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Newly identified gene mutation likely behind diabetes, insulin-producing tumors
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Researchers have identified a missense mutation in a gene responsible for the regulation of insulin secretion that is likely associated with two distinct phenotypes, including multiple insulin-producing neuroendocrine tumors and a rare type of non-insulin-dependent diabetes, according to findings reported in Proceedings of the National Academy of Sciences.
The mutation, identified as p.Ser64Phe in the MAFA gene, was identified by sequencing the exomes of multiple adults with insulinomatosis and diabetes from the same family, according to the researchers. The diabetes phenotype resembled maturity-onset diabetes of the young, or MODY.
“Targeted sequencing in a second independent family with an identical clinical phenotype revealed the same MAFA mutation, while no pathogenic variants were found in a series of patients with insulinomatosis with sporadic clinical presentation,” Donato Iacovazzo, MD, of the center for endocrinology at the London School of Medicine at Queen Mary University of London, and colleagues wrote. “Functional analysis demonstrated that the p.Ser64Phe mutation not only significantly increased the stability of MAFA, whose levels were unaffected by variable glucose concentrations in [beta]-cell lines, but also enhanced its transactivation activity.”
Researchers recruited 39 adults from two families with autosomal dominant insulinomatosis and diabetes (19 women) and nine patients with sporadic insulinomatosis (eight women), and extracted genomic DNA. The researchers performed exome sequencing in four participants with insulinomatosis from family 1, filtering heterozygous variants. The identified MAFA missense variant was investigated in silico using multiple prediction tools, and MAFA expression was assessed using immunohistochemistry in two familial insulinomatosis samples, eight sporadic insulinomatosis and six sporadic insulinoma controls, and classified as negative, weak, moderate, strong or patchy.
The researchers found that the mutation had a “profound effect” on MAFA turnover.
“Normally, MAFA is highly unstable in [beta] cells at low, nonstimulating glucose concentrations, while its stability is enhanced in the presence of high glucose concentrations,” the researchers wrote. “However, the p.Ser64Phe mutant was stable and abundant regardless of glucose levels. No significant differences were observed between transfected wild-type and mutant MAFA mRNA levels, confirming the posttranscriptional nature of the effect observed on protein turnover.”
“These data help us to understand the role of the insulin-regulating protein in beta-cell function and proliferation,” Márta Korbonits MD, PhD, professor of endocrinology and metabolism at the London School of Medicine at Queen Mary University of London, told Endocrine Today. “Our findings are important for families with these mutations.”
The researchers noted that the mechanisms explaining how the same gene mutation can lead to diabetes or insulinomatosis remains to be fully elucidated, adding that in vivo models will have to be developed to further investigate the effects of the mutation.
“We need to understand why some family members develop diabetes and why some develop insulin-secreting tumors,” Korbonits said. “Typically, but not exclusively, males developed diabetes and females insulin-secreting tumors. We need to develop a mouse model to be able to study this disease in more detail in experimental conditions. We also be looking at insulin-secreting cells where we introduced this gene mutation.” – by Regina Schaffer
For more information:
Donato Iacovazzo, MD, and Márta Korbonits MD, PhD, can be reached at d.iacovazzo@qmul.ac.uk and m.korbonits@qmul.ac.uk.
Disclosures: The authors report no relevant financial disclosures.
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