title: Over-expression of DSCAM and COL6A2 cooperatively generates congenital heart defects.
abstract: A significant current challenge in human genetics is the identification of interacting genetic loci mediating complex polygenic disorders. One of the best characterized polygenic diseases is Down syndrome (DS), which results from an extra copy of part or all of chromosome 21. A short interval near the distal tip of chromosome 21 contributes to congenital heart defects (CHD), and a variety of indirect genetic evidence suggests that multiple candidate genes in this region may contribute to this phenotype. We devised a tiered genetic approach to identify interacting CHD candidate genes. We first used the well vetted Drosophila heart as an assay to identify interacting CHD candidate genes by expressing them alone and in all possible pairwise combinations and testing for effects on rhythmicity or heart failure following stress. This comprehensive analysis identified DSCAM and COL6A2 as the most strongly interacting pair of genes. We then over-expressed these two genes alone or in combination in the mouse heart. While over-expression of either gene alone did not affect viability and had little or no effect on heart physiology or morphology, co-expression of the two genes resulted in ≈50% mortality and severe physiological and morphological defects, including atrial septal defects and cardiac hypertrophy. Cooperative interactions between DSCAM and COL6A2 were also observed in the H9C2 cardiac cell line and transcriptional analysis of this interaction points to genes involved in adhesion and cardiac hypertrophy. Our success in defining a cooperative interaction between DSCAM and COL6A2 suggests that the multi-tiered genetic approach we have taken involving human mapping data, comprehensive combinatorial screening in Drosophila, and validation in vivo in mice and in mammalian cells lines should be applicable to identifying specific loci mediating a broad variety of other polygenic disorders.
authors.affiliation: Section of Cell and Developmental Biology, University of California San Diego, La Jolla, California, USA.
authors.forename: Tamar R
authors.initials: TR
authors.lastname: Grossman
authors.forename: Amir
authors.initials: A
authors.lastname: Gamliel
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wessells
authors.forename: Ouarda
authors.initials: O
authors.lastname: Taghli-Lamallem
authors.forename: Kristen
authors.initials: K
authors.lastname: Jepsen
authors.forename: Karen
authors.initials: K
authors.lastname: Ocorr
authors.forename: Julie R
authors.initials: JR
authors.lastname: Korenberg
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.forename: Rolf
authors.initials: R
authors.lastname: Bodmer
authors.forename: Ethan
authors.initials: E
authors.lastname: Bier
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D024142:Collagen Type VI / Q000235:genetics* / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006321:Heart / Q000033:anatomy & histology / Q000502:physiology; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020412:Multifactorial Inheritance; D009206:Myocardium / Q000378:metabolism; D010641:Phenotype
chemical_list: C504344:COL6A2 protein, human; D015815:Cell Adhesion Molecules; D024142:Collagen Type VI; C110833:DSCAM protein, human; D029721:Drosophila Proteins; C491735:Dscam protein, mouse; C491736:Dscam1 protein, Drosophila
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