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Genetic basis of human left–right asymmetry disorders

Published online by Cambridge University Press:  27 January 2015

Hao Deng ,
Hong Xia  and
Sheng Deng
Hao Deng*
Affiliation:
Center for Experimental Medicine and Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Hong Xia
Affiliation:
Center for Experimental Medicine and Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha 410013, China Department of Emergency, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Sheng Deng
Affiliation:
Center for Experimental Medicine and Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha 410013, China Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China
*
*Corresponding author: Hao Deng, Professor of Center for Experimental Medicine and Professor of Neurology, Executive/Vice Director of Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, China. E-mail: hdeng008@yahoo.com
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Abstract

Humans and other vertebrates exhibit left–right (LR) asymmetric arrangement of the internal organs, and failure to establish normal LR asymmetry leads to internal laterality disorders, including situs inversus and heterotaxy. Situs inversus is complete mirror-imaged arrangement of the internal organs along LR axis, whereas heterotaxy is abnormal arrangement of the internal thoraco-abdominal organs across LR axis of the body, most of which are associated with complex cardiovascular malformations. Both disorders are genetically heterogeneous with reduced penetrance, presumably because of monogenic, polygenic or multifactorial causes. Research in genetics of LR asymmetry disorders has been extremely prolific over the past 17 years, and a series of loci and disease genes involved in situs inversus and heterotaxy have been described. The review highlights the classification, chromosomal abnormalities, pathogenic genes and the possible mechanism of human LR asymmetry disorders.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 16 , 2014 , e19
Copyright
Copyright © Cambridge University Press 2014 

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References

1Kosaki, K. and Casey, B. (1998) Genetics of human left–right axis malformations. Seminars in Cell and Developmental Biology 9, 89-99CrossRefGoogle ScholarPubMed
2Peeters, H. and Devriendt, K. (2006) Human laterality disorders. European Journal of Medical Genetics 49, 349-362CrossRefGoogle ScholarPubMed
3Jacobs, J.P. et al. (2007) The nomenclature, definition and classification of cardiac structures in the setting of heterotaxy. Cardiology in the Young 17 (Suppl 2), 1-28Google Scholar
4Lin, A.E. et al. (2000) Heterotaxy: associated conditions and hospital-based prevalence in newborns. Genetics in Medicine 2, 157-172Google Scholar
5Casey, B. et al. (1996) Autosomal dominant transmission of familial laterality defects. American Journal of Medical Genetics 61, 325-3283.0.CO;2-T>CrossRefGoogle ScholarPubMed
6Sutherland, M.J. and Ware, S.M. (2009) Disorders of left–right asymmetry: heterotaxy and situs inversus. American Journal of Medical Genetics part C – Seminars in Medical Genetics 151C, 307-317Google Scholar
7Kuehl, K.S. and Loffredo, C. (2002) Risk factors for heart disease associated with abnormal sidedness. Teratology 66, 242-248CrossRefGoogle ScholarPubMed
8Kuehl, K.S. and Loffredo, C.A. (2003) Population-based study of l-transposition of the great arteries: possible associations with environmental factors. Birth Defects Research part A – Clinical and Molecular Teratology 67, 162-167Google Scholar
9Bisgrove, B.W., Morelli, S.H. and Yost, H.J. (2003) Genetics of human laterality disorders: insights from vertebrate model systems. Annual Review of Genomics and Human Genetics 4, 1-32CrossRefGoogle ScholarPubMed
10Gebbia, M. et al. (1997) X-linked situs abnormalities result from mutations in ZIC3. Nature Genetics 17, 305-308Google Scholar
11Shiraishi, I. and Ichikawa, H. (2012) Human heterotaxy syndrome – from molecular genetics to clinical features, management, and prognosis. Circulation Journal 76, 2066-2075Google Scholar
12Vandenberg, L.N. and Levin, M. (2013) A unified model for left–right asymmetry? Comparison and synthesis of molecular models of embryonic laterality. Developmental Biology 379, 1-15Google Scholar
13Speder, P. et al. (2007) Strategies to establish left/right asymmetry in vertebrates and invertebrates. Current Opinion in Genetics and Development 17, 351-358CrossRefGoogle ScholarPubMed
14Marion, V. et al. (2012) Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet – Biedl syndrome with situs inversus and insertional polydactyly. Journal of Medical Genetics 49, 317-321Google Scholar
15Bataille, S. et al. (2011) Association of PKD2 (polycystin 2) mutations with left–right laterality defects. American Journal of Kidney Diseases 58, 456-460Google Scholar
16Otto, E.A. et al. (2003) Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left–right axis determination. Nature Genetics 34, 413-420Google Scholar
17Twigg, S.R. et al. (2012) Mutations in multidomain protein MEGF8 identify a Carpenter syndrome subtype associated with defective lateralization. American Journal of Human Genetics 91, 897-905Google Scholar
18Wessels, M.W. et al. (2010) Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: a new polyalanine disorder? Journal of Medical Genetics 47, 351-355Google Scholar
19Perles, Z. et al. (2012) A human laterality disorder associated with recessive CCDC11 mutation. Journal of Medical Genetics 49, 386-390Google Scholar
20Aylsworth, A.S. (2001) Clinical aspects of defects in the determination of laterality. American Journal of Medical Genetics 101, 345-355CrossRefGoogle ScholarPubMed
21Zariwala, M.A., Omran, H. and Ferkol, T.W. (2011) The emerging genetics of primary ciliary dyskinesia. Proceedings of the American Thoracic Society 8, 430-433Google Scholar
22Zariwala, M.A. et al. (2006) Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder effect in a common mutation. American Journal of Respiratory and Critical Care Medicine 174, 858-866Google Scholar
23Guichard, C. et al. (2001) Axonemal dynein intermediate-chain gene (DNAI1) mutations result in situs inversus and primary ciliary dyskinesia (Kartagener syndrome). American Journal of Human Genetics 68, 1030-1035Google Scholar
24Kennedy, M.P. et al. (2007) Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia. Circulation 115, 2814-2821Google Scholar
25Failly, M. et al. (2008) DNAI1 mutations explain only 2% of primary ciliary dykinesia. Respiration 76, 198-204Google Scholar
26Mitchison, H.M. et al. (2012) Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia. Nature Genetics 44, 381-389Google Scholar
27Hornef, N. et al. (2006) DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects. American Journal of Respiratory and Critical Care Medicine 174, 120-126Google Scholar
28Ibanez-Tallon, I., Gorokhova, S. and Heintz, N. (2002) Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus. Human Molecular Genetics 11, 715-721CrossRefGoogle ScholarPubMed
29Omran, H. et al. (2000) Homozygosity mapping of a gene locus for primary ciliary dyskinesia on chromosome 5p and identification of the heavy dynein chain DNAH5 as a candidate gene. American Journal of Respiratory Cell and Molecular Biology 23, 696-702Google Scholar
30Olbrich, H. et al. (2002) Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left–right asymmetry. Nature Genetics 30, 143-144Google Scholar
31Failly, M. et al. (2009) Mutations in DNAH5 account for only 15% of a non-preselected cohort of patients with primary ciliary dyskinesia. Journal of Medical Genetics 46, 281-286Google Scholar
32Jeganathan, D. et al. (2004) Loci for primary ciliary dyskinesia map to chromosome 16p12.1-12.2 and 15q13.1-15.1 in Faroe Islands and Israeli Druze genetic isolates. Journal of Medical Genetics 41, 233-240CrossRefGoogle ScholarPubMed
33Duriez, B. et al. (2007) A common variant in combination with a nonsense mutation in a member of the thioredoxin family causes primary ciliary dyskinesia. Proceedings of the National Academy of Sciences of the United States of America 104, 3336-3341Google Scholar
34Bartoloni, L. et al. (2002) Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia. Proceedings of the National Academy of Sciences of the United States of America 99, 10282-10286Google Scholar
35Supp, D.M. et al. (1997) Mutation of an axonemal dynein affects left–right asymmetry in inversus viscerum mice. Nature 389, 963-966Google Scholar
36Tanaka, Y., Okada, Y. and Hirokawa, N. (2005) FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left–right determination. Nature 435, 172-177Google Scholar
37McGrath, J. et al. (2003) Two populations of node monocilia initiate left–right asymmetry in the mouse. Cell 114, 61-73Google Scholar
38Schwabe, G.C. et al. (2008) Primary ciliary dyskinesia associated with normal axoneme ultrastructure is caused by DNAH11 mutations. Human Mutation 29, 289-298Google Scholar
39Knowles, M.R. et al. (2012) Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure. Thorax 67, 433-441Google Scholar
40Geremek, M. et al. (2006) Linkage analysis localises a Kartagener syndrome gene to a 3.5 cM region on chromosome 15q24-25. Journal of Medical Genetics 43, e1Google Scholar
41Loges, N.T. et al. (2008) DNAI2 mutations cause primary ciliary dyskinesia with defects in the outer dynein arm. American Journal of Human Genetics 83, 547-558Google Scholar
42Omran, H. et al. (2008) Ktu/PF13 is required for cytoplasmic pre-assembly of axonemal dyneins. Nature 456, 611-616CrossRefGoogle ScholarPubMed
43Loges, N.T. et al. (2009) Deletions and point mutations of LRRC50 cause primary ciliary dyskinesia due to dynein arm defects. American Journal of Human Genetics 85, 883-889Google Scholar
44Duquesnoy, P. et al. (2009) Loss-of-function mutations in the human ortholog of Chlamydomonas reinhardtii ODA7 disrupt dynein arm assembly and cause primary ciliary dyskinesia. American Journal of Human Genetics 85, 890-896Google Scholar
45Merveille, A.C. et al. (2011) CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nature Genetics 43, 72-78CrossRefGoogle ScholarPubMed
46Becker-Heck, A. et al. (2011) The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left–right axis formation. Nature Genetics 43, 79-84Google Scholar
47Blanchon, S. et al. (2012) Delineation of CCDC39/CCDC40 mutation spectrum and associated phenotypes in primary ciliary dyskinesia. Journal of Medical Genetics 49, 410-416Google Scholar
48Mazor, M. et al. (2011) Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1. American Journal of Human Genetics 88, 599-607Google Scholar
49Panizzi, J.R. et al. (2012) CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms. Nature Genetics 44, 714-719Google Scholar
50Horani, A. et al. (2012) Whole-exome capture and sequencing identifies HEATR2 mutation as a cause of primary ciliary dyskinesia. American Journal of Human Genetics 91, 685-693Google Scholar
51Kott, E. et al. (2012) Loss-of-function mutations in LRRC6, a gene essential for proper axonemal assembly of inner and outer dynein arms, cause primary ciliary dyskinesia. American Journal of Human Genetics 91, 958-964Google Scholar
52Serluca, F.C. et al. (2009) Mutations in zebrafish leucine-rich repeat-containing six-like affect cilia motility and result in pronephric cysts, but have variable effects on left–right patterning. Development 136, 1621-1631Google Scholar
53Onoufriadis, A. et al. (2013) Splice-site mutations in the axonemal outer dynein arm docking complex gene CCDC114 cause primary ciliary dyskinesia. American Journal of Human Genetics 92, 88-98Google Scholar
54Moore, D.J. et al. (2013) Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and outer dynein arms in humans and flies, cause primary ciliary dyskinesia. American Journal of Human Genetics 93, 346-356Google Scholar
55Zariwala, M.A. et al. (2013) ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6. American Journal of Human Genetics 93, 336-345Google Scholar
56Hjeij, R. et al. (2013) ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry. American Journal of Human Genetics 93, 357-367Google Scholar
57Onoufriadis, A. et al. (2014) Combined exome and whole-genome sequencing identifies mutations in ARMC4 as a cause of primary ciliary dyskinesia with defects in the outer dynein arm. Journal of Medical Genetics 51, 61-67Google Scholar
58Tarkar, A. et al. (2013) DYX1C1 is required for axonemal dynein assembly and ciliary motility. Nature Genetics 45, 995-1003Google Scholar
59Austin-Tse, C. et al. (2013) Zebrafish ciliopathy screen plus human mutational analysis identifies C21orf59 and CCDC65 defects as causing primary ciliary dyskinesia. American Journal of Human Genetics 93, 672-686Google Scholar
60Knowles, M.R. et al. (2013) Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms. American Journal of Human Genetics 93, 711-720Google Scholar
61Hjeij, R. et al. (2014) CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation. American Journal of Human Genetics 95, 257-274Google Scholar
62Olbrich, H. et al. (2012) Recessive HYDIN mutations cause primary ciliary dyskinesia without randomization of left–right body asymmetry. American Journal of Human Genetics 91, 672-684Google Scholar
63Castleman, V.H. et al. (2009) Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities. American Journal of Human Genetics 84, 197-209Google Scholar
64Wirschell, M. et al. (2013) The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans. Nature Genetics 45, 262-268Google Scholar
65Kott, E. et al. (2013) Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects. American Journal of Human Genetics 93, 561-570Google Scholar
66Horani, A. et al. (2013) CCDC65 mutation causes primary ciliary dyskinesia with normal ultrastructure and hyperkinetic cilia. PLoS One 8, e72299Google Scholar
67Wallmeier, J. et al. (2014) Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia. Nature Genetics 46, 646-651Google Scholar
68Olbrich, H. et al. (2003) Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Nature Genetics 34, 455-459Google Scholar
69Mochizuki, T. et al. (1998) Cloning of inv, a gene that controls left/right asymmetry and kidney development. Nature 395, 177-181Google Scholar
70Bellavia, S. et al. (2010) A homozygous mutation in INVS causing juvenile nephronophthisis with abnormal reactivity of the Wnt/beta-catenin pathway. Nephrology Dialysis Transplantation 25, 4097-4102CrossRefGoogle ScholarPubMed
71Bergmann, C. et al. (2008) Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. American Journal of Human Genetics 82, 959-970Google Scholar
72Fiskerstrand, T. et al. (2010) Identification of a gene for renal-hepatic-pancreatic dysplasia by microarray-based homozygosity mapping. Journal of Molecular Diagnostics 12, 125-131Google Scholar
73Simpson, M.A. et al. (2009) Lethal cystic kidney disease in Amish neonates associated with homozygous nonsense mutation of NPHP3. American Journal of Kidney Diseases 53, 790-795Google Scholar
74Chaki, M. et al. (2011) Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies. Kidney International 80, 1239-1245Google Scholar
75Hoff, S. et al. (2013) ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nature Genetics 45, 951-956Google Scholar
76Brancati, F. et al. (2007) CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders. American Journal of Human Genetics 81, 104-113Google Scholar
77Coppieters, F. et al. (2010) CEP290, a gene with many faces: mutation overview and presentation of CEP290base. Human Mutation 31, 1097-1108CrossRefGoogle ScholarPubMed
78Pennekamp, P. et al. (2002) The ion channel polycystin-2 is required for left–right axis determination in mice. Current Biology 12, 938-943CrossRefGoogle ScholarPubMed
79Oka, M., Mochizuki, T. and Kobayashi, S. (2014) A novel mutation of the PKD2 gene in a Japanese patient with autosomal dominant polycystic kidney disease and complete situs inversus. American Journal of Kidney Diseases 64, 660Google Scholar
80Deffert, C. et al. (2007) Recurrent insertional polydactyly and situs inversus in a Bardet-Biedl syndrome family. American Journal of Medical Genetics part A 143, 208-213Google Scholar
81Nachury, M.V. et al. (2007) A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129, 1201-1213Google Scholar
82Ansley, S.J. et al. (2003) Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome. Nature 425, 628-633Google Scholar
83Davidson, A.E. et al. (2013) Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa. American Journal of Human Genetics 93, 321-329Google Scholar
84Sparrow, D.B. et al. (2008) Mutation of Hairy-and-Enhancer-of-Split-7 in humans causes spondylocostal dysostosis. Human Molecular Genetics 17, 3761-3766Google Scholar
85Sparrow, D.B. et al. (2013) Mutation of HES7 in a large extended family with spondylocostal dysostosis and dextrocardia with situs inversus. American Journal of Medical Genetics part A 161, 2244-2249Google Scholar
86Raya, A. et al. (2004) Notch activity acts as a sensor for extracellular calcium during vertebrate left–right determination. Nature 427, 121-128Google Scholar
87Raya, A. et al. (2003) Notch activity induces Nodal expression and mediates the establishment of left–right asymmetry in vertebrate embryos. Genes and Development 17, 1213-1218Google Scholar
88Levin, M. (2005) Left–right asymmetry in embryonic development: a comprehensive review. Mechanisms of Development 122, 3-25Google Scholar
89Blum, M. et al. (2009) Xenopus, an ideal model system to study vertebrate left–right asymmetry. Developmental Dynamics 238, 1215-1225Google Scholar
90Pohl, C. (2011) Left–right patterning in the C. elegans embryo: unique mechanisms and common principles. Communicative and Integrative Biology 4, 34-40Google Scholar
91Okumura, T. et al. (2008) The development and evolution of left–right asymmetry in invertebrates: lessons from Drosophila and snails. Developmental Dynamics 237, 3497-3515Google Scholar
92Shapiro, A.J. et al. (2014) Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy. Chest 146, 1176-1186Google Scholar
93Bamford, R.N. et al. (2000) Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left–right laterality defects. Nature Genetics 26, 365-369CrossRefGoogle ScholarPubMed
94Kosaki, R. et al. (1999) Left–right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB. American Journal of Medical Genetics 82, 70-76Google Scholar
95Mohapatra, B. et al. (2009) Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations. Human Molecular Genetics 18, 861-871Google Scholar
96Kaasinen, E. et al. (2010) Recessively inherited right atrial isomerism caused by mutations in growth/differentiation factor 1 (GDF1). Human Molecular Genetics 19, 2747-2753Google Scholar
97Zaidi, S. et al. (2013) De novo mutations in histone-modifying genes in congenital heart disease. Nature 498, 220-223CrossRefGoogle ScholarPubMed
98De Luca, A. et al. (2010) Familial transposition of the great arteries caused by multiple mutations in laterality genes. Heart 96, 673-677Google Scholar
99Yang, X.F. et al. (2010) Mutation analysis of Cited2 in patients with congenital heart disease. Zhonghua Er Ke Za Zhi 48, 293-296Google Scholar
100Kosaki, K. et al. (1999) Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left–right axis development. American Journal of Human Genetics 64, 712-721Google Scholar
101Watanabe, Y. et al. (2002) Two novel frameshift mutations in NKX2.5 result in novel features including visceral inversus and sinus venosus type ASD. Journal of Medical Genetics 39, 807-811Google Scholar
102Hirayama-Yamada, K. et al. (2005) Phenotypes with GATA4 or NKX2.5 mutations in familial atrial septal defect. American Journal of Medical Genetics part A 135, 47-52Google Scholar
103Peeters, H. et al. (2006) Sesn1 is a novel gene for left–right asymmetry and mediating nodal signaling. Human Molecular Genetics 15, 3369-3377Google Scholar
104Tariq, M. et al. (2011) SHROOM3 is a novel candidate for heterotaxy identified by whole exome sequencing. Genome Biology 12, R91Google Scholar
105Sutherland, M.J. et al. (2013) Zic3 is required in the migrating primitive streak for node morphogenesis and left–right patterning. Human Molecular Genetics 22, 1913-1923Google Scholar
106Ware, S.M., Harutyunyan, K.G. and Belmont, J.W. (2006) Heart defects in X-linked heterotaxy: evidence for a genetic interaction of Zic3 with the nodal signaling pathway. Developmental Dynamics 235, 1631-1637Google Scholar
107Purandare, S.M. et al. (2002) A complex syndrome of left–right axis, central nervous system and axial skeleton defects in Zic3 mutant mice. Development 129, 2293-2302Google Scholar
108D'Alessandro, L.C., Casey, B. and Siu, V.M. (2013) Situs inversus totalis and a novel ZIC3 mutation in a family with X-linked heterotaxy. Congenital Heart Disease 8, E36-E40Google Scholar
109Ware, S.M. et al. (2004) Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects. American Journal of Human Genetics 74, 93-105Google Scholar
110Cowan, J., Tariq, M. and Ware, S.M. (2014) Genetic and functional analyses of ZIC3 variants in congenital heart disease. Human Mutation 35, 66-75Google Scholar
111Megarbane, A. et al. (2000) X-linked transposition of the great arteries and incomplete penetrance among males with a nonsense mutation in ZIC3. European Journal of Human Genetics 8, 704-708Google Scholar
112Schier, A.F. (2003) Nodal signaling in vertebrate development. Annual Review of Cell and Developmental Biology 19, 589-621Google Scholar
113Yan, Y.T. et al. (1999) Conserved requirement for EGF-CFC genes in vertebrate left–right axis formation. Genes and Development 13, 2527-2537Google Scholar
114Goldmuntz, E. et al. (2002) CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle. American Journal of Human Genetics 70, 776-780Google Scholar
115Kato, R., Yamada, Y. and Niikawa, N. (1996) De novo balanced translocation (6;18)(q21;q21.3 or q22) in a patient with heterotaxia. American Journal of Medical Genetics 66, 184-186Google Scholar
116Peeters, H. et al. (2003) PA26 is a candidate gene for heterotaxia in humans: identification of a novel PA26-related gene family in human and mouse. Human Genetics 112, 573-580Google Scholar
117Oh, S.P. and Li, E. (1997) The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes and Development 11, 1812-1826Google Scholar
118Ma, L. et al. (2012) Mutations in ZIC3 and ACVR2B are a common cause of heterotaxy and associated cardiovascular anomalies. Cardiology in the Young 22, 194-201CrossRefGoogle ScholarPubMed
119Saijoh, Y. et al. (2003) Left–right patterning of the mouse lateral plate requires nodal produced in the node. Developmental Biology 256, 160-172Google Scholar
120Yamamoto, M. et al. (2003) Nodal signaling induces the midline barrier by activating Nodal expression in the lateral plate. Development 130, 1795-1804Google Scholar
121Kinzel, D. et al. (2010) Pitchfork regulates primary cilia disassembly and left–right asymmetry. Developmental Cell 19, 66-77Google Scholar
122French, V.M. et al. (2012) NPHP4 variants are associated with pleiotropic heart malformations. Circulation Research 110, 1564-1574Google Scholar
123Lee, G. et al. (2011) UVRAG is required for organ rotation by regulating Notch endocytosis in Drosophila. Developmental Biology 356, 588-597Google Scholar
124Iida, A. et al. (2000) Identification of a gene disrupted by inv(11)(q13.5;q25) in a patient with left–right axis malformation. Human Genetics 106, 277-287Google Scholar
125Tanaka, C. et al. (2007) Long-range action of Nodal requires interaction with GDF1. Genes & Development 21, 3272-3282Google Scholar
126Rankin, C.T. et al. (2000) Regulation of left–right patterning in mice by growth/differentiation factor-1. Nature Genetics 24, 262-265Google Scholar
127Nakao, A. et al. (1997) Identification of Smad2, a human Mad-related protein in the transforming growth factor beta signaling pathway. Journal of Biological Chemistry 272, 2896-2900Google Scholar
128von Both, I. et al. (2004) Foxh1 is essential for development of the anterior heart field. Developmental Cell 7, 331-345CrossRefGoogle ScholarPubMed
129Weninger, W.J. et al. (2005) Cited2 is required both for heart morphogenesis and establishment of the left–right axis in mouse development. Development 132, 1337-1348Google Scholar
130Meno, C. et al. (1998) lefty-1 is required for left–right determination as a regulator of lefty-2 and nodal. Cell 94, 287-297Google Scholar
131Lyons, I. et al. (1995) Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes and Development 9, 1654-1666CrossRefGoogle ScholarPubMed
132Arceci, R.J. et al. (1993) Mouse GATA-4: a retinoic acid-inducible GATA-binding transcription factor expressed in endodermally derived tissues and heart. Molecular and Cellular Biology 13, 2235-2246Google Scholar
133Brown, C.R. et al. (2004) The cardiac determination factor, Nkx2-5, is activated by mutual cofactors GATA-4 and Smad1/4 via a novel upstream enhancer. Journal of Biological Chemistry 279, 10659-10669Google Scholar
134Crispino, J.D. et al. (2001) Proper coronary vascular development and heart morphogenesis depend on interaction of GATA-4 with FOG cofactors. Genes and Development 15, 839-844Google Scholar
135Rupp, P.A. et al. (2002) Identification, genomic organization and mRNA expression of CRELD1, the founding member of a unique family of matricellular proteins. Gene 293, 47-57Google Scholar
136Robinson, S.W. et al. (2003) Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. American Journal of Human Genetics 72, 1047-1052Google Scholar
137Fakhro, K.A. et al. (2011) Rare copy number variations in congenital heart disease patients identify unique genes in left–right patterning. Proceedings of the National Academy of Sciences of the United States of America 108, 2915-2920Google Scholar
138Boskovski, M.T. et al. (2013) The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality. Nature 504, 456-459Google Scholar
139Zhang, Z. et al. (2009) Massively parallel sequencing identifies the gene Megf8 with ENU-induced mutation causing heterotaxy. Proceedings of the National Academy of Sciences of the United States of America 106, 3219-3224Google Scholar
140Frank, V. et al. (2013) Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression. Human Molecular Genetics 22, 2177-2185Google Scholar
141Fukui, H. et al. (2012) The ciliary protein Nek8/Nphp9 acts downstream of Inv/Nphp2 during pronephros morphogenesis and left–right establishment in zebrafish. Febs Letters 586, 2273-2279Google Scholar
142Manning, D.K. et al. (2013) Loss of the ciliary kinase Nek8 causes left–right asymmetry defects. Journal of the American Society of Nephrology 24, 100-112Google Scholar
143Lee, J.D., Migeotte, I. and Anderson, K.V. (2010) Left–right patterning in the mouse requires Epb4.1l5-dependent morphogenesis of the node and midline. Developmental Biology 346, 237-246Google Scholar
144Kevelam, S.H. et al. (2012) A patient with a mild holoprosencephaly spectrum phenotype and heterotaxy and a 1.3 Mb deletion encompassing GLI2. American Journal of Medical Genetics part A 158A, 166-173Google Scholar
145Muncke, N. et al. (2003) Missense mutations and gene interruption in PROSIT240, a novel TRAP240-like gene, in patients with congenital heart defect (transposition of the great arteries). Circulation 108, 2843-2850Google Scholar
146Wessels, M.W. et al. (2008) A new syndrome with noncompaction cardiomyopathy, bradycardia, pulmonary stenosis, atrial septal defect and heterotaxy with suggestive linkage to chromosome 6p. Human Genetics 122, 595-603Google Scholar
147Vitale, E. et al. (2001) Suggestive linkage of situs inversus and other left–right axis anomalies to chromosome 6p. Journal of Medical Genetics 38, 182-185Google Scholar
148Lin, C.R. et al. (1999) Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis. Nature 401, 279-282Google Scholar
149Marques, S. et al. (2004) The activity of the Nodal antagonist Cerl-2 in the mouse node is required for correct L/R body axis. Genes and Development 18, 2342-2347CrossRefGoogle ScholarPubMed
150Dowdle, W.E. et al. (2011) Disruption of a ciliary B9 protein complex causes Meckel syndrome. American Journal of Human Genetics 89, 94-110Google Scholar
151Barratt, K.S., Glanville-Jones, H.C. and Arkell, R.M. (2014) The Zic2 gene directs the formation and function of node cilia to control cardiac situs. Genesis 52, 626-635Google Scholar