Family pedigree enriched for diabetes and end-stage renal disease and identification of ADIPOQ mutation. a Family pedigree, diabetes (shaded), and end-stage renal disease (ESRD; red outline) and ADIPOQ mutation (p.Gly93GlufsTer73). Wild-type carriers ADIPOQ insertion (I) or mut ADIPOQ deletion (D; red) is indicated. b Structure of wild-type (top) and mutant (bottom) adiponectin protein. Wild-type adiponectin monomers consist of a 244 amino acid protein composed of four domains; N-terminal signal sequence (19 amino acids), variable region (23 amino acids), collagen domain (66 amino acids) and C-terminal globular domain (136 amino acids). A 10-nucleotide deletion (CCCGAGGCTTT→C, designated as ∆CCGAGGCTTT) at amino acid 93 creates a frameshift that truncates the adipanectin protein and generates a new peptide that terminates 73 amino acids after this deletion. c The PHEVOR graph uses Human Phenotype Ontology (HPO) terms and links to Gene Ontology terms to prioritize potentially deleterious alleles using terms for a) kidney disease: HP:0000077 (Kidney anomaly), HP:0000112 (Nephropathy), and HP :0003774 ( CKD stage 5) and b) diabetes: HP:0000819 (diabetes) and HP:0005978 (type 2 diabetes) and combination of pVAAST old values ​​and PHEVOR scores. PHEVOR scores (in-axis) for each gene (point) plotted on the genome (x-axis, chromosomes 1-Y). d Chromatogram after Sanger sequencing of a non-carrier from the family (WT) and 6 carriers identified by whole-genome sequencing and pVAAST/PHEVOR analysis. credit: npj Genomic Medicine (2022). DOI: 10.1038/s41525-022-00314-z
A rare genetic mutation may help explain why some families are more susceptible to diabetes and kidney failure, according to a new study by University of Utah health scientists. They say the discovery, made across generations of the same family, could eventually lead to better treatments for these diseases among a number of patients, whether or not they inherited the mutation.
“In the past, we’ve seen sporadic cases here and there, but this is the first family to demonstrate that this mutation can be inherited,” says Marcus Pezzolesi, PhD, MPH, corresponding author of the study and U of U Health associate professor of internal medicine in the department of nephrology. “What’s exciting is that treatments are being developed that can improve this condition, not just in this family, but more broadly among at-risk diabetes patients kidney diseases.”
The study, conducted in collaboration with the Joslin Diabetes Center and Harvard Medical School in Boston, is published in npj Genomic Medicine.
Scientists have long known that overweight or obese people produce less adiponectin, a hormone that promotes insulin sensitivityslow down cell death, and reduces inflammation. As a result, these people are more prone to insulin resistancetype 2 diabetes, kidney disease, and other life-threatening conditions.
To determine whether there might be a genetic cause for diabetic kidney disease, Pezzolesi and colleagues analyzed DNA samples from 14 members of the same family collected at the Joslin Diabetes Center. Only six of family members three generations had diabetes and end-stage renal disease.
Digging deeper, the researchers used whole-genome sequencing to pinpoint a defect in a gene called ADIPOQ, which codes for the protein adiponectin. The mutation shortens the gene, disrupting its ability to produce a hormone that breaks down ceramides, a fatty substance similar to cholesterol. As a result, people with the mutation have higher ceramide levels. Previous research suggests that ceramides are a the driving force underlies type 2 diabetes and may contribute to diabetic kidney disease.
In laboratory studies of embryonic human kidney cells, the researchers found that only one copy of this mutation was able to reduce the production of adipanectin. The researchers determined that this mutation occurs in about one in every 57,000 people.
Overall, carriers of the genetic mutation had about 85% less adiponectin and 30% higher levels of ceramides circulating in their blood compared to non-carriers in the same family, who were used as a control group.
“What’s most exciting to me is that this discovery allows us to confirm decades of animal research,” says William Holland, Ph.D., one of the study’s authors and associate professor of nutrition and integrative medicine at U of U Health. physiology. “The biological effects of adiponectin in the regulation of insulin sensitivity, glucose tolerance, and ceramide levels are well established in mice, and the current study shows that loss of adiponectin impairs metabolic health in humans.”
Although the study was conducted in a single form familyHolland says his findings could have broad implications for the diagnosis and treatment of these conditions in many people. “We can use these results as a starting point to develop personalized drugs that mimic the beneficial effects of adiponectin and reduce the risk of diabetes and kidney disease,” he says.
Christopher A. Simeone et al. Dominant negative ADIPOQ mutation in a diabetic family with renal disease, hypoadiponectinemia, and hyperceramidemia, npj Genomic Medicine (2022). DOI: 10.1038/s41525-022-00314-z
Citation: Discovery of rare genetic mutation in one family could lead to better diabetes treatment (16 Aug 2022) Retrieved 16 Aug 2022 from https://medicalxpress.com/news/2022-08-rare-genetic-mutation- family-diabetes. html
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