Novel Point Mutations of CITED2 Gene Are Associated with Non-familial Congenital Heart Disease (CHD) in Sporadic Pediatric Patients

Dianatpour, S.; Khatami, Mehri; Heidari, Mohammad; Hadadzadeh, Mehdi

doi:10.1007/s12010-019-03125-8

Cited by 16 publications

(12 citation statements)

References 25 publications

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“…The developmental process of the heart is a tightly regulated process that requires intricate interplay between transcription factors, several cardiac-specific genes, and signaling pathways [68] .Both genetic [69,70] and environmental factors [71] play essential roles during cardiac development. Gene mutations [72] and some teratogens [73,74] can interfere with normal development (embryogenesis) of the heart leading to congenital heart defects.…”

Section: Embryogenesis Of the Heartmentioning

confidence: 99%

Congenital heart diseases: genetics, non-inherited risk factors, and signaling pathways

Suluba

Liu

Xia

et al. 2020

Egypt J Med Hum Genet

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Background: Congenital heart diseases (CHDs) are the most common congenital anomalies with an estimated prevalence of 8 in 1000 live births. CHDs occur as a result of abnormal embryogenesis of the heart. Congenital heart diseases are associated with significant mortality and morbidity. The damage of the heart is irreversible due to a lack of regeneration potential, and usually, the patients may require surgical intervention. Studying the developmental biology of the heart is essential not only in understanding the mechanisms and pathogenesis of congenital heart diseases but also in providing us with insight towards developing new preventive and treatment methods. Main body: The etiology of congenital heart diseases is still elusive. Both genetic and environmental factors have been implicated to play a role in the pathogenesis of the diseases. Recently, cardiac transcription factors, cardiacspecific genes, and signaling pathways, which are responsible for early cardiac morphogenesis have been extensively studied in both human and animal experiments but leave much to be desired. The discovery of novel genetic methods such as next generation sequencing and chromosomal microarrays have led to further study the genes, non-coding RNAs and subtle chromosomal changes, elucidating their implications to the etiology of congenital heart diseases. Studies have also implicated non-hereditary risk factors such as rubella infection, teratogens, maternal age, diabetes mellitus, and abnormal hemodynamics in causing CHDs. These etiological factors raise questions on multifactorial etiology of CHDs. It is therefore important to endeavor in research based on finding the causes of CHDs. Finding causative factors will enable us to plan intervention strategies and mitigate the consequences associated with CHDs. This review, therefore, puts forward the genetic and non-genetic causes of congenital heart diseases. Besides, it discusses crucial signaling pathways which are involved in early cardiac morphogenesis. Consequently, we aim to consolidate our knowledge on multifactorial causes of CHDs so as to pave a way for further research regarding CHDs. Conclusion: The multifactorial etiology of congenital heart diseases gives us a challenge to explicitly establishing specific causative factors and therefore plan intervention strategies. More well-designed studies and the use of novel genetic technologies could be the way through the discovery of etiological factors implicated in the pathogenesis of congenital heart diseases.

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Section: Embryogenesis Of the Heartmentioning

confidence: 99%

Congenital heart diseases: genetics, non-inherited risk factors, and signaling pathways

Suluba

Liu

Xia

et al. 2020

Egypt J Med Hum Genet

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“…Many diseaseassociated variations in the UTR region of human genes have been reported, and it was predicted that these nucleotide changes strongly lead to secondary structural alterations. 36,37 In our study, we identified 8 various microRNAs in which binding site disrupt/enhance through 3 nucleotide variations in 3′-UTR of VPREB1 (c.*15 A > G; rs6001563, c.*59 T > C; rs2285019, and c.*76 G > A; rs140258192) which are showed in Table 3.…”

Section: Discussionmentioning

confidence: 95%

Mutational Analysis of the VPREB1 Gene of Pre-BCR Complex in a Cohort of Sporadic Pediatric Patients With B-Cell Acute Lymphoblastic Leukemia

Naji

Khatami

Heidari

et al. 2022

Journal of Pediatric Hematology/Oncology

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During bone marrow B-cell development, the pre-B-cell receptor is formed by the association of the immunoglobulin heavy chain with a surrogate light chain, which is encoded by the VPREB1, and λ5 genes. It is known that pre-BCR signaling signifies a critical checkpoint at the pre-B-cell stage. Thus, failure pre-BCR signaling is proposed as a critical factor for the development of B-cell acute lymphoblastic leukemia (B-ALL). B-ALL is the most common pediatric cancer and is one of the leading causes of death in children. Until now, several molecular analyses were performed for genomic alterations in B-ALL, but for genomic analysis of the VPREB1 gene and its rare variations, limited studies have been conducted. In this study, using polymerase chain reaction and direct sequencing of 88 pediatric patients with B-ALL, we investigated the genomic region of the VPREB1 gene to find sequence variations of this gene. Our study presented ten homozygous and heterozygous point mutations and heterozygous nucleotide deletions, in the VPREB1 gene in 36 boys and 32 girls' patients. Our Bioinformatics assay results presented that these variations may alter the RNA folding, protein structure, and therefore probable effect on the protein function. These results propose that nucleotide changes probably contribute to B-ALL pathogenesis.

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“…The role of the variants in the coding region of CITED2 has been well described, but the variants in the promoter region of this gene have not been reported [ 11 , 27 ] as mentioned above. This study, for the first time, investigates the variants of the promoter region of the CITED2 gene in ASD patients and demonstrates the causing effect of these variants in the development of ASD.…”

Section: Discussionmentioning

confidence: 99%

“…In some reports, CITED2 variants in the coding region were detected to be associated with cardiac malformations, including ASD, VSD, TOF, etc. [ 11 , 32 ]. TFs, two chromatin-modifying enzymes, and TFs combine to activate genes and are recruited to promoters in precise order.…”

Section: Discussionmentioning

confidence: 99%

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Genetic Variants of CITED2 Gene Promoter in Human Atrial Septal Defects: Case-Control Study and Cellular Functional Verification

Chen

Hou

et al. 2022

JCDD

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Atrial septal defect (ASD) is one of the most common forms of congenital heart disease (CHD). Genetic variants in the coding region of the CITED2 gene are known to be significantly correlated with CHD, but the role of variants in the promoter region of CITED2 is unknown. We investigated variants in the promoter of the CITED2 gene in 625 subjects (332 ASD and 293 healthy controls) through Sanger sequencing. Four variants in the CITED2 gene promoter were found only in eight ASD patients with zero occurrence in the control subjects (one case of g.4078A>C(rs1165649373), one case of g.4240C>A(rs1235857801), four cases of g.4935C>T(rs111470468), two cases of g.5027C>T(rs112831934)). Cellular functional analysis showed that these four variants significantly changed the transcriptional activity of the CITED2 gene promoter in HEK-293 and HL-1 cells. Electrophoretic mobility change assay results and JASPAR database analysis demonstrated that these variants created or destroyed a series of possible transcription factor binding sites, resulting in changes in the expression of CITED2 protein. We conclude that the variants of CITED2 promoter in ASD patients affect the transcriptional activity and are likely involved in the occurrence and development of ASD. These findings provide new perspectives on the pathogenesis and potential therapeutic insights of ASD.

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Novel Point Mutations of CITED2 Gene Are Associated with Non-familial Congenital Heart Disease (CHD) in Sporadic Pediatric Patients

Cited by 16 publications

References 25 publications

Congenital heart diseases: genetics, non-inherited risk factors, and signaling pathways

Congenital heart diseases: genetics, non-inherited risk factors, and signaling pathways

Mutational Analysis of the VPREB1 Gene of Pre-BCR Complex in a Cohort of Sporadic Pediatric Patients With B-Cell Acute Lymphoblastic Leukemia

Genetic Variants of CITED2 Gene Promoter in Human Atrial Septal Defects: Case-Control Study and Cellular Functional Verification

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