exome sequencing analysis revealed that they both had a paternally inherited mutation in EDEM2. Gene knockdown assays using rat pancreatic cell lines showed that the deletion of EDEM2 led to suppressed insulin secretion. Further tests showed that downregulation of EDEM2 led to a huge decline in the expression of INS1 and INS2, which regulate insulin secretion, as well as –PXD1 and GLUT2, which control the development of insulin-producing beta cells and their glucose uptake.

The findings have important implications for the treatment and diagnosis of monogenic diabetes. “Monogenic diabetes is often mistakenly diagnosed as T1DM,” says Alhaidan, adding that “correct diagnosis will lead to better treatment, management, and surveillance of complications, as well as having important implications for siblings and offspring.” 

The researchers suggest that targeting the actions of EDEM2 and the link with PXD1 downregulation may help restore insulin levels in patients suffering EDEM2-related monogenic diabetes.

The researchers carried out an extended family segregation study and showed that the EDEM2 mutation was present in two other family members — the paternal grandmother, aged 76, and the paternal sister, aged 56. However, unlike the girl and her father, these two family members had no history of diabetes and did not display symptoms of monogenic diabetes. The researchers therefore conclude that the EDEM2 mutation has limited penetrance, meaning that it is possible for some people to carry the mutation without ever displaying symptoms of monogenic diabetes.

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