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A dominant negative ADIPOQ mutation in a diabetic family with renal disease, hypoadiponectinemia, and hyperceramidemia.

ABSTRACT: Adiponectin, encoded by ADIPOQ, is an insulin-sensitizing, anti-inflammatory, and renoprotective adipokine that activates receptors with intrinsic ceramidase activity. We identified a family harboring a 10-nucleotide deletion mutation in ADIPOQ that cosegregates with diabetes and end-stage renal disease. This mutation introduces a frameshift in exon 3, resulting in a premature termination codon that disrupts translation of adiponectin's globular domain. Subjects with the mutation had dramatically reduced circulating adiponectin and increased long-chain ceramides levels. Functional studies suggest that the mutated protein acts as a dominant negative through its interaction with non-mutated adiponectin, decreasing circulating adiponectin levels, and correlating with metabolic disease.

SUBMITTER: Simeone CA

PROVIDER: S-EPMC9307825 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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A dominant negative ADIPOQ mutation in a diabetic family with renal disease, hypoadiponectinemia, and hyperceramidemia.

Simeone Christopher A CA Wilkerson Joseph L JL Poss Annelise M AM Banks James A JA Varre Joseph V JV Guevara Jose Lazaro JL Hernandez Edgar Javier EJ Gorsi Bushra B Atkinson Donald L DL Turapov Tursun T Frodsham Scott G SG Morales Julio C Fierro JCF O'Neil Kristina K Moore Barry B Yandell Mark M Summers Scott A SA Krolewski Andrzej S AS Holland William L WL Pezzolesi Marcus G MG

NPJ genomic medicine 20220722 1

Adiponectin, encoded by ADIPOQ, is an insulin-sensitizing, anti-inflammatory, and renoprotective adipokine that activates receptors with intrinsic ceramidase activity. We identified a family harboring a 10-nucleotide deletion mutation in ADIPOQ that cosegregates with diabetes and end-stage renal disease. This mutation introduces a frameshift in exon 3, resulting in a premature termination codon that disrupts translation of adiponectin's globular domain. Subjects with the mutation had dramaticall ...[more]

PMID: 35869090

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Project description:BackgroundPrimary ciliary dyskinesia (PCD) is a clinically heterogeneous group of autosomal or, less frequently, X-chromosomal recessive inheritance syndrome of motile cilia dysfunction characterized by neonatal respiratory distress, oto-sino-pulmonary disease, infertility and situs inversus. Recently, type 43 PCD (CILD43, OMIM#618699) was established by autosomal-dominant loss-of-function mutations identified in Forkhead box J1 (FOXJ1). However, the functional validation of FOXJ1 mutations in humans and mice has not been fully performed. Here we studied a three-generation family with heterotaxy and proband with complex congenital heart disease (CHD).MethodsWe performed whole-exome sequencing to investigate the causative variant of this family and generated gene knock-in mice carrying the human equivalent mutation by homologous recombination. Then, microscopy analysis was used to characterize the phenotype and ciliary ultrastructure of the model. Effects of the variant on heart anomaly were preliminarily explored through transcriptome sequencing.ResultsA novel heterozygous deletion variant (c.1129delC/p.Leu377Trpfs*76) of FOXJ1 was discovered that exerts a dominant-negative effect (DNE) in vitro. Notably, both homozygous (Foxj1c.1129delT/c.1129delT) and heterozygous (Foxj1+/c.1129delT) mice developed situs inversus, hydrocephalus and showed a disruption of trachea cilia structure, whereas these abnormalities were only observed in previously reported Foxj1-/-, not Foxj1+/- mice. Thus, a more severe phenotype and higher expressivity of our mouse model further indicated the DNE of this mutation. Meanwhile, several cardiomyopathy-related genes were differentially expressed in the homozygous Foxj1 knock-in mouse hearts, pointing to a probable function in cardiac pathology.ConclusionsOverall, our study results showed that c.1129delC mutation in FOXJ1 was regarded as the cause of situs inversus in this family and this mutant showed a capacity of DNE over wild-type FOXJ1, causing more serious consequences than the allelic deletion of Foxj1.

Dataset Information

A dominant negative ADIPOQ mutation in a diabetic family with renal disease, hypoadiponectinemia, and hyperceramidemia.

Publications

A dominant negative ADIPOQ mutation in a diabetic family with renal disease, hypoadiponectinemia, and hyperceramidemia.

Similar Datasets

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