Genetics of Human Laterality Disorders: Insights from Vertebrate Model Systems

Annual Review of Genomics and Human Genetics

Volumn 4, Issue , 2003, Pages 1-32

  Bisgrove, Brent W ^a   Morelli, Susan H ^a   Yost, H Joseph ^a  

^a UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

Author keywords

Asplenia; Heterotaxy; Left right asymmetry; Midline development; Polysplenia

Indexed keywords

ASYMMETRIC GENE EXPRESSION; CONGENITAL HEART DISEASE; DIAGNOSTIC ACCURACY; DISEASE CLASSIFICATION; DISPARATE LATERALITY PHENOTYPE; EMBRYO AXIS; GENE EXPRESSION; GENETIC DISORDER; HETEROTAXY SYNDROME; HUMAN LATERALITY DISORDER; MESODERM; MIDLINE PHENOTYPE; MORBIDITY; MORPHOGENESIS; MORTALITY; ORGAN SITUS DEFECT; PHENOTYPE; REVIEW; SITUS INVERSUS; VERTEBRATE; ZEBRA FISH;

ANIMALS; BODY PATTERNING; FEMALE; GENE EXPRESSION; GENETIC DISEASES, INBORN; HUMANS; MALE; MICE; PEDIGREE; ZEBRAFISH;

DANIO RERIO; VERTEBRATA;

EID: 0038191205     PISSN: 15278204     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.genom.4.070802.110428     Document Type: Review

References (209)

1. Adachi H, Saijoh Y, Mochida K, Ohishi S, Hashiguchi H, et al. 1999. Determination of left/right asymmetric expression of nodal by a left-side-specific enhancer with sequence similarity to a lefty-2 enhancer. Genes Dev. 13:1589-600
2. Afzelius BA. 1976. A Human syndrome caused by immotile cilia. Science 193:317-19
3. Alexander J, Rothenberg M, Henry GL, Stainier DY. 1999. Casanova plays an early and essential role in endoderm formation in zebrafish. Dev. Biol. 215:343-57
4. Aplan PD, Lombardi DP, Kirsch IR. 1991. Structural characterization of SIL, a gene frequently disrupted in T-cell acute lymphoblastic leukemia. Mol. Cell Biol. 11:5462-69
5. Arnold GL, Bixler D, Girod D. 1983. Probable autosomal recessive inheritance of polysplenia, situs inversus and cardiac defects in an amish family. Am. J. Med. Genet. 16:35-42.
6. Balci S, Bostanoglu S, Altinok G, Ozaltin F. 2000. New syndrome?: Three sibs diagnosed prenatally with situs inversus totalis, renal and pancreatic dysplasia, and cysts. Am. J. Med. Genet. 90:185-87
7. Bamford RN, Roessler E, Burdine RD, Saplakoglu U, dela Cruz J, et al. 2000. Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with Human left-right laterality defects. Nat. Genet. 26:365-69
8. Bartsch O, Wagner A, Hinkel GK, Krebs P, Stumm M, et al. 1999. FISH studies in 45 patients with Rubinstein-Taybi syndrome: deletions associated with polysplenia, hypoplastic left heart and death in infancy. Eur J. Hum. Genet. 7:748-56
9. Bisgrove BW, Essner JJ, Yost HJ. 1999. Regulation of midline development by antagonism of lefty and nodal signaling. Development 126:3253-62
10. Bisgrove BW, Essner JJ, Yost HJ. 2000. Multiple pathways in the midline regulate concordant brain, heart and gut left-right asymmetry. Development 127:3567-79
11. Bisgrove BW, Yost HJ. 2001. Classification of left-right patterning defects in zebrafish, mice, and Humans. Am. J. Med. Genet. 101:315-23
12. Bowers PN, Brueckner M, Yost HJ. 1996. The genetics of left-right development and heterotaxia. Semin. Perinatol. 20:577-88
13. Brand M, Heisenberg CP, Warga RM, Pelegri F, Karlstrom RO, et al. 1996. Mutations affecting development of the midline and general body shape during zebrafish embryogenesis. Development 123:129-42
14. Branford WW, Yost HJ. 2002. Lefty-dependant inhibition of nodal-and wnt-responsive organizer gene expression is essential for normal gastrulation. Curr. Biol. 12:2136-41
15. Brennan J, Norris DP, Robertson EJ. 2002. Nodal activity in the node governs left-right asymmetry. Genes Dev. 16:2339-44
16. Brody SL, Yan XH, Wuerffel MK, Song SK, Shapiro SD. 2000. Ciliogenesis and left-right axis defects in forkhead factor HFH-4-null mice. Am. J. Respir. Cell Mol. Biol. 23:45-51
17. Brown NA, Wolpert L. 1990. The development of handedness in left/right asymmetry. Development 109:1-9
18. Burdine RD, Schier AF. 2000. Conserved and divergent mechanisms in left-right axis formation. Genes Dev. 14:763-76
19. Campione M, Steinbeisser H, Schweickert A, Deissler K, van Bebber F, et al. 1999. The homeobox gene Pitx2:mediator of asymmetric left-right signaling in vertebrate heart and gut looping. Development 126:1225-34
20. Capdevila J, Vogan KJ, Tabin CJ, Izpisua Belmonte JC. 2000. Mechanisms of left-right determination in vertebrates. Cell 101:9-21
21. Carmi R, Boughman JA, Rosenbaum KR. 1992. Human situs determination is probably controlled by several different genes. Am. J. Med. Genet. 44:246-49
22. Carrel T, Purandare SM, Harrison W, Elder F, Fox T, et al. 2000. The X-linked mouse mutation Bent tail is associated with a deletion of the Zic3 locus. Hum. Mol. Genet. 9:1937-42
23. Casey B. 1998. Two rights make a wrong: Human left-right malformations. Hum. Mol. Genet. 7:1565-71
24. Cesko I, Hajdu J, Toth T, Marton T, Papp C, Papp Z. 1997. Ivemark syndrome with asplenia in siblings. J. Pediatr. 130:822-24
25. Chang H, Zwijsen A, Vogel H, Huylebroeck D, Matzuk MM. 2000. Smad5 is essential for left-right asymmetry in mice. Dev. Biol. 219:71-78
26. Chen J, Knowles HJ, Hebert JL, Hackett BP. 1998. Mutation of the mouse hepatocyte nuclear factor/forkhead homologue 4 gene results in an absence of cilia and random left-right asymmetry. J. Clin. Invest. 102:1077-82
27. Chen J-N, van Bebber F, Goldstein AM, Serluca FC, Jackson D, et al. 2001. Genetic steps to organ laterality in zebrafish. Comput. Funct. Genomics 2:60-68
28. Chen JN, van Eeden FJ, Warren KS, Chin A, Nusslein-Volhard C, et al. 1997. Left-right pattern of cardiac BMP4 may drive asymmetry of the heart in zebrafish. Development 124:4373-82
29. Chen Y, Schier AF. 2001. The zebrafish Nodal signal Squint functions as a morphogen. Nature 411:607-10
30. Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, et al. 1996. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383:407-13
31. Chib P, Grover DN, Shahi BN. 1977. Unusual occurrence of dextrocardia with situs inversus in succeeding generations of a family. J. Med. Genet. 14:30-32
32. Chin AJ, Tsang M, Weinberg ES. 2000. Heart and gut chiralities are controlled independently from initial heart position in the developing zebrafish. Dev. Biol. 227:403-21
33. Collignon J, Varlet I, Robertson EJ. 1996. Relationship between asymmetric nodal expression and the direction of embryonic turning. Nature 381:155-58
34. Concha ML, Burdine RD, Russell C, Schier AF, Wilson SW. 2000. A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain. Neuron 28:399-409
35. Constam DB, Robertson EJ. 2000. SPC4/ PACE4 regulates a TGFbeta signaling network during axis formation. Genes Dev. 14:1146-55
36. Constam DB, Robertson EJ. 2000. Tissue-specific requirements for the proprotein convertase Furin/SPC1 during embryonic turning and heart looping. Development 127:245-54
37. Danos MC, Yost HJ. 1994. The effects of notochord deletion on left-right cardiac asymmetries. Dev. Biol. 163:545
38. Danos MC, Yost HJ. 1995. Linkage of cardiac left-right asymmetry and dorsal-anterior development in Xenopus. Development 121:1467-74
39. Danos MC, Yost HJ. 1996. Role of notochord in specification of cardiac left-right orientation in zebrafish and xenopus. Dev. Biol. 177:96-103
40. de la Monte SM, Hutchins GM. 1985. Sisters with polysplenia. Am. J. Med. Genet. 21:171-76
41. Debrus S, Sauer U, Gilgenkrantz S, Jost W, Jesberger HJ, Bouvagnet P. 1997. Autosomal recessive lateralization and midline defects: blastogenesis recessive 1. Am. J. Med. Genet. 68:401-4
42. Delaroche I, Bruni L, Giannotti A, Giampaolo R, Aebischer ML. 1984. Trisomy for the short arm of chromosome 10. Report of a new case resulting from segregation of a maternal balanced translocation t(10qter-q11::14p11-qter). Helv. Paediatr. Acta 39:161-66
43. Digilio MC, Marino B, Giannotti A, Di Donate R, Dallapiccola B. 2000. Heterotaxy with left atrial isomerism in a patient with deletion 18p. Am. J. Med. Genet. 94:198-200
44. Dufort D, Schwartz L, Harpal K, Rossant J. 1998. The transcription factor HNF3beta is required in visceral endoderm for normal primitive streak morphogenesis. Development 125:3015-25
45. el Kalla S, Mathews AR, Menon NS. 1992. del(18p) syndrome with complex tetralogy of Fallot in an infant with 45,X,t(Y;18)(q12;q11.2). Am. J. Med. Genet. 42:665-66
46. Eliasson R, Mossberg B, Cammer P, Afzelius B. 1977. The immotile-cilia syndrome: A congenital ciliary abnormality as an etiologic factor in chronic airway infections and male sterility. N. Engl. J. Med. 297:1
47. Essner JJ, Vogan KJ, Wagner MK, Tabin CJ, Yost HJ, Brueckner M. 2002. Conserved function for embryonic nodal cilia. Nature 418:37-38
48. Faisst AM, Alvarez-Bolado G, Treichel D, Gruss P. 2002. Rotatin is a novel gene required for axial rotation and left-right specification in mouse embryos. Mech. Dev. 113:15-28
49. Feldman B, Gates MA, Egan ES, Dougan ST, Rennebeck G, et al. 1998. Zebrafish organizer development and germ-layer formation require nodal-related signals. Nature 395:181-85
50. Freeman SB, Muralidharan K, Pettay D, Blackston RD, May KM. 1996. Asplenia syndrome in a child with a balanced reciprocal translocation of chromosomes 11 and 20 [46,XX,t(11;20)(q13.1;q13.13)]. Am. J. Med. Genet. 61:340-44
51. Fujiwara T, Dehart DB, Sulik KK, Hogan BL. 2002. Distinct requirements for extra-embryonic and embryonic bone morphogenetic protein 4 in the formation of the node and primitive streak and coordination of left-right asymmetry in the mouse. Development 129:4685-96
52. Fullana A, Garcia-Frias E, Martinez-Frias ML, Razquin S, Quero J. 1986. Caudal deficiency and asplenia anomalies in sibs. Am. J. Med. Genet. Suppl. 2:23-29
53. Gage PJ, Suh H, Camper SA. 1999. Dosage requirement of Pitx2 for development of multiple organs. Development 126:4643-51
54. Gaio U, Schweickert A, Fischer A, Garratt AN, MI, T et al. 1999. A role of the cryptic gene in the correct establishment of the left-right axis. Curr. Biol. 9:1339-42
55. Gebbia M, Ferrero GB, Pilia G, Bassi MT, Aylsworth A, et al. 1997. X-linked situs abnormalities result from mutations in ZIC3. Nat. Genet. 17:305-8
56. Gemel J, Gorry M, Ehrlich GD, MacArthur CA. 1996. Structure and sequence of Human FGF8. Genomics 35:253-57
57. Gemma A, Hagiwara K, Vincent F, Ke Y, Hancock AR, et al. 1998. hSmad5 gene, a Human hSmad family member: its full length cDNA, genomic structure, promoter region and mutation analysis in Human tumors. Oncogene 16:951-56
58. Genuardi M, Pomponi MG, Sammito V, Bellussi A, Zollino M, Neri G. 1993. Split hand/split foot anomaly in a family segregating a balanced translocation with breakpoint on 7q22.1. Am. J. Med. Genet. 47:823-31
59. Halpern ME, Ho RK, Walker C, Kimmel CB. 1993. Induction of muscle pioneers and floor plate is distinguished by the zebrafish no tail mutation. Cell 75:99-111
60. Hamada H, Meno C, Watanabe D, Saijoh Y. 2002. Establishment of vertebrate left-right asymmetry. Nat. Rev. Genet. 3:103-13
61. Hammerschmidt M, Pelegri F, Mullins MC, Kane DA, Brand M, et al. 1996. Mutations affecting morphogenesis during gastrulation and tail formation in the zebrafish, Danio rerio. Development 123:143-51
62. Hatta K, Kimmel CB, Ho RK, Walker C. 1991. The cyclops mutation blocks specification of the floor plate of the zebrafish central nervous system. Nature 350:339-41
63. Heisenberg CP, Nusslein-Volhard C. 1997. The function of silberblick in the positioning of the eye anlage in the zebrafish embryo. Dev. Biol. 184:85-94
64. Heymer J, Kuehn M, Ruther U. 1997. The expression pattern of nodal and lefty in the mouse mutant Ft suggests a function in the establishment of handedness. Mech. Dev. 66:5-11
65. Hou JW, Wang TR. 1996. Amelia, dextrocardia, asplenia, and congenital short bowel in deleted ring chromosome 4. J. Med. Genet. 33:879-81
66. Hummel KP, Chapman DB. 1959. Visceral inversion and associated anomalies in the mouse. J. Hered. 50:9-13
67. Hyatt BA, Lohr JL, Yost HJ. 1996. Initiation of vertebrate left-right axis formation by maternal vg1. Nature 384:62-65
68. Hyatt BA, Yost HJ. 1998. The left-right coordinator:the role of Vg1 in organizing left-right axis formation. Cell 93:37-46
69. Iida A, Emi M, Matsuoka R, Hiratsuka E, Okui K, et al. 2000. Identification of a gene disrupted by inv(11)(q13.5;q25) in a patient with left-right axis malformation. Hum. Genet. 106:277-87
70. Ioffe E, Stanley P. 1994. Mice lacking N-acetylglucosaminyltransferase I activity die at mid-gestation, revealing an essential role for complex or hybrid N-linked carbohydrates. Proc. Natl. Acad. Sci. USA 91:728-32
71. Isaac A, Sargent MG, Cooke J. 1997. Control of vertebrate left-right asymmetry by a snail-related zinc finger gene. Science 275:1301-4
72. Ivemark B. 1955. Implication of agenesis of the spleen on the pathogenesis of conotruncus anomalies in childhood. Acta Paediatr. Scand. Suppl. 104:590-92
73. Izraeli S, Lowe LA, Bertness VL, Good DJ, Dorward DW, et al. 1999. The SIL gene is required for mouse embryonic axial development and left-right specification. Nature 399:691-94
74. Kane HA, Borgaonkar D, McDermott M, Septimus S, Movahhedian H. 1991. 18p monosomy syndrome. Pediatr. Cardiol. 12:133
75. Kartagener M, Strucki P. 1962. Bronchiectasis with situs inversus. Arch. Pediatr. 79:193
76. Kato R, Yamada Y, Niikawa N. 1996. De novo balanced translocation (6;18) (q21;q21.3 or q22) in a patient with heterotaxia. Am. J. Med. Genet. 66:184-86. Erratum. 1997. Am. J. Med. Genet. 70(1): 104
77. Kiefer MC, Tucker JE, Joh R, Landsberg KE, Saltman D, Barr PJ. 1991. Identification of a second Human subtilisin-like protease gene in the fes/fps region of chromosome 15. DNA Cell Biol. 10:757-69
78. Kimmel CB, Kane DA, Walker C, Warga RM, Rothman MB. 1989. A mutation that changes cell movement and cell fate in the zebrafish embryo. Nature 337:358-62
79. King T, Beddington RS, Brown NA. 1998. The role of the brachyury gene in heart development and left-right specification in the mouse. Mech. Dev. 79:29-37
80. Kitamura K, Miura H, Miyagawa-Tomita S, Yanazawa M, Katoh-Fukui Y, et al. 1999. Mouse Pitx2 deficiency leads to anomalies of the ventral body wall, heart, extra-and periocular mesoderm and right pulmonary isomerism. Development 126: 5749-58
81. Koiffmann CP, Wajntal A, de Souza DH, Gonzalez CH, Coates MV. 1993. Human situs determination and chromosome constitution 46,XY,ins(7;8)(q22;q12q24) . Am. J. Med. Genet. 47:568-69
82. Kosaki K, Bassi MT, Kosaki R, Lewin M, Belmont J, et al. 1999. Characterization and mutation analysis of Human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development. Am. J. Hum. Genet. 64:712-21
83. Kosaki K, Casey B. 1998. Genetics of Human left-right axis malformations. Semin. Cell Dev. Biol. 9:89-99
84. Kosaki R, Gebbia M, Kosaki K, Lewin M, Bowers P, et al. 1999. Left-right axis malformations associated with mutations in ACVR2B, the gene for Human activin receptor type IIB. Am. J. Med. Genet. 82:70-76
85. Kramer KL, Barnette JE, Yost HJ. 2002. PKCy regulates syndecan-2 inside-out signaling durng Xenopus left-right development. Cell 111:981-90
86. Kramer KL, Yost HJ. 2002. Ectodermal syndecan-2 mediates left-right axis formation in migrating mesoderm as a cell-nonautonomous vg1 cofactor. Dev. Cell 2:115-24
87. Layton WW. 1976. Random determination of a developmental process: reversal of normal visceral asymmetry in the mouse. J. Hered. 67:336-38
88. Levin M, Johnson RL, Stern CD, Kuehn M, Tabin C. 1995. A molecular pathway determining left-right asymmetry in chick embryogenesis. Cell 82:803-14
89. Levin M, Mercola M. 1998. Gap junctions are involved in the early generation of left-right asymmetry. Dev. Biol. 203:90-105
90. Levin M, Mercola M. 1999. Gap junction-mediated transfer of left-right patterning signals in the early chick blastoderm is upstream of shh asymmetry in the node. Development 126:4703-14
91. Levin M, Pagan S, Roberts DJ, Cooke J, Kuehn MR, Tabin CJ. 1997. Left/right patterning signals and the independent regulation of different aspects of situs in the chick embryo. Dev. Biol. 189:57-67
92. Levin M, Thorlin T, Robinson KR, Nogi T, Mercola M. 2002. Asymmetries in H+/K+-ATPase and cell membrane potentials comprise a very early step in left-right patterning. Cell 111:77-89
93. Liang JO, Etheridge A, Hantsoo L, Rubinstein AL, Nowak SJ, et al. 2000. Asymmetric nodal signaling in the zebrafish diencephalon positions the pineal organ. Development 127:5101-12
94. Lin AE, Ticho BS, Houde K, Westgate M, Holmes LB. 2000. Heterotaxy: Associated conditions and hospital-based prevalence in newborns. Genet. Med. 2:157-72
95. Lin CR, Kioussi C, O'Connell S, Briata P, Szeto D, et al. 1999. Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis. Nature 401:279-82
96. Liu C, Liu W, Lu MF, Brown NA, Martin JF. 2001. Regulation of left-right asymmetry by thresholds of Pitx2c activity. Development 128:2039-48
97. Logan M, Pagan-Westphal SM, Smith DM, Paganessi L, Tabin CJ. 1998. The transcription factor Pitx2 mediates situs-specific morphogenesis in response to left-right asymmetric signals. Cell 94:307-17
98. Lohr JL, Danos MC, Yost HJ. 1997. Left-right asymmetry of a nodal-related gene is regulated by dorsoanterior midline structures during Xenopus development. Development 124:1465-72
99. Lowe LA, Supp DM, Sampath K, Yokoyama T, Wright CVE, et al. 1996. Conserved left-right asymmetry of nodal expression and alterations in murine situs inversus. Nature 381:158-61
100. Lu MF, Pressman C, Dyer R, Johnson RL, Martin JF. 1999. Function of Rieger syndrome gene in left-right asymmetry and craniofacial development. Nature 401:276-78
101. Maiti AK, Bartoloni L, Mitchison HM, Meeks M, Chung E, et al. 2000. No deleterious mutations in the FOXJ1 (alias HFH-4) gene in patients with primary ciliary dyskinesia (PCD). Cytogenet. Cell Genet. 90:119-22
102. Marszalek JR, Ruiz-Lozano P, Roberts E, Chien KR, Goldstein LS. 1999. Situs in-versus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II Proc. Natl. Acad. Sci. USA 96:5043-48
103. Martinez-Frias ML. 1995. Primary midline developmental field. I. Clinical and epidemiological characteristics. Am. J. Med. Genet. 56:374-81
104. Martinez-Frias ML. 2001. Heterotaxia as an outcome of maternal diabetes: An epidemiological study. Am. J. Med. Genet. 99:142-46
105. Melloy PG, Ewart JL, Cohen MF, Desmond ME, Kuehn MR, Lo CW. 1998. No turning, a mouse mutation causing left-right and axial patterning defects. Dev. Biol. 193:77-89
106. Meno C, Gritsman K, Ohishi S, Ohfuji Y, Heckscher E, et al. 1999. Mouse Lefty2 and zebrafish antivin are feedback inhibitors of nodal signaling during vertebrate gastrulation. Mol. Cell 4:287-98
107. Meno C, Ito Y, Saijoh Y, Matsuda Y, Tashiro K, et al. 1997. Two closely-related left-right asymmetrically expressed genes, lefty-1 and lefty-2: their distinct expression domains, chromosomal linkage and direct neuralizing activity in Xenopus embryos. Genes Cells 2:513-24
108. Meno C, Saijoh Y, Fujii H, Ikeda M, Yokoyama T, et al. 1996. Left-right asymmetric expression of the TGFb-family member lefty in mouse embryos. Nature 381:151-55
109. Meno C, Shimono A, Saijoh Y, Yashiro K, Mochida K, et al. 1998. lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Cell 94:287-97
110. Meno C, Takeuchi J, Sakuma R, Koshiba-Takeuchi K, Ohishi S, et al. 2001. Diffusion of nodal signaling activity in the absence of the feedback inhibitor Lefty2. Dev. Cell 1:127-38
111. Metzler M, Gertz A, Sarkar M, Schachter H, Schrader JW, Marth JD. 1994. Complex asparagine-linked oligosaccharides are required for morphogenic events during post-implantation development. EMBO J. 13:2056-65
112. Meyers EN, Martin GR. 1999. Differences in left-right axis pathways in mouse and chick: functions of FGF8 and SHH. Science 285:403-6
113. Mincheva A, Lichter P, Schutz G, Kaestner KH. 1997. Assignment of the Human genes for hepatocyte nuclear factor 3-alpha, -beta, and -gamma (HNF3A, HNF3B, HNF3G) to 14q12-q13, 20p11, and 19q13.2-q13.4. Genomics 39:417-19
114. Mochizuki T, Saijoh Y, Tsuchiya K, Shirayoshi Y, Takai S, et al. 1998. Cloning of inv, a gene that controls left/right asymmetry and kidney development. Nature 395:177-81
115. Monsoro-Burq A, Le Douarin NM. 2001. BMP4 plays a key role in left-right patterning in chick embryos by maintaining Sonic Hedgehog asymmetry. Mol. Cell 7:789-99
116. Morelli SH, Yost HJ, Bamshad M. 2001. Are defects of laterality disturbances of the midline? Proc. Greenwood Genet. Cent. 20:101-2
117. Morelli SH, Young L, Reid B, Ruttenberg H, Bamshad MJ. 2001. Clinical analysis of families with heart, midline, and laterality defects. Am. J. Med. Genet. 101:388-92
118. Morgan D, Turnpenny L, Goodship J, Dai W, Majumder K, et al. 1998. Inversin, a novel gene in the vertebrate left-right axis pathway, is partially deleted in the inv mouse. Nat. Genet. 20:149-56
119. Morishima M, Yasui H, Ando M, Nakazawa M, Takao A. 1996. Influence of genetic and maternal diabetes in the pathogenesis of visceroatrial heterotaxy in mice. Teratology 54:183-90
120. Movahhedian HR, Kane HA, Borgaonkar D, McDermott M, Septimus S. 1991. Heart disease associated with deletion of the short arm of chromosome 18. Del. Med. J. 63:285-89
121. Murcia NS, Richards WG, Yoder BK, Mucenski ML, Dunlap JR, Woychik RP. 2000. The Oak Ridge Polycystic Kidney (orpk) disease gene is required for left-right axis determination. Development 127:2347-55
122. Nakano S, Okuno T, Hojo H, Misawa S, Abe T. 1977. 18p-syndrome associated with hemivertebrae, fused ribs and micropenis. Jinrui Idengaku Zasshi 22:27-32
123. Nanni L, Ming JE, Bocian M, Steinhaus K, Bianchi DW, et al. 1999. The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Hum. Mol. Genet. 8:2479-88
124. Niikawa N, Kohsaka S, Mizumoto M, Hamada I, Kajii T. 1983. Familial clustering of situs inversus totalis, and asplenia and polysplenia syndromes. Am. J. Med. Genet. 16:43-47
125. Nomura M, Li E. 1998. Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature 393:786-90
126. Nonaka S, Shiratori H, Saijoh Y, Hamada H. 2002. Determination of left-right patterning of the mouse embryo by artificial nodal flow. Nature 418:96-99
127. Nonaka S, Tanaka Y, Okada Y, Takeda S, Harada A, et al. 1998. Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 95:829-37
128. Norris DP, Brennan J, Bikoff EK, Robertson EJ. 2002. The Foxh1-dependent autoregulatory enhancer controls the level of Nodal signals in the mouse embryo. Development 129:3455-68
129. Norris DP, Robertson EJ. 1999. Asymmetric and node-specific nodal expression patterns are controlled by two distinct cis-acting regulatory elements. Genes Dev. 13:1575-88
130. Nowaczyk MJ, Huggins MJ, Tomkins DJ, Rossi E, Ramsay JA, et al. 2000. Holo-prosencephaly, sacral anomalies, and situs ambiguus in an infant with partial monosomy 7q/trisomy 2p and SHH and HLXB9 haploinsufficiency. Clin. Genet. 57:388-93
131. Odenthal J, Haffter P, Vogelsang E, Brand M, van Eeden FJ, et al. 1996. Mutations affecting the formation of the notochord in the zebrafish, Danio rerio. Development 123:103-15
132. Oh SP, Li E. 1997. The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev. 11:1812-26
133. Okada Y, Nonaka S, Tanaka Y, Saijoh Y, Hamada H, Hirokawa N. 1999. Abnormal nodal flow precedes situs inversus in iv and inv mice. Mol. Cell 4:459-68
134. Olbrich H, Haffner K, Kispert A, Volkel A, Volz A, et al. 2002. Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry. Nat. Genet. 30:143-44
135. Onuchic LF, Schrick JJ, Ma J, Hudson T, Guay-Woodford LM, et al. 1995. Sequence analysis of the Human hTg737 gene and its polymorphic sites in patients with autosomal recessive polycystic kidney disease. Mamm. Genome 6:805-8
136. Opitz JM. 1985. Editorial comment on the paper by de la Monte and Hutchins on familial polysplenia. Am. J. Med. Genet. 21:175-76
137. Osada SI, Saijoh Y, Frisch A, Yeo CY, Adachi H, et al. 2000. Activin/nodal responsiveness and asymmetric expression of a Xenopus nodal-related gene converge on a FAST-regulated module in intron 1. Development 127:2503-14
138. Pagan-Westphal SM, Tabin CJ. 1998. The transfer of left-right positional information during chick embryogenesis. Cell 93:25-35
139. Pan Y, McCaskill CD, Thompson KH, Hicks J, Casey B, et al. 1998. Paternal isodisomy of chromosome 7 associated with complete situs inversus and immotile cilia. Am. J. Hum. Genet. 62:1551-55
140. Partridge JB, Scott O, Deverall PB, Macartney FJ. 1975. Visualization and measurement of the main bronchi by tomography as an objective indicator of thoracic situs in congenital heart disease. Circulation 51:188-96
141. Patel K, Isaac A, Cooke J. 1999. Nodal signalling and the roles of the transcription factors SnR and Pitx2 in vertebrate left-right asymmetry. Curr. Biol. 9:609-12
142. Pennarun G, Escudier E, Chapelin C, Bridoux AM, Cacheux V, et al. 1999. Loss-of-function mutations in a Human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia. Am. J. Hum. Genet. 65:1508-19
143. Pennekamp P, Karcher C, Fischer A, Schweickert A, Skryabin B, et al. 2002. The ion channel polycystin-2 is required for left-right axis determination in mice. Curr. Biol. 12:938-43
144. Phoon CK, Neill CA. 1994. Asplenia syndrome:insight into embryology through an analysis of cardiac and extracardiac anomalies. Am. J. Cardiol. 73:581-87
145. Piedra ME, Icardo JM, Albajar M, Rodriguez-Rey JC, Ros MA. 1998. Pitx2 participates in the late phase of the pathway controlling left-right asymmetry. Cell 94:319-24
146. Piedra ME, Ros MA. 2002. BMP signaling positively regulates Nodal expression during left right specification in the chick embryo. Development 129:3431-40
147. Pinar H, Rogers BB. 1992. Renal dysplasia, situs inversus totalis, and multisystem fibrosis:a new syndrome. Pediatr. Pathol. 12:215-21
148. Pogoda HM, Solnica-Krezel L, Driever W, Meyer D. 2000. The zebrafish forkhead transcription factor FoxH1/Fast1 is a modulator of nodal signaling required for organizer formation. Curr. Biol. 10:1041-49
149. Psychoyos D, Stern CD. 1996. Restoration of the organizer after radical ablation of Hensen's node and the anterior primitive streak in the chick embryo. Development 122:3263-73
150. Purandare SM, Ware SM, Kwan KM, Gebbia M, Bassi MT, et al. 2002. A complex syndrome of left-right axis, central nervous system and axial skeleton defects in Zic3 mutant mice. Development 129:2293-302
151. Ramsdell AF, Yost HJ. 1999. Cardiac looping and the vertebrate left-right axis: antagonism of left-sided Vg1 activity by a right-sided ALK2-dependent BMP pathway. Development 126:5195-205
152. Rankin CT, Bunton T, Lawler AM, Lee SJ. 2000. Regulation of left-right patterning in mice by growth/differentiation factor-1. Nat. Genet. 24:262-65
153. Rebagliati MR, Toyama R, Haffter P, Dawid IB. 1998. Cyclops encodes a nodal-related factor involved in midline signaling. Proc. Natl. Acad. Sci. USA 95:9932-37
154. Reddy KS, Flannery D, Farrer RJ. 1999. Microdeletion of chromosome sub-band 2q37.3 in two patients with abnormal situs viscerum. Am. J. Med. Genet. 84:460-68
155. Rodriguez Esteban C, Capdevila J, Economides AN, Pascual J, Ortiz A, Izpisua Belmonte JC. 1999. The novel Cer-like protein Caronte mediates the establishment of embryonic left-right asymmetry. Nature 401:243-51
156. Roessler E, Belloni E, Gaudenz K, Jay P, Berta P, et al. 1996. Mutations in the Human Sonic Hedgehog gene cause holo-prosencephaly. Nat. Genet. 14:357-60
157. Ryan AK, Blumberg B, Rodriguez-Esteban C, Yonei-Tamura S, Tamura K, et al. 1998. Pitx2 determines left-right asymmetry of internal organs in vertebrates. Nature 394:545-51
158. Saijoh Y, Adachi H, Mochida K, Ohishi S, Hirao A, Hamada H. 1999. Distinct transcriptional regulatory mechanisms underlie left-right asymmetric expression of lefty-1 and lefty-2. Genes Dev. 13:259-69
159. Saijoh Y, Adachi H, Sakuma R, Yeo CY, Yashiro K, et al. 2000. Left-right asymmetric expression of lefty2 and nodal is induced by a signaling pathway that includes the transcription factor FAST2. Mol. Cell 5:35-47
160. Sakuma R, Ohnishi Yi Y, Meno C, Fujii H, Juan H, et al. 2002. Inhibition of Nodal signalling by Lefty mediated through interaction with common receptors and efficient diffusion. Genes Cells 7:401-12
161. Sampath K, Rubinstein AL, Cheng AM, Liang JO, Fekany K, et al. 1998. Induction of the zebrafish ventral brain and floor-plate requires cyclops/nodal signalling. Nature 395:185-89
162. Schier AF, Neuhauss SC, Helde KA, Talbot WS, Driever W. 1997. The one-eyed pinhead gene functions in mesoderm and endoderm formation in zebrafish and interacts with no tail. Development 124:327-42
163. Schilling TF, Concordet JP, Ingham PW. 1999. Regulation of left-right asymmetries in the zebrafish by Shh and BMP4. Dev. Biol. 210:277-87
164. Schlange T, Arnold HH, Brand T. 2002. BMP2 is a positive regulator of Nodal signaling during left-right axis formation in the chicken embryo. Development 129:3421-29
165. Schneider A, Mijalski T, Schlange T, Dai W, Overbeek P, et al. 1999. The homeobox gene NKX3.2 is a target of left-right signalling and is expressed on opposite sides in chick and mouse embryos. Curr. Biol. 9:911-14
166. Schneider H, Brueckner M. 2000. Of mice and men: dissecting the genetic pathway that controls left-right asymmetry in mice and Humans. Am. J. Med. Genet. 97:258-70
167. Schrick JJ, Onuchic LF, Reeders ST, Korenberg J, Chen XN, et al. 1995. Characterization of the Human homologue of the mouse Tg737 candidate polycystic kidney disease gene. Hum. Mol. Genet. 4:559-67
168. Sefton M, Sanchez S, Nieto MA. 1998. Conserved and divergent roles for members of the Snail family of transcription factors in the chick and mouse embryo. Development 125:3111-21
169. Seo JW, Brown NA, Ho SY, Anderson RH. 1992. Abnormal laterality and congenital cardiac anomalies. Relations of visceral and cardiac morphologies in the iv/iv mouse. Circulation 86:642-50
170. Shen MM, Schier AF. 2000. The EGF-CFC gene family in vertebrate development. Trends Genet. 16:303-9
171. Shields DC, Ramsbottom D, Donoghue C, Pinjon E, Kirke PN, et al. 2000. Association between historically high frequencies of neural tube defects and the Human T homologue of mouse T (Brachyury). Am. J. Med. Genet. 92:206-11
172. Shiratori H, Sakuma R, Watanabe M, Hashiguchi H, Mochida K, et al. 2001. Two-step regulation of left-right asymmetric expression of Pitx2:initiation by nodal signaling and maintenance by Nkx2. Mol. Cell 7:137-49
173. Sirotkin HI, Gates MA, Kelly PD, Schier AF, Talbot WS. 2000. Fast 1 is required for the development of dorsal axial structures in zebrafish. Curr. Biol. 10:1051-54
174. Smith M, Herrell S, Lusher M, Lako L, Simpson C, et al. 1999. Genomic organisation of the Human chordin gene and mutation screening of candidate Cornelia de Lange syndrome genes. Hum. Genet. 105:104-11
175. Smith SM, Dickman ED, Thompson RP, Sinning AR, Wunsch AM, Markwald RR. 1997. Retinoic acid directs cardiac laterality and the expression of early markers of precardiac asymmetry. Dev. Biol. 182:162-71
176. Spemann H, Falkenberg H. 1919. Uber asymmetriche Entwicklung und situs in-versus viscerum bei Zwillingen und Doppelbildungen. Arch. Entwicklungsmech. Org. 45:371-422
177. Stoler JM, Holmes LB. 1992. A case of agnathia, situs inversus, and a normal central nervous system. Teratology 46:213-16
178. Supp DM, Brueckner M, Kuehn MR, Witte DP, Lowe LA, et al. 1999. Targeted deletion of the ATP binding domain of left-right dynein confirms its role in specifying development of left-right asymmetries. Development 126:5495-504
179. Supp DM, Witte DP, Potter SS, Brueckner M. 1997. Mutation of an axonemal dynein affects left-right asymmetry in in-versus viscerum mice. Nature 389:963-66
180. Takeda S, Yonekawa Y, Tanaka Y, Okada Y, Nonaka S, Hirokawa N. 1999. Left-right asymmetry and kinesin superfamily protein KIF3A:new insights in determination of laterality and mesoderm induction by kif3A-/-mice analysis. J. Cell Biol. 145:825-36
181. Talbot WS, Trevarrow B, Halpern ME, Melby AE, Farr G, et al. 1995. A homeobox gene essential for zebrafish notochord development. Nature 378:150-57
182. Thomas KR, Capecchi MR. 1987. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell 51:503-12
183. Torgersen J. 1949. Genetic factors in visceral asymmetry and in the development and Pathologic changes of lungs, heart and abdominal organs. Arch. Pathol. 47:566-93
184. Toriello HV, Kokx N, Higgins JV, Hofman R, Waterman DF. 1986. Sibs with the polyasplenia developmental field defect. Am. J. Med. Genet. Suppl. 2:31-36
185. Tsuji A, Hine C, Tamai Y, Yonemoto K, Mon K, et al. 1997. Genomic organization and alternative splicing of Human PACE4 (SPC4), kexin-like
186. Tsukui T, Capdevila J, Tamura K, Ruiz-Lozano P, Rodriguez-Esteban C, et al. 1999. Multiple left-right asymmetry defects in Shh(-/-) mutant mice unveil a convergence of the shh and retinoic acid pathways in the control of Lefty-1. Proc. Natl. Acad. Sci. USA 96:11376-81
187. Urioste M, Martinez-Frias ML, Bermejo E, Jimenez N, Romero D, et al. 1994. Short rib-polydactyly syndrome and pericentric inversion of chromosome 4. Am. J. Med. Genet. 49:94-97
188. Vitale E, Brancolini V, De Rienzo A, Bird L, Allada V, et al. 2001. Suggestive linkage of situs inversus and other left-right axis anomalies to chromosome 6p. J. Med. Genet. 38:182-85
189. Wagner MK, Yost HJ. 2000. Left-right development: the roles of nodal cilia. Curr. Biol. 10:R149-51
190. Wang TH, Johnston K, Hsieh CL, Dennery PA. 1994. Terminal deletion of the long arm of chromosome 2 in a premature infant with karyotype:46,XY,del(2) (q37). Am. J. Med. Genet. 49:399-401
191. Warburton D. 1991. De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am. J. Hum. Genet. 49:995-1013
192. Whitman M. 2001. Nodal signaling in early vertebrate embryos: themes and variations. Dev. Cell 1:605-17
193. Wilson GN, Stout JP, Schneider NR, Zneimer SM, Gilstrap LC. 1991. Balanced translocation 12/13 and situs abnormalities:homology of early pattern formation in man and lower organisms? Am. J. Med. Genet. 38:601-7
194. Xie J, Murone M, Luoh SM, Ryan A, Gu Q, et al. 1998. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391:90-92
195. Yan YT, Gritsman K, Ding J, Burdine RD, Corrales JD, et al. 1999. Conserved requirement for EGF-CFC genes in vertebrate left-right axis formation. Genes Dev. 13:2527-37
196. Yashiro K, Saijoh Y, Sakuma R, Tada M, Tomita N, et al. 2000. Distinct transcriptional regulation and phylogenetic divergence of Human LEFTY genes. Genes Cells 5:343-57
197. Yip B, Chen SH, Mulder H, Hoppener JW, Schachter H. 1997. Organization of the Human beta-1,2-N-acetylglucosaminyltransferase I gene (MGAT1), which controls complex and hybrid N-glycan synthesis. Biochem J. 321:465-74
198. Yokouchi Y, Vogan KJ, Pearse RV, 2nd, Tabin CJ. 1999. Antagonistic signaling by Caronte, a novel Cerberus-related gene, establishes left-right asymmetric gene expression. Cell 98:573-83
199. Yokoyama T, Copeland NG, Jenkins NA, Montgomery CA, Elder FF, Overbeek PA. 1993. Reversal of left-right asymmetry: a situs inversus mutation. Science 260:679-82
200. Yoshioka H, Meno C, Koshiba K, Sugihara M, Itoh H, et al. 1998. Pitx2, a bicoid-type homeobox gene, is involved in a lefty-signaling pathway in determination of left-right asymmetry. Cell 94:299-305
201. Yoshiura K, Leysens NJ, Chang J, Ward D, Murray JC, Muenke M. 1997.Genomic structure, sequence, and mapping of Human FGF8 with no evidence for its role in craniosynostosis/limb defect syndromes. Am. J. Med. Genet. 72:354-62
202. Yost HJ. 1995. Vertebrate left-right development. Cell 82:689-92
203. Yost HJ. 1999. Diverse initiation in a conserved left-right pathway? Curr. Opin. Genet. Dev. 9:422-26
204. Yu X, St. Amand TR, Wang S, Li G, Zhang Y, et al. 2001. Differential expression and functional analysis of Pitx2 isoforms in regulation of heart looping in the chick. Development 128:1005-13
205. Yuan S, Schoenwolf GC. 1998. De novo induction of the organizer and formation of the primitive streak in an experimental model of notochord reconstitution in avian embryos. Development 125:201-13
206. Zhang XM, Ramalho-Santos M, Mc-Mahon AP. 2001. Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R symmetry by the mouse node. Cell 106:781-92
207. Zhou S, Zawel L, Lengauer C, Kinzler KW, Vogelstein B. 1998. Characterization of Human FAST-1, a TGF beta and activin signal transducer. Mol. Cell 2:121-27
208. Zhu L, Marvin MJ, Gardiner A, Lassar AB, Mercola M, et al. 1999. Cerberus regulates left-right asymmetry of the embryonic head and heart. Curr. Biol. 9:931-38
209. Zlotogora J, Schimmel MS, Glaser Y. 1987. Familial situs inversus and congenital heart defects. Am. J. Med. Genet. 26:181-84