Pharmacogenomics and Personalized Medicine (Jan 2022)
An Analysis of the Pathogenic Genes and Mutation Sites of Macrodactyly
Abstract
Jian-Feng Li,1 Guang-Lei Tian,2 Hui Pan,3 Wen-Tong Zhang,1 Da-Cun Li,1 Jing-Da Liu,1 Liang Zhao,1 Hai-Lei Li1 1Department of Hand Surgery, Beijing Shunyi District Hospital; Shunyi Teaching Hospital of Capital Medical University, Beijing, 101300, People’s Republic of China; 2Department of Hand Surgery, Beijing Jishuitan Hospital; Peking University Fourth School of Clinical Medicine, Beijing, 100035, People’s Republic of China; 3Department of Pathology, Beijing Shunyi District Hospital; Shunyi Teaching Hospital of Capital Medical University, Beijing, 101300, People’s Republic of ChinaCorrespondence: Jian-Feng LiDepartment of Hand Surgery, Beijing Shunyi District Hospital; Shunyi Teaching Hospital of Capital Medical University, No. 3 Guangming South Street, Shunyi District, Beijing, 101300, People’s Republic of China, Tel +86 10 69423220, Email [email protected]: This study aimed to explore the pathogenic genes and mutation sites of macrodactyly.Methods: Whole-exome sequencing was performed on the pathological tissue and peripheral blood of 12 patients with macrodactyly who were operated in our hospital between June 2018 and May 2020. In order to conduct comprehensive bioinformatics analysis and screen the pathogenic genes of macrodactyly, the patients were divided into four groups: macrodactyly of finger group, macrodactyly of foot group, macrodactyly and syndactyly of finger group, and macrodactyly and syndactyly of foot group. The results of the whole-exome sequencing were verified using Sanger sequencing in order to clarify the pathogenic genes and mutation sites of macrodactyly, and immunohistochemical analysis of the protein signaling pathways encoded by the pathogenic genes was performed to observe the protein expression and further verify the mutant genes.Results: In the comprehensive bioinformatics analysis and Sanger verification of the whole-exome sequencing, the PIK3CA gene mutation was screened as the pathogenic gene of macrodactyly. The mutation sites were identified as the p.E542K (c.G1624A) and p.E545K (c.G1633A) sites of exon10 and the p.H1047R (c.A3140G) and p.G1049R (c.G3145C) sites of exon21. Among these, the p.G1049R (c.G3145C) locus was found in macrodactyly for the first time. The mutation of the PIK3CA gene was also found to lead to increased expression of serine-threonine kinase (AKT) in adipocytes in the PI3K-AKT-mTOR signaling pathway.Conclusion: Mutation of the PIK3CA gene leads to the enhancement of the PI3K-AKT-mTOR signaling pathway, which is the cause of macrodactyly. There is also some diversity in PIK3CA gene mutation sites.Keywords: hand deformity, foot deformity, macrodactyly, PIK3CA gene
