Mutational burden and potential oligogenic model of <i>TBX6</i>‐mediated genes in congenital scoliosis

Yang, Yang; Zhao, Sen; Zhang, Yuanqiang; Wang, Shengru; Shao, Jiashen; Liu, Bowen; Li, Yaqi; Yan, Zihui; Niu, Yuchen; Li, Xiaoxin; Wang, Lianlei; Ye, Yongyu; Weng, Xisheng; Wu, Zhihong; Scoliosis, Deciphering Disorders Involving; study, COmorbidities; Zhang, Jianguo; Wu, Nan

doi:10.1002/mgg3.1453

Cited by 6 publications

(4 citation statements)

References 37 publications

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“…Wallin et al's study suggested that mice with PAX1 gene defect exhibited signs of vertebral body and disc loss and ultimately CSD [ 16 ]. Generally speaking, TBX-6 is associated with segmented CS, while LMXIA is related to dysplastic CS [ 17 ]. These data indicate the differential gene expression in different types of CS.…”

Section: Introductionmentioning

confidence: 99%

Bioinformatics Analysis and Experimental Verification Identify Downregulation of COL27A1 in Poor Segmental Congenital Scoliosis

et al. 2022

Computational and Mathematical Methods in Medicine

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Background. Congenital scoliosis (CS) represents the congenital defect disease, and poor segmental congenital scoliosis (PSCS) represents one of its types. Delayed intervention can result in disability and paralysis. In this study, we would identify the core biomarkers for PSCS progression through bioinformatics analysis combined with experimental verification. Methods. This work obtained the GSE11854 expression dataset associated with somite formation in the GEO database, which covers data of 13 samples. Thereafter, we utilized the edgeR of the R package to obtain DEGs in this dataset. Then, GO annotation, KEGG analyses, and DO annotation of DEGs were performed by “clusterProfiler” of the R package. This study performed LASSO regression for screening the optimal predicting factors for somite formation. Through RNA sequencing based on peripheral blood samples from healthy donors and PSCS cases, we obtained the RNA expression patterns and screen out DEGs using the R package DESeq2. The present work analyzed COL27A1 expression in PSCS patients by the RT-PCR assay. Results. A total of 443 genes from the GSE11854 dataset were identified as DEGs, which were involved in BP associated with DNA replication, CC associated with chromosomal region, and MF associated with ATPase activity. These DEGs were primarily enriched in the TGF-β signaling pathway and spinal deformity. Further, LASSO regression suggested that 9 DEGs acted as the signature markers for somite formation. We discovered altogether 162 DEGs in PSCS patients, which were involved in BP associated with cardiac myofibril assembly and MF associated with structural constituent of muscle. However, these 162 DEGs were not significantly correlated with any pathways. Finally, COL27A1 was identified as the only intersected gene between the best predictors for somite formation and PSCS-related DEGs, which was significantly downregulated in PSCS patients. Conclusion. This work sheds novel lights on DEGs related to the PSCS pathogenic mechanism, and COL27A1 is the possible therapeutic target for PSCS. Findings in this work may contribute to developing therapeutic strategies for PSCS.

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Section: Introductionmentioning

confidence: 99%

Bioinformatics Analysis and Experimental Verification Identify Downregulation of COL27A1 in Poor Segmental Congenital Scoliosis

et al. 2022

Computational and Mathematical Methods in Medicine

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“…As a multifactorial disease with a prevalence of ~1/1000 live births [1,7], genetic perturbations, gene-environment interactions, and epigenetic changes are suspected to play a role in the etiology of CVMs [4,8]. Previously, we have reported the mutational burden and potential oligogenic models underpinning CVM development, as well as compound heterozygous inheritance model in TBX6-associated congenital scoliosis (TACS) [9,25,26]. The combined effect of deleterious variants in multiple genes might synergistically lead to the development of the malformations, which gives insight into the complex diseasecausing model of CVMs.…”

Section: Discussionmentioning

confidence: 99%

Disruptive NADSYN1 Variants Implicated in Congenital Vertebral Malformations

Lin

Zhao

et al. 2021

Genes

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Genetic perturbations in nicotinamide adenine dinucleotide de novo (NAD) synthesis pathway predispose individuals to congenital birth defects. The NADSYN1 encodes the final enzyme in the de novo NAD synthesis pathway and, therefore, plays an important role in NAD metabolism and organ embryogenesis. Biallelic mutations in the NADSYN1 gene have been reported to be causative of congenital organ defects known as VCRL syndrome (Vertebral-Cardiac-Renal-Limb syndrome). Here, we analyzed the genetic variants in NADSYN1 in an exome-sequenced cohort consisting of patients with congenital vertebral malformations (CVMs). A total number of eight variants in NADSYN1, including two truncating variants and six missense variants, were identified in nine unrelated patients. All enrolled patients presented multiple organ defects, with the involvement of either the heart, kidney, limbs, or liver, as well as intraspinal deformities. An in vitro assay using COS-7 cells demonstrated either significantly reduced protein levels or disrupted enzymatic activity of the identified variants. Our findings demonstrated that functional variants in NADSYN1 were involved in the complex genetic etiology of CVMs and provided further evidence for the causative NADSYN1 variants in congenital NAD Deficiency Disorder.

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“…Classical Homocystinuria (OMIM # 236200) is a rare autosomal recessive disorder (incidence between 1/335,000 and 1/200,000) of the methionine metabolism, manifesting with an abnormal accumulation of total homocysteine in the blood, increased excretion of homocysteine in urine, an elevated methionine blood concentration along with a decrease in plasma cystathionine. The genetic defect is in the cystathionine beta-synthase gene ( CBS ), resulting in a deficiency of cystathionine synthetase enzyme activity [ 94 ]. The clinical features of untreated homocystinuria usually manifest in the first or second decade of life and include myopia, ectopia lentis, mitral valve prolapse, accelerated skeletal growth, osteoporosis, skeletal anomalies resembling MFS (body habitus, pectus deformity, kyphoscoliosis, hernias), thromboembolic events and variable intellectual disability.…”

Section: Genetically Related Disorders In Mfs Differential Diagnosismentioning

confidence: 99%

Marfan Syndrome: Enhanced Diagnostic Tools and Follow-up Management Strategies

et al. 2023

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Marfan syndrome (MFS) is a rare inherited autosomic disorder, which encompasses a variety of systemic manifestations caused by mutations in the Fibrillin-1 encoding gene (FBN1). Cardinal clinical phenotypes of MFS are highly variable in terms of severity, and commonly involve cardiovascular, ocular, and musculoskeletal systems with a wide range of manifestations, such as ascending aorta aneurysms and dissection, mitral valve prolapse, ectopia lentis and long bone overgrowth, respectively. Of note, an accurate and prompt diagnosis is pivotal in order to provide the best treatment to the patients as early as possible. To date, the diagnosis of the syndrome has relied upon a systemic score calculation as well as DNA mutation identification. The aim of this review is to summarize the latest MFS evidence regarding the definition, differences and similarities with other connective tissue pathologies with severe systemic phenotypes (e.g., Autosomal dominant Weill–Marchesani syndrome, Loeys–Dietz syndrome, Ehlers–Danlos syndrome) and clinical assessment. In this regard, the management of MFS requires a multidisciplinary team in order to accurately control the evolution of the most severe and potentially life-threatening complications. Based on recent findings in the literature and our clinical experience, we propose a multidisciplinary approach involving specialists in different clinical fields (i.e., cardiologists, surgeons, ophthalmologists, orthopedics, pneumologists, neurologists, endocrinologists, geneticists, and psychologists) to comprehensively characterize, treat, and manage MFS patients with a personalized medicine approach.

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Mutational burden and potential oligogenic model of TBX6‐mediated genes in congenital scoliosis

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 6 publications

References 37 publications

Bioinformatics Analysis and Experimental Verification Identify Downregulation of COL27A1 in Poor Segmental Congenital Scoliosis

Bioinformatics Analysis and Experimental Verification Identify Downregulation of COL27A1 in Poor Segmental Congenital Scoliosis

Disruptive NADSYN1 Variants Implicated in Congenital Vertebral Malformations

Marfan Syndrome: Enhanced Diagnostic Tools and Follow-up Management Strategies

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