AKAP2identified as a novel gene mutated in a Chinese family with adolescent idiopathic scoliosis

Abstract

BackgroundAdolescent idiopathic scoliosis exhibits high heritability and is one of the most common spinal deformities found in adolescent populations. However, little is known about the disease-causing genes in families with adolescent idiopathic scoliosis exhibiting Mendelian inheritance.ObjectiveThe aim of this study was to identify the causative gene in a family with adolescent idiopathic scoliosis.MethodsWhole-exome sequencing was performed on this family to identify the candidate gene. Sanger sequencing was conducted to validate the candidate mutations and familial segregation. Real-time QPCR was used to measure the expression level of the possible causative gene.ResultsWe identified the mutation c.2645A>C (p.E882A) within the AKAP2 gene, which cosegregated with the adolescent idiopathic scoliosis phenotypes. AKAP2 is located in a previously reported linkage locus (IS4) on chromosome 9q31.2–q34.2 and has been implicated in skeletal development. The mutation was absent in dbSNP144, ESP6500 and 503 ethnicity-matched controls. Real-time QPCR revealed that the mRNA expression level in the patients was increased significantly compared with the family controls (p<0.0001).ConclusionsAKAP2 was therefore implicated as a novel gene mutated in a Chinese family with adolescent idiopathic scoliosis. Further studies should be conducted to validate the results from the perspective of both the genetics and pathogenesis of this disease.

Rare coding variants in MAPK7 predispose to adolescent idiopathic scoliosis

“…In addition, whole-exome sequencing (WES) of a Chinese AIS family identified a rare variant in the A-kinase anchor protein 2 gene (AKAP2; MIM# 604582) (Li et al, 2016). However, in both cases, the underlying pathogenic pathways remain unclear as little is known regarding the normal functions of the two affected genes.…”

Whole-Genome Methylation Analysis of Phenotype Discordant Monozygotic Twins Reveals Novel Epigenetic Perturbation Contributing to the Pathogenesis of Adolescent Idiopathic Scoliosis

“…Based on genome-wide association study (GWAS) and other similar association studies, single nucleotide polymorphisms (SNPs) of several genes such as GPR126 (Kou et al, 2013;Liu et al, 2018), PAX1 (Sharma et al, 2015;Liu et al, 2019), LBX1 (Takahashi et al, 2011;Liu et al, 2017), and BNC2 (Ogura et al, 2015), were known to increase the risk of AIS. There was also evidence that rare mutations of some genes may be responsible for AIS, such as FBN1 (Buchan et al, 2014a), AKAP2 (Li et al, 2016) and MAPK7 (Gao et al, 2017). Other studies illustrated the association between CNV and AIS (Buchan et al, 2014b).…”

“…Although studies to discover the underlying mechanisms of AIS had been conducted for many years, the etiology is still unclear. Previous studies showed that genetic factors from single nucleotide variant (SNV) to copy number variants (CNV), played a pivotal role in the development of AIS (Kesling and Reinker, 1997;Li et al, 2016;Gao et al, 2017). Based on genome-wide association study (GWAS) and other similar association studies, single nucleotide polymorphisms (SNPs) of several genes such as GPR126 (Kou et al, 2013;Liu et al, 2018), PAX1 (Sharma et al, 2015;Liu et al, 2019), LBX1 (Takahashi et al, 2011;Liu et al, 2017), and BNC2 (Ogura et al, 2015), were known to increase the risk of AIS.…”

A Missense Mutation in <i>GJA8</i> Encoding Connexin 50 in a Chinese Pedigree with Autosomal Dominant Congenital Cataract

“…Library construction was performed by the customed Roche NimbleGen SeqCap EZ System (Roche, Madison, Wisconsin, USA), and 90-cycles Paired-end sequencing was conducted on Illumina HiSeq2500 Analyzers (Illumin, San Diego, California, USA). Read mapping and variant analysis procedures were as described previously (Li et al 2016b). On the basis of dbSNP database (www.ncbi.nlm.nih.gov/SNP/), Exome Variant Server database (http://evs.gs.washington.edu/EVS/), the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/index.php) and 1,000 Genomes (http://browser.1000genomes.org/index.html) annotation, the high-frequency (minor allele frequency ≥ 0.01) polymorphism variations were excluded.…”