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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2009

Open Access 01-12-2009 | Research article

ALDH1A2 (RALDH2) genetic variation in human congenital heart disease

Authors: Marilene Pavan, Viviane F Ruiz, Fábio A Silva, Tiago J Sobreira, Roberta M Cravo, Michelle Vasconcelos, Lívia P Marques, Sonia MF Mesquita, José E Krieger, Antônio AB Lopes, Paulo S Oliveira, Alexandre C Pereira, José Xavier-Neto

Published in: BMC Medical Genetics | Issue 1/2009

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Abstract

Background

Signaling by the vitamin A-derived morphogen retinoic acid (RA) is required at multiple steps of cardiac development. Since conversion of retinaldehyde to RA by retinaldehyde dehydrogenase type II (ALDH1A2, a.k.a RALDH2) is critical for cardiac development, we screened patients with congenital heart disease (CHDs) for genetic variation at the ALDH1A2 locus.

Methods

One-hundred and thirty-three CHD patients were screened for genetic variation at the ALDH1A2 locus through bi-directional sequencing. In addition, six SNPs (rs2704188, rs1441815, rs3784259, rs1530293, rs1899430) at the same locus were studied using a TDT-based association approach in 101 CHD trios. Observed mutations were modeled through molecular mechanics (MM) simulations using the AMBER 9 package, Sander and Pmemd programs. Sequence conservation of observed mutations was evaluated through phylogenetic tree construction from ungapped alignments containing ALDH8 s, ALDH1Ls, ALDH1 s and ALDH2 s. Trees were generated by the Neighbor Joining method. Variations potentially affecting splicing mechanisms were cloned and functional assays were designed to test splicing alterations using the pSPL3 splicing assay.

Results

We describe in Tetralogy of Fallot (TOF) the mutations Ala151Ser and Ile157Thr that change non-polar to polar residues at exon 4. Exon 4 encodes part of the highly-conserved tetramerization domain, a structural motif required for ALDH oligomerization. Molecular mechanics simulation studies of the two mutations indicate that they hinder tetramerization. We determined that the SNP rs16939660, previously associated with spina bifida and observed in patients with TOF, does not affect splicing. Moreover, association studies performed with classical models and with the transmission disequilibrium test (TDT) design using single marker genotype, or haplotype information do not show differences between cases and controls.

Conclusion

In summary, our screen indicates that ALDH1A2 genetic variation is present in TOF patients, suggesting a possible causal role for this gene in rare cases of human CHD, but does not support the hypothesis that variation at the ALDH1A2 locus is a significant modifier of the risk for CHD in humans.
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Literature
1.
Nora JJ: Multifactorial inheritance hypothesis for the etiology of congenital heart diseases. The genetic-environmental interaction. Circulation. 1968, 38 (3): 604-617.CrossRefPubMed
2.
Blanchard EM, Iizuka K, Christe M, Conner DA, Geisterfer-Lowrance A, Schoen FJ, Maughan DW, Seidman CE, Seidman JG: Targeted ablation of the murine alpha-tropomyosin gene. Circ Res. 1997, 81 (6): 1005-1010.CrossRefPubMed
3.
Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, et al: GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature. 2003, 424 (6947): 443-447. 10.1038/nature01827.CrossRefPubMed
4.
5.
Bonne G, Carrier L, Richard P, Hainque B, Schwartz K: Familial hypertrophic cardiomyopathy: from mutations to functional defects. Circ Res. 1998, 83 (6): 580-593.CrossRefPubMed
6.
Ewart AK, Morris CA, Atkinson D, Jin W, Sternes K, Spallone P, Stock AD, Leppert M, Keating MT: Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet. 1993, 5 (1): 11-16. 10.1038/ng0993-11.CrossRefPubMed
7.
Guerrero PA, Schuessler RB, Davis LM, Beyer EC, Johnson CM, Yamada KA, Saffitz JE: Slow ventricular conduction in mice heterozygous for a connexin43 null mutation. J Clin Invest. 1997, 99 (8): 1991-1998. 10.1172/JCI119367.CrossRefPubMedPubMedCentral
8.
9.
Kastner P, Messaddeq N, Mark M, Wendling O, Grondona JM, Ward S, Ghyselinck N, Chambon P: Vitamin A deficiency and mutations of RXRalpha, RXRbeta and RARalpha lead to early differentiation of embryonic ventricular cardiomyocytes. Development. 1997, 124 (23): 4749-4758.PubMed
10.
Gruber PJ, Kubalak SW, Pexieder T, Sucov HM, Evans RM, Chien KR: RXR alpha deficiency confers genetic susceptibility for aortic sac, conotruncal, atrioventricular cushion, and ventricular muscle defects in mice. J Clin Invest. 1996, 98 (6): 1332-1343. 10.1172/JCI118920.CrossRefPubMedPubMedCentral
11.
Wilson JG, Warkany J: Cardiac and aortic arch anomalies in the offspring of vitamin A deficient rats correlated with similar human anomalies. Pediatrics. 1950, 5 (4): 708-725.PubMed
12.
Burd L, Deal E, Rios R, Adickes E, Wynne J, Klug MG: Congenital heart defects and fetal alcohol spectrum disorders. Congenit Heart Dis. 2007, 2 (4): 250-255. 10.1111/j.1747-0803.2007.00105.x.CrossRefPubMed
13.
Moss JB, Xavier-Neto J, Shapiro MD, Nayeem SM, McCaffery P, Drager UC, Rosenthal N: Dynamic patterns of retinoic acid synthesis and response in the developing mammalian heart. Dev Biol. 1998, 199 (1): 55-71. 10.1006/dbio.1998.8911.CrossRefPubMed
14.
Xavier-Neto J, Rosenthal N, Silva FA, Matos TG, Hochgreb T, Linhares VL: Retinoid signaling and cardiac anteroposterior segmentation. Genesis. 2001, 31 (3): 97-104. 10.1002/gene.10009.CrossRefPubMed
15.
Harrison EH: Mechanisms of digestion and absorption of dietary vitamin A. Annu Rev Nutr. 2005, 25: 87-103. 10.1146/annurev.nutr.25.050304.092614.CrossRefPubMed
16.
Simoes-Costa MS, Azambuja AP, Xavier-Neto J: The search for non-chordate retinoic acid signaling: lessons from chordates. J Exp Zoolog B Mol Dev Evol. 2008, 310 (1): 54-72. 10.1002/jez.b.21139.CrossRef
17.
Kawaguchi R, Yu J, Honda J, Hu J, Whitelegge J, Ping P, Wiita P, Bok D, Sun H: A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. Science. 2007, 315 (5813): 820-825. 10.1126/science.1136244.CrossRefPubMed
18.
Golzio C, Martinovic-Bouriel J, Thomas S, Mougou-Zrelli S, Grattagliano-Bessieres B, Bonniere M, Delahaye S, Munnich A, Encha-Razavi F, Lyonnet S, et al: Matthew-Wood syndrome is caused by truncating mutations in the retinol-binding protein receptor gene STRA6. Am J Hum Genet. 2007, 80 (6): 1179-1187. 10.1086/518177.CrossRefPubMedPubMedCentral
19.
Pasutto F, Sticht H, Hammersen G, Gillessen-Kaesbach G, Fitzpatrick DR, Nurnberg G, Brasch F, Schirmer-Zimmermann H, Tolmie JL, Chitayat D, et al: Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation. Am J Hum Genet. 2007, 80 (3): 550-560. 10.1086/512203.CrossRefPubMedPubMedCentral
20.
Sandell LL, Sanderson BW, Moiseyev G, Johnson T, Mushegian A, Young K, Rey JP, Ma JX, Staehling-Hampton K, Trainor PA: RDH10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development. Genes Dev. 2007, 21 (9): 1113-1124. 10.1101/gad.1533407.CrossRefPubMedPubMedCentral
21.
Niederreither K, McCaffery P, Drager UC, Chambon P, Dolle P: Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. Mech Dev. 1997, 62 (1): 67-78. 10.1016/S0925-4773(96)00653-3.CrossRefPubMed
22.
Niederreither K, Vermot J, Messaddeq N, Schuhbaur B, Chambon P, Dolle P: Embryonic retinoic acid synthesis is essential for heart morphogenesis in the mouse. Development. 2001, 128 (7): 1019-1031.PubMed
23.
Miller SA, Dykes DD, Polesky HF: A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988, 16 (3): 1215-10.1093/nar/16.3.1215.CrossRefPubMedPubMedCentral
24.
Deak KL, Dickerson ME, Linney E, Enterline DS, George TM, Melvin EC, Graham FL, Siegel DG, Hammock P, Mehltretter L, et al: Analysis of ALDH1A2, CYP26A1, CYP26B1, CRABP1, and CRABP2 in human neural tube defects suggests a possible association with alleles in ALDH1A2. Birth Defects Res A Clin Mol Teratol. 2005, 73 (11): 868-875. 10.1002/bdra.20183.CrossRefPubMed
25.
Church DM, Stotler CJ, Rutter JL, Murrell JR, Trofatter JA, Buckler AJ: Isolation of genes from complex sources of mammalian genomic DNA using exon amplification. Nat Genet. 1994, 6 (1): 98-105. 10.1038/ng0194-98.CrossRefPubMed
26.
Wigler M, Sweet R, Sim GK, Wold B, Pellicer A, Lacy E, Maniatis T, Silverstein S, Axel R: Transformation of mammalian cells with genes from prokaryotes and eukaryotes. 1979. Biotechnology. 1992, 24: 444-452.PubMed
27.
Saitou N, Nei M: The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol. 1987, 4 (4): 406-425.PubMed
28.
Petrey D, Xiang Z, Tang CL, Xie L, Gimpelev M, Mitros T, Soto CS, Goldsmith-Fischman S, Kernytsky A, Schlessinger A, et al: Using multiple structure alignments, fast model building, and energetic analysis in fold recognition and homology modeling. Proteins. 2003, 53 (Suppl 6): 430-435. 10.1002/prot.10550.CrossRefPubMed
29.
Laskowski RAMM, Moss DS, Thornton JM: PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Cryst. 1993, 26: 283-291. 10.1107/S0021889892009944.CrossRef
30.
Case DA, Cheatham TE, Darden T, Gohlke H, Luo R, Merz KM, Onufriev A, Simmerling C, Wang B, Woods RJ: The Amber biomolecular simulation programs. J Comput Chem. 2005, 26 (16): 1668-1688. 10.1002/jcc.20290.CrossRefPubMedPubMedCentral
31.
Yu B, Sawyer NA, Chiu C, Oefner PJ, Underhill PA: DNA mutation detection using denaturing high-performance liquid chromatography (DHPLC). Curr Protoc Hum Genet. 2006, Chapter 7 (Unit7): 10-PubMed
32.
Tabor HK, Risch NJ, Myers RM: Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev Genet. 2002, 3 (5): 391-397. 10.1038/nrg796.CrossRefPubMed
33.
Gioli-Pereira L, Pereira AC, Bergara D, Mesquita S, Lopes AA, Krieger JE: Frequency of 22q11.2 microdeletion in sporadic non-syndromic tetralogy of Fallot cases. Int J Cardiol. 2008, 126 (3): 374-378. 10.1016/j.ijcard.2007.04.043.CrossRefPubMed
34.
Lamb AL, Newcomer ME: The structure of retinal dehydrogenase type II at 2.7 A resolution: implications for retinal specificity. Biochemistry. 1999, 38 (19): 6003-6011. 10.1021/bi9900471.CrossRefPubMed
35.
Blair Hedges S, Kumar S: Genomic clocks and evolutionary timescales. Trends Genet. 2003, 19 (4): 200-206. 10.1016/S0168-9525(03)00053-2.CrossRefPubMed
36.
Steinmetz CG, Xie P, Weiner H, Hurley TD: Structure of mitochondrial aldehyde dehydrogenase: the genetic component of ethanol aversion. Structure. 1997, 5 (5): 701-711. 10.1016/S0969-2126(97)00224-4.CrossRefPubMed
37.
Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, et al: Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome Res. 2006, 16 (1): 55-65. 10.1101/gr.4039406.CrossRefPubMedPubMedCentral
38.
Shen LX, Basilion JP, Stanton VP: Single-nucleotide polymorphisms can cause different structural folds of mRNA. Proc Natl Acad Sci USA. 1999, 96 (14): 7871-7876. 10.1073/pnas.96.14.7871.CrossRefPubMedPubMedCentral
39.
Elliott DA, Kirk EP, Yeoh T, Chandar S, McKenzie F, Taylor P, Grossfeld P, Fatkin D, Jones O, Hayes P, et al: Cardiac homeobox gene NKX2-5 mutations and congenital heart disease: associations with atrial septal defect and hypoplastic left heart syndrome. J Am Coll Cardiol. 2003, 41 (11): 2072-2076. 10.1016/S0735-1097(03)00420-0.CrossRefPubMed
40.
Schluterman MK, Krysiak AE, Kathiriya IS, Abate N, Chandalia M, Srivastava D, Garg V: Screening and biochemical analysis of GATA4 sequence variations identified in patients with congenital heart disease. Am J Med Genet A. 2007, 143A (8): 817-823. 10.1002/ajmg.a.31652.CrossRefPubMed
41.
Goldmuntz E, Geiger E, Benson DW: NKX2.5 mutations in patients with tetralogy of fallot. Circulation. 2001, 104 (21): 2565-2568. 10.1161/hc4601.098427.CrossRefPubMed
42.
Kamp van der MW, Mulholland AJ: Computational enzymology: insight into biological catalysts from modelling. Nat Prod Rep. 2008, 25 (6): 1001-1014. 10.1039/b600517a.CrossRefPubMed
43.
Yoshida A, Rzhetsky A, Hsu LC, Chang C: Human aldehyde dehydrogenase gene family. Eur J Biochem. 1998, 251 (3): 549-557. 10.1046/j.1432-1327.1998.2510549.x.CrossRefPubMed
44.
Klyosov AA: Kinetics and specificity of human liver aldehyde dehydrogenases toward aliphatic, aromatic, and fused polycyclic aldehydes. Biochemistry. 1996, 35 (14): 4457-4467. 10.1021/bi9521102.CrossRefPubMed
45.
Moore SA, Baker HM, Blythe TJ, Kitson KE, Kitson TM, Baker EN: Sheep liver cytosolic aldehyde dehydrogenase: the structure reveals the basis for the retinal specificity of class 1 aldehyde dehydrogenases. Structure. 1998, 6 (12): 1541-1551. 10.1016/S0969-2126(98)00152-X.CrossRefPubMed
46.
Vermot J, Niederreither K, Garnier JM, Chambon P, Dolle P: Decreased embryonic retinoic acid synthesis results in a DiGeorge syndrome phenotype in newborn mice. Proc Natl Acad Sci USA. 2003, 100 (4): 1763-1768. 10.1073/pnas.0437920100.CrossRefPubMedPubMedCentral
47.
Bertola DR, Pereira AC, de Oliveira PS, Kim CA, Krieger JE: Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation. Am J Med Genet A. 2004, 130A (4): 378-383. 10.1002/ajmg.a.30270.CrossRefPubMed
48.
Kaufman ES, McNitt S, Moss AJ, Zareba W, Robinson JL, Hall WJ, Ackerman MJ, Benhorin J, Locati ET, Napolitano C, et al: Risk of death in the long QT syndrome when a sibling has died. Heart Rhythm. 2008, 5 (6): 831-836. 10.1016/j.hrthm.2008.02.029.CrossRefPubMedPubMedCentral
49.
Maron BJ, Seidman JG, Seidman CE: Proposal for contemporary screening strategies in families with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004, 44 (11): 2125-2132. 10.1016/j.jacc.2004.08.052.CrossRefPubMed
50.
Stiller CA, Lennox EL, Wilson LM: Incidence of cardiac septal defects in children with Wilms' tumour and other malignant diseases. Carcinogenesis. 1987, 8 (1): 129-132. 10.1093/carcin/8.1.129.CrossRefPubMed
51.
Geiser CF, Schindler AM: Long survival in a male with 18-trisomy syndrome and Wilms' tumor. Pediatrics. 1969, 44 (1): 111-116.PubMed
52.
Karayalcin G, Shanske A, Honigman R: Wilms' tumor in a 13-year old girl with trisomy 18. Am J Dis Child. 1981, 135 (7): 665-666.PubMed
53.
Ruteshouser EC, Huff V: Familial Wilms tumor. Am J Med Genet C Semin Med Genet. 2004, 129C (1): 29-34. 10.1002/ajmg.c.30025.CrossRefPubMed
54.
Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R: WT-1 is required for early kidney development. Cell. 1993, 74 (4): 679-691. 10.1016/0092-8674(93)90515-R.CrossRefPubMed
55.
Cartegni L, Chew SL, Krainer AR: Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet. 2002, 3 (4): 285-298. 10.1038/nrg775.CrossRefPubMed
56.
Buratti E, Muro AF, Giombi M, Gherbassi D, Iaconcig A, Baralle FE: RNA folding affects the recruitment of SR proteins by mouse and human polypurinic enhancer elements in the fibronectin EDA exon. Mol Cell Biol. 2004, 24 (3): 1387-1400. 10.1128/MCB.24.3.1387-1400.2004.CrossRefPubMedPubMedCentral
57.
Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV: Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet. 2003, 12 (3): 205-216. 10.1093/hmg/ddg055.CrossRefPubMed
58.
Capon F, Allen MH, Ameen M, Burden AD, Tillman D, Barker JN, Trembath RC: A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups. Hum Mol Genet. 2004, 13 (20): 2361-2368. 10.1093/hmg/ddh273.CrossRefPubMed
59.
Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM: A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science. 2007, 315 (5811): 525-528. 10.1126/science.1135308.CrossRefPubMed
Metadata
Title
ALDH1A2 (RALDH2) genetic variation in human congenital heart disease
Authors
Marilene Pavan
Viviane F Ruiz
Fábio A Silva
Tiago J Sobreira
Roberta M Cravo
Michelle Vasconcelos
Lívia P Marques
Sonia MF Mesquita
José E Krieger
Antônio AB Lopes
Paulo S Oliveira
Alexandre C Pereira
José Xavier-Neto
Publication date
01-12-2009
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2009
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/1471-2350-10-113

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