Association of ventricular septal defect with rare variations of the HAND2 gene
LI Mei-Kun, PANG Shu-Chao, YAN Bo
Cheeloo College of Medicine, Shandong University, Jinan 250012, China/Institute of Precision Medicine, Jining Medical University, Jining, Shandong 272029, China (Yan B, Email: yanbo@mail.jnmc.edu.cn)
Abstract：Objective To study the association of ventricular septal defect (VSD) with rare variations in the promoter region of HAND2 gene, as well as related molecular mechanisms. Methods Blood samples were collected from 349 children with VSD and 345 healthy controls. The target fragments were amplified by polymerase chain reaction and sequenced to identify the rare variation sites in the promoter region of the HAND2 gene. Dual-luciferase reporter assay was used to perform a functional analysis of the variation sites. Electrophoretic mobility shift assay (EMSA) was used to investigate related molecular mechanisms. TRANSFAC and JASPAR databases were used to predict transcription factors. Results Sequencing revealed that three variation sites (g.173530852A>G, g.173531173A>G, and g.173531213C>G) were only observed in the promoter region of the HAND2 gene in 10 children with VSD, among whom 4 children had only one variation site. The dual-luciferase reporter assay revealed that g.173531213C>G reduced the transcriptional activity of the HAND2 gene promoter. EMSA and transcription factor prediction revealed that g.173531213C>G created a binding site for transcription factor. Conclusions The rare variation, g.173531213C>G, in the promoter region of the HAND2 gene participates in the development and progression of VSD possibly by affecting the binding of transcription factors. Citation:Chinese Journal of Contemporary Pediatrics, 2023, 25(4): 388-393
Tsao CW, Aday AW, Almarzooq ZI, et al. Heart disease and stroke statistics—2022 update: a report from the American Heart Association[J]. Circulation, 2022, 145(8): e153-e639. PMID: 35078371. DOI: 10.1161/CIR.0000000000001052.
Muto M, Sugita K, Matsuba T, et al. How should we treat representative neonatal surgical diseases with congenital heart disease?[J]. Pediatr Surg Int, 2022, 38(9): 1235-1240. PMID: 35838788. DOI: 10.1007/s00383-022-05178-z.
Luo M, Wang T, Huang P, et al. Association of maternal betaine-homocysteine methyltransferase (BHMT) and BHMT2 genes polymorphisms with congenital heart disease in offspring[J]. Reprod Sci, 2023, 30(1): 309-325. PMID: 35835902. DOI: 10.1007/s43032-022-01029-3.
8 Zhao K, Yang Z. The second heart field: the first 20 years[J]. Mamm Genome, 2022. Epub ahead of print. PMID: 36550326. DOI: 10.1007/s00335-022-09975-8.
Moore-Morris T, van Vliet PP, Andelfinger G, et al. Role of epigenetics in cardiac development and congenital diseases[J]. Physiol Rev, 2018, 98(4): 2453-2475. PMID: 30156497. DOI: 10.1152/physrev.00048.2017.
Firulli AB, McFadden DG, Lin Q, et al. Heart and extra-embryonic mesodermal defects in mouse embryos lacking the bHLH transcription factor Hand1[J]. Nat Genet, 1998, 18(3): 266-270. PMID: 9500550. DOI: 10.1038/ng0398-266.
Srivastava D, Thomas T, Lin Q, et al. Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND[J]. Nat Genet, 1997, 16(2): 154-160. PMID: 9171826. DOI: 10.1038/ng0697-154.
Shen L, Li XF, Shen AD, et al. Transcription factor HAND2 mutations in sporadic Chinese patients with congenital heart disease[J]. Chin Med J (Engl), 2010, 123(13): 1623-1627. PMID: 20819618.
Tanaka AJ, Cho MT, Willaert R, et al. De novo variants in EBF3 are associated with hypotonia, developmental delay, intellectual disability, and autism[J]. Cold Spring Harb Mol Case Stud, 2017, 3(6): a002097. PMID: 29162653. PMCID: PMC5701309. DOI: 10.1101/mcs.a002097.
Nameki N, Takizawa M, Suzuki T, et al. Structural basis for the interaction between the first SURP domain of the SF3A1 subunit in U2 snRNP and the human splicing factor SF1[J]. Protein Sci, 2022, 31(10): e4437. PMID: 36173164. PMCID: PMC9514218. DOI: 10.1002/pro.4437.
