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Exome Sequencing Finds Mutation in Families With High, Low Blood Sugar Conditions

NEW YORK (GenomeWeb) – Two families in which some people have contradictory conditions due to high blood sugar and low blood sugar levels share a missense mutation, according to a new study.

Both families contain members with diabetes and others with insulinomatosis, multiple pancreatic tumors that produce insulin and lower blood sugar levels.

Researchers from Queen Mary University of London and elsewhere sequenced the exomes of four affected members of one family to find a missense mutation in the MAFA gene. As they reported in the Proceedings of the National Academy of Sciences, the researchers then found that same mutation among other members of that first family as well as in the second family.

"We were initially surprised about the association of two apparently contrasting conditions within the same families," author Márta Korbonits from Queen Mary University of London said in a statement. "Our research shows that, surprisingly, the same gene defect can impact the insulin-producing beta cells of the pancreas to lead to these two opposing medical conditions."

Korbonits and her colleagues sequenced the exomes of four affected people from the first family to find they all shared a missense mutation in the MAFA gene. When they tested all 25 members of that family for the mutation, they found an additional 14 members who were heterozygous for it and two who were homozygous. Seven of the heterozygous individuals had insulinomas, 10 had diabetes, and one was unaffected. The homozygous individuals had diabetes as well as congenital cataracts or glaucoma.

MAFA encodes a transcription factor that is enriched within the beta cells of the pancreas, where it regulates the expression of insulin and acts as a barometer for glucose. This, the researchers noted, was the first time MAFA has been linked to a disease, though it has been found to have oncogenic potential when overexpressed in vitro

Targeted sequencing of a second family with the same disease pattern likewise uncovered this missense MAFA mutation. Five individuals from this family with the mutation had insulinomatosis, one had diabetes, and two were not thought to be affected. In addition, three deceased family members — two with diabetes and one with insulinomatosis — were obligate carriers, the researchers noted.

They also tested a cohort of nine people with sporadic insulinomatosis for the mutation, but none harbored it.

This missense mutation leads to serine being swapped for phenylalanine at a highly conserved residue in the N-terminal transactivating domain of the MAFA protein, the researchers noted. Korbonits and her colleagues suspected that this substitution at residue 64 affects its neighboring residue, Ser65, which has previously been shown to be a priming phosphorylation site. They said that the mutation appears to boost the transactivation capacity of the MAFA protein.

They likewise found that MAFA protein with the p.Ser64Phe mutation is more stable and doesn't turn over as quickly as the wild-type protein does.

The researchers noted that increased activity and higher MAFA protein levels are predicted to induce the expression of cell-cycle regulation genes and affect insulin secretion.

However, the researchers noted that the mechanisms underlying the link between MAFA and insulinomatosis or diabetes is not yet clear. "We believe this gene defect is critical in the development of the disease and we are now performing further studies to determine how this defect can, on the one hand, impair the production of insulin to cause diabetes, and on the other, cause insulinomas," first author Donato Iacovazzo added.