Corrigendum: Whole-exome sequencing identifies a novel CPT2 mutation in a pedigree with gout.

[This corrects the article DOI: 10.3389/fcell.2022.802635.].

Whole-Exome Sequencing Identifies a Novel CPT2 Mutation in a Pedigree With Gout.

Background: Gout is a common inflammatory arthritis, and its exact pathogenesis remains unclear. Multiple studies have demonstrated that genetic factors play important roles in the development of gout. This study aims to investigate the genetic basis of gout in a three-generation pedigree of affected individuals. Methods: Whole-exome sequencing (WES), comprehensive variant analyses, and co-segregation testing were performed. The effects of candidate variants on protein localization and cellular expression were analyzed, as were interactions with gout-related genes. Results: After comprehensive bioinformatic analysis, Sanger sequencing validation, and pedigree co-segregation analysis, we identified a rare heterozygous missense variant (c.1891C > T, p.R631C) in CPT2. Although no associated changes in localization were observed, the fluorescence intensity of p.R631C mutants was obviously reduced in comparison to the wild-type protein, suggesting that protein degradation is induced by the mutant. Furthermore, our results also indicate that the c.1891C > T variant influences the ability of CPT2 to bind UCP2. Conclusion: This study identified a rare CPT2 mutation in a large Chinese pedigree with gout. Functional studies were used to define the effect of this mutant. This study provides novel insight into the genetic etiology of gout.

Unraveling the genetic causes in large pedigrees with gout by whole­exome sequencing.

Gout is a common type of inflammatory arthritis that is clinically and genetically heterogeneous. The genetic aetiology remains unclear, and mainly relies on previous genome­wide association studies focused on sporadic cases. The present study aimed to identify the genetic basis of gout in three families using whole­exome sequencing (WES). WES was performed in the probands, and family members were involved in the co­segregation analysis. In total, three deleterious rare or novel missense mutations were identified in ATP­binding cassette super­family G member 2 (ABCG2), protein kinase CGMP­dependent 2 (PRKG2) and adrenoceptor ß3 (ADRB3) genes in three different families. In addition, certain gout­associated candidate genes were revealed to be shared among the co­expression and protein­protein interaction (PPI) networks of ABCG2, PRKG2 and ADRB3. Furthermore, the disease ontology analysis of the genes present in the co­expression network exhibited significant (P<0.05) enrichment in hyperuricemia, gout, cardiovascular system disease and metabolic disease. In addition, genes involved in the PPI network were significantly enriched in the purine nucleoside monophosphate biosynthetic process, urate transport and biological processes associated with glycose metabolism. Collectively, to the best of our knowledge, the present study was the first to use WES to identify three candidate rare or novel deleterious mutations in three families with gout. The present results provided novel insights that may improve the current understanding of the molecular genetic basis underlying gout. Importantly, the present results may facilitate the improvement of clinical diagnosis and the development of novel personalized therapies.

Whole-Exome Sequencing Reveals a Rare Missense Variant in SLC16A9 in a Pedigree with Early-Onset Gout.

Gout is a common inflammatory arthritis triggered by monosodium urate deposition after longstanding hyperuricemia. In the general community, the disease is largely polygenic in genetic architecture, with many polymorphisms having been identified in gout or urate-associated traits. In a small proportion of cases, rare high penetrant mutations associated with monogenic segregation of the disease in families have been demonstrated to be disease causative. In this study, we recruited a two-generation pedigree with early-onset gout. To elucidate the genetic predisposition, whole-exome sequencing (WES) was performed. After comprehensive variant analyses and cosegregation testing, we identified a missense variant (c.277C>A, p.L93M) in SLC16A9, an extremely rare variant in genetic databases. Moreover, in silico assessments showed strong pathogenicity. This variant cosegregated with the disease phenotype perfectly in the family and is located in a highly conserved functional domain. A few studies supported our results of the association between SLC16A9 and gout and serum urate levels. In conclusion, we provide the first evidence for the association of rare missense in SLC16A9 with early-onset gout. These findings not only expand our current understanding of gout but also may have further implications for the treatment and prevention of gout.