http://informahealthcare.com/bmk ISSN: 1354-750X (print), 1366-5804 (electronic) Biomarkers, 2014; 19(8): 674–678 ! 2014 Informa UK Ltd. DOI: 10.3109/1354750X.2014.978895

RESEARCH ARTICLE

Association between polymorphisms in AXIN1 gene and atrial septal defect Yan Pu1#*, Peng Chen1*, Bin Zhou2, Yanyun Wang2, Yaping Song2, Ying Peng3, Li Rao3, and Lin Zhang1 1

Department of Forensic Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, P.R. China, Laboratory of Molecular Translational Medicine, West China Institute of Women and Children’s Health, Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, P.R. China, and 3Department of Cardiology, West China Hospital of Sichuan University, Chengdu, Sichuan, P.R. China

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Abstract

Keywords

Context: AXIN1 is a central component of Wnt signalling pathway which is essential for embryonic development. Objective: To investigate whether polymorphisms of AXIN1 contribute to ASD susceptibility. Materials and methods: Three tag SNPs (rs12921862, rs370681 and rs1805105) in AXIN1 were genotyped in 208 ASD patients and 302 healthy controls using polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) in a Chinese population. Results: Significantly increased ASD risk was observed to be associated with the A allele of rs12921862 (p50.0001, OR ¼ 3.096, 95% CI ¼ 2.037–4.717). Increased ASD risk was observed to be associated with rs370681 in a codominant (p ¼ 0.043, OR ¼ 1.52, 95% CI ¼ 1.04–2.22) and overdominant model (p ¼ 0.016, OR ¼ 1.57, 95% CI ¼ 1.08–2.27). Conclusion: rs12921862 and rs370681 may contribute to ASD susceptibility.

Atrial septal defects, AXIN1, genetic susceptibility, polymorphism, Wnt signalling pathway

Introduction Congenital heart disease (CHD) is ‘‘a gross structural abnormality of the heart or intrathoracic great vessels that is actually or potentially of functional significance’’(Mitchell et al., 1971). It is a heart problem caused by improper development of the heart during fetal development (Chinawa et al., 2013).With a prevalence of 4–50 per 1000 live births, it has been regarded as one of the most common birth defects in humans (Pierpont et al., 2007). Additionally, it is also a significant cause of morbidity and mortality in children (Menahem, 1998). Most of the known causes of CHD are sporadic genetic changes, but genes regulating the complex developmental sequence have only been partly elucidated (Srivastava, 2006). Even though the abnormal genes that cause these disorders are present at birth, the cardiomyopathy is rarely detected at this time but usually presents later in childhood or adolescence (Hoffman & Kaplan, 2002). Atrial septal defect (ASD) is the third most common type of congenital heart disease, with an estimated incidence of 56 per 100 000 livebirths (Hoffman & Kaplan, 2002). Included in this group of malformations are several types #Yan Pu is responsible for statistical design and analysis. E-mail: [email protected]. *These authors contributed equally to this work. Address for correspondence: Lin Zhang, Department of Forensic Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, P.R. China. Fax: +86 28 85405541. E-mail: [email protected]

History Received 29 August 2014 Revised 15 October 2014 Accepted 16 October 2014 Published online 30 October 2014

of atrial communications that allow shunting of blood between the systemic and the pulmonary circulations (Geva et al., 2014). Symptoms at presentation are nonspecific and most often include fatigue and exertional dyspnea (Brickner et al., 2000). Long-term complications of uncorrected ASD include atrial arrhythmias, right ventricular dilatation and failure, pulmonary hypertension, and paradoxical embolism (Sankey, 2013). Most atrial septal defects are sporadic with no identifiable cause. Abnormalities in genes essential to cardiac septation have been associated with ASD (Maitra et al., 2009). The Wnt signalling pathway regulates cellular proliferation, differentiation, morphology and motility, is essential for development and organogenesis (Bienz & Clevers, 2000; Nakajima et al., 2003; Satoh et al., 2000). In the so-called ‘‘canonical’’ pathway, Wnts activate the powerful transcription factor b-catenin which regulates cell proliferation and can promote myogenesis or osteogenesis (Logan and Nusse, 2004). AXIN1, a central component of the canonical Wnt signal transduction machinery, is the rate limiting factor for the b-catenin destruction complex assembly (Chia & Costantini, 2005; Xie et al., 2011). Complete inactivation of AXIN1 function leads to early embryonic lethality at E9.5 with forebrain truncation, neural tube defects, and embryonic axis duplications (Chia & Costantini, 2005; Chia et al., 2009; Perry et al., 1995; Zeng et al., 1997). Given the important role of the Wnt/b-catenin pathway during embryonic development, we decided to test the hypothesis that common polymorphic variants of the genes

AXIN1 gene and atrial septal defect

DOI: 10.3109/1354750X.2014.978895

encoding crucial components of this signaling pathway might contribute to the susceptibility to ASD. AXIN1 the encoding gene for AXIN1 is located within a 65 kb region on chromosome 16p13.3. To investigate if AXIN1 is involved in the development of ASD, we selected three tag SNPs (rs12921862, rs370681 and rs1805105) and detected their association with ASD in a case-control study of 208 unrelated ASD patients and 302 healthy control subjects in a Chinese Han population.

Material and methods

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Subjects The present study was performed with the approval of the ethics committee of the West China First University Hospital of Sichuan University and all the subjects gave written informed consent to participate. A hospital based case-control study was conducted including 208 unrelated ASD patients ranging in age from 1 to 65 years old (mean ± SD, 29.62 ± 16.34; male/female, 63/145) between June 2008 and October 2012 at the First University Hospital of Sichuan University. The diagnosis of ASD was based on patient’s history, physical examination, electrocardiogram and echocardiogram. Clinical data were collected from the hospital record section. A group of control subjects including 302 healthy controls ranging in age from 12 to 48 years old (mean ± SD, 26.69 ± 6.33; male/female, 100/202) was selected randomly from a routine health survey in the same hospital. Subjects with any personal or family history of heart disease or other serious disease were intentionally excluded.

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procedure was performed according to instruction manual. The genotypes of the three SNPs selected (i.e. rs12921862, rs1805105, rs370681) were analyzed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Primers were established with online software (http://frodo.wi.mit.edu/primer3/). Primer sequences, PCR reaction conditions, restriction enzymes used to digest the PCR products (New England BioLabs Inc.; Beverly, MA) and length of products were presented in Table 1. A 6% polyacrylamide gel was used to distinguish the restriction fragments. About 20% of the samples were randomly selected to perform the repeated assays and the results were 100% concordant. The genotypes were confirmed by DNA sequencing analysis. Statistical analysis All data analyses were carried out by SPSS 13.0 statistical software (SPSS Inc, Chicago, IL). Allele and genotype frequency of AXIN1 gene rs12921862, rs370681 and rs1805105 were obtained by directed counting and HardyWeinberg equilibrium was evaluated by the chi-square test. Genotypic association tests in a case-control pattern assuming codominant, dominant, recessive, overdominant, or logadditive genetic models were performed using SNPstats (Sole et al., 2006). Odds ratio (OR) and respective 95% confidence intervals (CI) were reported to evaluate the effects of any difference between alleles and genotypes. A p50.05 was regarded as statistically significant.

Result SNP selection and genotyping A tag SNP is a representative SNP in a region of the genome with high linkage disequilibrium (the nonrandom association of alleles at two or more loci). We have selected tag SNPs according to data of tag SNPs genotyped in the CHB population sample of the HapMap Project (Data Release 24/ phase II, NCBI build 36 assembly, dpSNPb126). Tag SNPs of AXIN1 gene, rs370681, rs12921862 located in the intron region, and rs1805105 located in the synonymous codon region, respectively, were picked out for population CHB using the algorithm-Tagger-pairwise Tagging from the international HapMap project (http://www.hapmap.org/ index.html.zh). Genomic DNA of each individual was extracted from 200 ml of EDTA-anticoagulated peripheral blood samples by a DNA isolation kit from Bioteke (Peking, China). The

All three SNPs (rs12921862, rs370681, rs1805105) in AXIN1 gene were successfully genotyped in 208 ASD patients and 302 healthy control subjects. Genotype distribution of these three polymorphisms in our cases and control subjects were consistent with Hardy-Weinberg equilibrium. Allele frequencies of these three polymorphisms for 208 ASD patients and 302 control subjects are shown in Table 2, significantly increased ASD risk was observed to be associated with A allele of rs12921862 (p50.0001, OR ¼ 3.096, 95% CI ¼ 2.037–4.717), but allele frequency of rs37081 and rs1805105 were not significantly different between ASD patients and control subjects (rs370681: p ¼ 0.476, OR ¼ 1.112, 95% CI ¼ 0.840–1.474; rs1805105: p ¼ 0.716, OR ¼ 0.944, 95% CI ¼ 0.710–1.255). As shown in Table 3, for rs12921862 polymorphism, significantly increased ASD risk was found to be associated

Table 1. Primier sequences and reaction conditions for genotyping three tagSNPs in AXIN1 gene.

SNPs

Primer sequence

Annealing temperature ( C)

Restriction enzyme

Product size, bp

rs12921862

F: CTCACGCCAGTGCCTCTACT R: ATGCCATCCATGTGGAAACT

66

ScrFI

A: 216 C: 108+108

rs1805105

F: CTGGATACCTGCCGACCTTA R: ACCTTTCCCTGGCTTGTTCT

66

FokI

C: 245 T: 186+59

rs370681

F: GAGGCCTAAGCTCCAGGCACT R: AAGGAAAGTGGGTTCTCCACCCA

66

BtsI

T: 166 C: 150+16

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Biomarkers, 2014; 19(8): 674–678

Table 2. Data of selected polymorphisms in AXIN1 gene among ASD and controls.

Allele

ASD patients n ¼ 208(%)

Controls n ¼ 302(%)

rs12921862

C A

346 (83.2%) 70 (16.8%)

rs370681

C T

rs1805105

T C

Polymorphisms

OR (95%CI)

p Value

567 (93.9%) 37 (6.1%)

3.096 (2.037–4.717)

50.0001

307 (73.8%) 109 (26.2%)

433 (71.7%) 171 (28.3%)

1.112 (0.840–1.474)

0.476

306 (73.6%) 110 (26.4%)

451 (74.7%) 153 (25.3%)

0.944 (0.710–1.255)

0.716

No corresponds to the number of individuals. Bold faced values indicate a significant difference at the 5% level.

Table 3. Genotype frequencies of selected polymorphisms in AXIN1 gene among ASD and controls and their association with ASD risk.

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Genetic model rs12921862 Codominant Dominant Recessive Overdominant

genotype

ASD patients n ¼ 208(%)

Controls n ¼ 302(%)

C/C A/C A/A C/C A/C-A/A C/C-A/C A/A C/C-A/A A/C

149 48 11 149 59 197 11 160 48

271 25 6 271 31 296 6 277 25

(71.6%) (23.1%) (5.3%) (71.6%) (28.4%) (94.7%) (5.3%) (76.9%) (23.1%)

(89.7%) (8.3%) (2%) (89.7%) (10.3%) (98%) (2%) (91.7%) (8.3%)

Log-additive rs370681 Codominant Dominant Recessive Overdominant

C/C C/T T/T C/C C/T-T/T C/C-C/T T/T C/C-T/T C/T

120 67 21 120 88 187 21 141 67

(57.7%) (32.2%) (10.1%) (57.7%) (42.3%) (89.9%) (10.1%) (67.8%) (32.2%)

152 129 21 152 150 281 21 173 129

(50.3%) (42.7%) (7%) (50.3%) (49.7%) (93%) (7%) (57.3%) (42.7%)

Log-additive rs1805105 Codominant Dominant Recessive Overdominant

T/T C/T C/C T/T C/T-C/C T/T-C/T C/C T/T-C/C C/T

119 68 21 119 89 187 21 140 68

(57.2%) (32.7%) (10.1%) (57.2%) (42.8%) (89.9%) (10.1%) (67.3%) (32.7%)

Log-additive

174 103 25 174 128 277 25 199 103

(57.6%) (34.1%) (8.3%) (57.6%) (42.4%) (91.7%) (8.3%) (65.9%) (34.1%)

Logistic regressiona OR(95%CI) 1.00 3.49 (2.07–5.89) 3.33 (1.21–9.20) 1.00 3.46 (2.15–5.59) 1.00 2.75 (1.00–7.57) 1.00 3.32 (1.97–5.60) 2.57 (1.73–3.82)

p Value 50.0001 50.0001 0.043 50.0001 50.0001

1.00 1.52 (1.04–2.22) 0.79 (0.41–1.51) 1.00 1.35 (0.94–1.92) 1.00 0.67 (0.35–1.25) 1.00 1.57 (1.08–2.27) 1.11 (0.84–1.46) 1.00 1.04 (0.70–1.52) 0.81 (0.44–1.52) 1.00 0.98 (0.69–1.41) 1.00 0.80 (0.44–1.48) 1.00 1.07 (0.73–1.55) 0.95 (0.73–1.24)

0.043 0.1 0.21 0.016 0.47 0.77 0.93 0.48 0.74 0.71

No corresponds to the number of individuals. Bold faced values indicate a significant difference at the 5% level. a Adjusted by age.

with AC (p50.0001, OR ¼ 3.49, 95% CI ¼ 2.07–5.89) and AA (p50.0001, OR ¼ 3.33, 95% CI ¼ 1.21–9.20) genotype in a codominant model, compared with CC genotype. And significantly increased ASD susceptibility was also associated with A allele carriers (p50.0001, OR ¼ 3.46, 95% CI ¼ 2.15–5.59) in a dominant model. Moreover, the AC heterozygote carriers have a 3.32-fold ASD risk in an overdominant model (p50.0001, OR ¼ 3.32, 95% CI ¼ 1.97–5.60), compared with the homozygote AA/CC genotypes carriers. For rs370681, significantly increased

ASD susceptibility was found to be associated with the CT genotype in a codominant model, compared with CC genotype (p ¼ 0.043, OR ¼ 1.52, 95% CI ¼ 1.04–2.22). Moreover, the CT heterozygote carriers have a 1.57-fold ASD risk in an overdominant model (p ¼ 0.016, OR ¼ 1.57, 95% CI ¼ 1.08–2.27), compared with the homozygote CC/TT genotypes carriers. But for genotypic association analysis, no statistically significant difference was observed between ASD patients and control subjects for rs1805105 polymorphism.

AXIN1 gene and atrial septal defect

DOI: 10.3109/1354750X.2014.978895

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Discussion In the present study, for the first time we have identified the association between these three tagSNPs of AXIN1 gene and ASD risk. Our results suggested the allele A of rs12921862 may increase ASD susceptibility. We calculated the sample power with ‘‘Power and Sample Size Calculation’’ software (version 3.0.43, Nashville, TN), and our study had more than 80% power to detect the association between this polymorphism of AXIN1 and ASD susceptibility. Genotypic association analyses have revealed the potential relationship between rs370681 and ASD susceptibility. The Wnt/b-catenin signaling pathway has major roles throughout development, stem cell maintenance and regeneration is essential for organogenesis (Satoh et al., 2000; Schneider et al., 2012). Existing evidences have indicated an association between this pathway and numerous congenital anomalies, such as cryptorchidism, cleft lip and bicuspid aortic valve (Harisis et al., 2013; Mostowska et al., 2012; Wooten et al., 2010). AXIN1, a key negative regulator of canonical Wnt signaling has been suggested to play an important role during embryogenesis (Xie et al., 2011). Ubiquitously expressed AXIN1 has been involved in the formation of embryonic neural axis (Perry et al., 1995). Taken it together, there may be an important role AXIN1 play in cardiogenesis, even cardiac septation. AXIN1, the encoding gene for AXIN1, existing researches have indicated its broad association with human cancers, such as hepatocellular carcinoma, colon cancer and prostate cancer (Taniguchi et al., 2002; Webster et al., 2000; Yardy et al., 2009). Mutations in AXIN1 have been involved in diseases associated with processes of human development such as medulloblastoma and caudal duplication anomalies (Baeza et al., 2003; Oates et al., 2006). Ablations of the Axin family genes demonstrated that they modulate Wnt signaling in key processes of mammalian development (Yu et al., 2007). And, in the present study, we have also observed a potential relation between AXIN1 and ASD. Cardiac development is a complex biological process requiring the integration of cell commitment, morphogenesis, and excitation-contraction coupling (Schott et al., 1998). And genetic changes have always been involved in the pathogenesis of these diseases (Chen et al., 2014; Pu et al., 2014; Srivastava, 2006). It is well known that, the production of proteins is genetically determined, and genetic variations of AXIN1 may influence the genetic susceptibility to human diseases. In the present study, we have identified the association between polymorphisms (rs12921862 and rs370681) in AXIN1 and ASD susceptibility, probably due to their influences on AXIN1 production. However, the precise mechanisms engaged in the regulation of AXIN1 production remained unclear, further studies are necessary to confirm its mechanism. It seems that, the Wnt/b-catenin pathway appears to play a role in the etiology of ASD, which is one of the most common congenital heart anomalies. Taken together, it is biologically plausible that SNPs in AXIN1 may have effect on individual’s susceptibility to ASD. These polymorphisms might become useful prognostic biomarkers for ASD patients and novel genetic therapeutic interventions involving AXIN1 can be envisaged. Nonetheless, the precise mechanism AXIN1

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may have in the development of ASD remained unclear, further studies are necessary to confirm these findings. Although we detected the association between the SNPs in AXIN1 and ASD, there were limitations in our study. One is that we did not test the expression level of AXIN1, which restricted our further research on whether the SNPs have effect on the AXIN1 expression level. Another is that the number of the study subjects is limited. Further large-scale studies still need to be done. In conclusion, we found that polymorphisms in AXIN1 were significantly associated with ASD risk. These findings indicate that genetic variation in AXIN1 gene may be related to the development of ASD. Nevertheless, due to the genetic variation among different ethnic groups, further studies are needed to explore the association of these polymorphisms and the risk for ASD in diverse ethnic populations.

Declaration of interest No competing financial interests exist. This work was supported by the National Natural Science Foundation of China (No. 81270289, No. 81300170); the Funds for International Cooperation and Exchange of Sichuan Province (No. 2012HH0032), and the Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 20110181110011).

References Baeza N, Masuoka J, Kleihues P, Ohgaki H. (2003). AXIN1 mutations but not deletions in cerebellar medulloblastomas. Oncogene 22:632–6. Bienz M, Clevers H. (2000). Linking colorectal cancer to Wnt signaling. Cell 103:311–20. Brickner ME, Hillis LD, Lange RA. (2000). Congenital heart disease in adults. First of two parts. N Engl J Med 342:256–63. Chen P, Zhang K, Zhou B, et al. (2014). The variations in the IL1RL1 gene and susceptibility to preeclampsia. Immunol Invest 43:424–35. Chia IV, Costantini F. (2005). Mouse axin and axin2/conductin proteins are functionally equivalent in vivo. Mol Cell Biol 25:4371–6. Chia IV, Kim MJ, Itoh K, et al. (2009). Both the RGS domain and the six C-terminal amino acids of mouse Axin are required for normal embryogenesis. Genetics 181:1359–68. Chinawa JM, Obu HA, Eke CB, Eze JC. (2013). Pattern and clinical profile of children with complex cardiac anomaly at University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu State, Nigeria. Niger J Clin Pract 16:462–7. Geva T, Martins JD, Wald RM. (2014). Atrial septal defects. Lancet 383: 1921–32. Harisis GN, Chen N, Farmer PJ, et al. (2013). Wnt signalling in testicular descent: a candidate mechanism for cryptorchidism in Robinow syndrome. J Pediatr Surg 48:1573–7. Hoffman JI, Kaplan S. (2002). The incidence of congenital heart disease. J Am Coll Cardiol 39:1890–900. Logan CY, Nusse R. (2004). The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810. Maitra M, Schluterman MK, Nichols HA, et al. (2009). Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development. Dev Biol 326:368–77. Menahem S. (1998). Counselling strategies for parents of infants with congenital heart disease. Cardiol Young 8:400–7. Mitchell SC, Korones SB, Berendes HW. (1971). Congenital heart disease in 56,109 births. Incidence and natural history. Circulation 43: 323–32. Mostowska A, Hozyasz KK, Wojcicki P, et al. (2012). Association of DVL2 and AXIN2 gene polymorphisms with cleft lip with or without cleft palate in a Polish population. Birth Defects Res A Clin Mol Teratol 94:943–50.

Biomarkers Downloaded from informahealthcare.com by RMIT University on 08/15/15 For personal use only.

678

Y. Pu et al.

Nakajima M, Fukuchi M, Miyazaki T, et al. (2003). Reduced expression of Axin correlates with tumour progression of oesophageal squamous cell carcinoma. Br J Cancer 88:1734–9. Oates NA, van Vliet J, Duffy DL, et al. (2006). Increased DNA methylation at the AXIN1 gene in a monozygotic twin from a pair discordant for a caudal duplication anomaly. Am J Hum Genet 79: 155–62. Perry 3rd WL, Vasicek TJ, Lee JJ, et al. (1995). Phenotypic and molecular analysis of a transgenic insertional allele of the mouse Fused locus. Genetics 141:321–32. Pierpont ME, Basson CT, Benson Jr DW, et al. (2007). Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 115: 3015–38. Pu Y, Zhang Z, Zhou B, et al. (2014). Association of an insertion/ deletion polymorphism in IL1A 3’-UTR with risk for cervical carcinoma in Chinese Han Women. Hum Immunol 75:740–4. Sankey C. (2013). Atrial septal defect in an adult patient. J Gen Intern Med 28:1524. Satoh S, Daigo Y, Furukawa Y, et al. (2000). AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 24:245–50. Schneider PN, Slusarski DC, Houston DW. (2012). Differential role of Axin RGS domain function in Wnt signaling during anteroposterior patterning and maternal axis formation. PLoS One 7:e44096.

Biomarkers, 2014; 19(8): 674–678

Schott JJ, Benson DW, Basson CT, et al. (1998). Congenital heart disease caused by mutations in the transcription factor NKX2–5. Science 281: 108–11. Sole X, Guino E, Valls J, et al. (2006). SNPStats: a web tool for the analysis of association studies. Bioinformatics 22:1928–9. Srivastava D. (2006). Making or breaking the heart: from lineage determination to morphogenesis. Cell 126:1037–48. Taniguchi K, Roberts LR, Aderca IN, et al. (2002). Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene 21:4863–71. Webster MT, Rozycka M, Sara E, et al. (2000). Sequence variants of the axin gene in breast, colon, and other cancers: an analysis of mutations that interfere with GSK3 binding. Genes Chromosomes Cancer 28: 443–53. Wooten EC, Iyer LK, Montefusco MC, et al. (2010). Application of gene network analysis techniques identifies AXIN1/PDIA2 and endoglin haplotypes associated with bicuspid aortic valve. PLoS One 5:e8830. Xie R, Jiang R, Chen D. (2011). Generation of Axin1 conditional mutant mice. Genesis 49:98–102. Yardy GW, Bicknell DC, Wilding JL, et al. (2009). Mutations in the AXIN1 gene in advanced prostate cancer. Eur Urol 56:486–94. Yu HM, Liu B, Costantini F, Hsu W. (2007). Impaired neural development caused by inducible expression of Axin in transgenic mice. Mech Dev 124:146–56. Zeng L, Fagotto F, Zhang T, et al. (1997). The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell 90:181–92.

Association between polymorphisms in AXIN1 gene and atrial septal defect.

AXIN1 is a central component of Wnt signalling pathway which is essential for embryonic development...
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