Hostname: page-component-586b7cd67f-t7czq Total loading time: 0 Render date: 2024-11-24T11:16:57.875Z Has data issue: false hasContentIssue false
  • English
  • Français

Variants of the CFC1 gene in patients with laterality defects associated with congenital cardiac disease

Published online by Cambridge University Press:  20 April 2007

Elif Seda Selamet Tierney ,
Zvi Marans ,
Melissa B. Rutkin  and
Wendy K. Chung
Elif Seda Selamet Tierney
Affiliation:
Division of Pediatric Cardiology, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University, College of Physicians & Surgeons, New York, NY, United States of America
Zvi Marans
Affiliation:
Division of Pediatric Cardiology, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University, College of Physicians & Surgeons, New York, NY, United States of America
Melissa B. Rutkin
Affiliation:
Department of Radiology, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University, College of Physicians & Surgeons, New York, NY, United States of America
Wendy K. Chung
Affiliation:
Division of Molecular Genetics, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University, College of Physicians & Surgeons, New York, NY, United States of America
Get access Rights & Permissions [Opens in a new window]

Abstract

Objectives: This study was designed to assess the frequency and types of genetic variants in CFC1 in children with laterality disorders associated with cardiovascular involvement. Background: Laterality syndromes are estimated to comprise 3% of neonates with congenital cardiac disease. Genetic predisposition in some cases of laterality defects has been suggested by associated chromosomal anomalies and familial aggregation, often within consanguineous families, suggesting autosomal recessive inheritance. Mice with induced homozygous mutations in cfc1, and heterozygous CFC1 mutations in humans, have been associated with laterality defects. Methods: Direct sequence analysis of the coding sequence of CFC1 was performed in 42 subjects with laterality defects and congenital cardiac disease. Results: We identified 3 synonymous coding variants, 3 non-synonymous coding variants (N21H, R47Q, and R78W), and 2 intronic variants in CFC1. The N21H variant was observed in 3 of 19 affected Caucasians, and the R47Q variant in another 2. Neither polymorphism was observed in Caucasian controls. Furthermore, all subjects with the N21H polymorphism had double outlet right ventricle. Transmission of both the N21H and R47Q polymorphisms from unaffected parents was demonstrated, and all three non-synonymous variants had significant allele frequencies in unaffected African-American subjects, suggesting that other factors must also contribute to laterality defects. Conclusions: Three non-synonymous variants in CFC1 were identified, the N21H variant being associated with laterality defects in Caucasians, but not fully penetrant. One or more of these non-synonymous missense variants may act as a susceptibility allele in conjunction with other genes, and/or environmental factors, to cause laterality defects.

Keywords

Heterotaxypolymorphismisomerismgeneticsmutation
Type
Original Article
Information
Cardiology in the Young , Volume 17 , Issue 3 , June 2007 , pp. 268 - 274
Copyright
© 2007 Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Van der Velde M. Fetal Heterotaxy Syndrome. Frontiers in Fetal Health 2001; 3: 163–165.Google Scholar
Kosaki K, Casey B. Genetics of human left right axis malformations. Cell Dev Biol 1998; 9: 89–99.Google Scholar
Supp DM, Brueckner M, Kuehn MR, et al. Targeted deletion of the ATP binding domain of left-right dynein confirms its role in specifying development of left-right asymmetries. Development 1999; 126: 5495–5504.Google Scholar
Marszalek JR, Ruiz-Lozano P, Roberts E, Chien KR, Goldstein LS. Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II. Proc Natl Acad Sci USA 1999; 96: 5043–5048.Google Scholar
Takeda S, Yonekawa Y, Tanaka Y, Okada Y, Nonaka S, Hirokowa N. Left-right asymmetry and kinesin superfamily protein KIF3a: new insights in determination of laterality and mesoderm induction by kif3a-/- mice analysis. J Cell Bio 1999; 145: 825–826.Google Scholar
Nonaka S, Tanaka Y, Okada Y, et al. Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3 B motor protein. Cell 1998; 95: 829–837.Google Scholar
Meyers EN, Martin G. Differences in left-right axis pathways in mouse and chick: functions of FGF8 and SHH. Science 1999; 285: 403–406.Google Scholar
Oh SP, Li E. The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev 11: 1997; 1812–1826.Google Scholar
Gaio U, Schweickert A, Fisher A, et al. A role of the cryptic gene in the correct establishment of the left-right axis. Curr Biol 1999; 9: 1339–1342.Google Scholar
Meno C, Shimono A, Saijoh Y, et al. Lefty-1 is required for left-right determination as a regular of lefty-2 and nodal. Cell 1998; 94: 287–297.Google Scholar
Chen JN, van Eeden FJ, Warren KS, et al. Left-right patterning of cardiac BMP4 may drive asymmetry of the heart in zebrafish. Development 1997; 124: 4373–4382.Google Scholar
Schilling TF, Concordet JP, Ingham PW. Regulation of left-right asymmetries in the zebrafish by Shh and BMP4. Dev Biol 1999; 210: 277–287.Google Scholar
Bisgrove BW, Essner JJ, Yost HJ. Multiple pathways in the midline regulate concordant brain, heart and gut left-right asymmetry. Development 2000; 127: 3567–3579.Google Scholar
Gage PJ, Suh H, Camper SA. Dosage requirement of Pitx2 for development of multiple organs. Development 1999; 126: 4642–4651.Google Scholar
Kitamura K, Miura H, Miyagawa-Tomita S, et al. Mouse Pitx2 deficiency leads to anomalies of the ventral body wall, heart, extra- and periocular mesoderm and right pulmonary isomerism. Development 1999; 125: 5749–5758.Google Scholar
Lin CR, Kioussi C, O'Connell S, et al. Pitx2 regulated lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis. Nature 1999; 381: 279–282.Google Scholar
Danos MC, Yost HJ. Role of notochord in specification of cardiac left-right orientation in zebrafish and Xenopus. Dev Biol 1996; 177: 96–103.Google Scholar
Shen MM, Shier AF. The EGF-CFC gene family in vertebrate development. Trends Genet 2000; 16: 303–309.Google Scholar
Yan YT, Gritsman K, Ding J, et al. Conserved requirement for EGF-CFC genes in vertebrate left-right axis formation. Genes Dev 1999; 13: 2527–2537.Google Scholar
Kosaki K, Bassi MT, Kosaki R, et al. Characterization and mutation analysis of human LEFTYA and LEFTYB, homologues of murine genes implicated in left right axis development. Am J Hum Genet 1999; 64: 712–721.Google Scholar
Casey B. The scales always tip to the left: left right anatomy of the thorax and abdomen. Curr Opin Genet Dev 2000; 10: 257–261.Google Scholar
Bamford RN, Roessler E, Burdine RD, et al. Loss-of-function mutation in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nature Genet 2000; 26: 365–369.Google Scholar
Goldmuntz E, Bamford R, Karkera JD, de la Cruz J, Roessler E, Muenke M. CFC1 mutations in subjects with transposition of the great arteries and double-outlet right ventricle. Am J Hum Genet 2002; 70: 776–780.Google Scholar
Breslow JL. Isolation and characterization of cDNA clones for human apolipoprotein AI. Proc Natl Acad Sci USA 1982; 7922: 6861–6865.Google Scholar
Chung WK. Exonic and intronic sequence variation in the human leptin receptor gene LEPR. Diabetes 1997; 46: 1509–1511.Google Scholar