Abstract
Epistatic interactions have an important role in phenotypic variability, yet the genetic dissection of such phenomena remains challenging1. Here we report the identification of a novel locus, MGC1203, that contributes epistatic alleles to Bardet–Biedl syndrome (BBS), a pleiotropic, oligogenic disorder2,3,4,5,6,7,8,9. MGC1203 encodes a pericentriolar protein that interacts and colocalizes with the BBS proteins. Sequencing of two independent BBS cohorts revealed a significant enrichment of a heterozygous C430T mutation in patients, and a transmission disequilibrium test (TDT) showed strong over-transmission of this variant. Further analyses showed that the 430T allele enhances the use of a cryptic splice acceptor site, causing the introduction of a premature termination codon (PTC) and the reduction of steady-state MGC1203 messenger RNA levels. Finally, recapitulation of the human genotypes in zebrafish shows that modest suppression of mgc1203 exerts an epistatic effect on the developmental phenotype of BBS morphants. Our data demonstrate how the combined use of biochemical, genetic and in vivo tools can facilitate the dissection of epistatic phenomena, and enhance our appreciation of the genetic basis of phenotypic variability.
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References
Badano, J. L. & Katsanis, N. Beyond Mendel: an evolving view of human genetic disease transmission. Nature Rev. Genet. 3, 779–789 (2002)
Badano, J. L. et al. Identification of a novel Bardet–Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. Am. J. Hum. Genet. 72, 650–658 (2003)
Badano, J. L. et al. Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet–Biedl patients with two mutations at a second BBS locus. Hum. Mol. Genet. 12, 1651–1659 (2003)
Beales, P. L. et al. Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet–Biedl syndrome. Am. J. Hum. Genet. 72, 1187–1199 (2003)
Fan, Y. et al. Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet–Biedl syndrome. Nature Genet. 36, 989–993 (2004)
Fauser, S., Munz, M. & Besch, D. Further support for digenic inheritance in Bardet–Biedl syndrome. J. Med. Genet. 40, e104 (2003)
Katsanis, N. et al. Triallelic inheritance in Bardet–Biedl syndrome, a mendelian recessive disorder. Science 293, 2256–2259 (2001)
Katsanis, N. et al. BBS4 is a minor contributor to Bardet–Biedl syndrome and may also participate in triallelic inheritance. Am. J. Hum. Genet. 71, 22–29 (2002)
Li, J. B. et al. Comparative genomic identification of conserved flagellar and basal body proteins that includes a novel gene for Bardet–Biedl syndrome. Cell 117, 541–552 (2004)
Ansley, S. J. et al. Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome. Nature 425, 628–633 (2003)
Chiang, A. P. et al. Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet–Biedl syndrome (BBS3). Am. J. Hum. Genet. 75, 475–484 (2004)
Katsanis, N. et al. Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet–Biedl syndrome. Nature Genet. 26, 67–70 (2000)
Mykytyn, K. et al. Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nature Genet. 28, 188–191 (2001)
Mykytyn, K. et al. Identification of the gene (BBS1) most commonly involved in Bardet–Biedl syndrome, a complex human obesity syndrome. Nature Genet. 31, 435–438 (2002)
Nishimura, D. Y. et al. Positional cloning of a novel gene on chromosome 16q causing Bardet–Biedl syndrome (BBS2). Hum. Mol. Genet. 10, 865–874 (2001)
Slavotinek, A. M. et al. Mutations in MKKS cause Bardet–Biedl syndrome. Nature Genet. 26, 15–16 (2000)
Badano, J. L., Teslovich, T. M. & Katsanis, N. The centrosome in human genetic disease. Nature Rev. Genet. 6, 194–205 (2005)
Katsanis, N. The oligogenic properties of Bardet–Biedl syndrome. Hum. Mol. Genet. 13, R65–R71 (2004)
Kim, J. C. et al. The Bardet–Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nature Genet. 36, 462–470 (2004)
Kim, J. C. eta l. MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet–Biedl syndrome, is a novel centrosomal component required for cytokinesis. J. Cell Sci. 118, 1007–1020 (2005)
Cartegni, L., Wang, J., Zhu, Z., Zhang, N. Q. & Krainer, A. R. ESEfinder: a web resource to identify exonic splice enhancers. Nucleic Acids Res. 31, 3568–3571 (2003)
Fu, X. & Maniatis, T. Isolation of a complementary DNA that encodes the mammalian splicing factor SC35. Science 256, 533–538 (1992)
Gabut, M. et al. The SR protein SC35 is responsible for aberrant splicing of the E1α pyruvate dehydrogenase mRNA in a case of mental retardation with lactic acidosis. Mol. Cell. Biol. 25, 3286–3294 (2005)
Li, X. & Manley, J. L. Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Cell 122, 365–378 (2005)
Lele, Z. et al. parachute/n-cadherin is required for morphogenesis and maintained integrity of the zebrafish neural tube. Development 129, 3281–3294 (2002)
Ross, A. J. et al. Disruption of Bardet–Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nature Genet. 37, 1135–1140 (2005)
Simons, M. et al. Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signalling pathways. Nature Genet. 37, 537–543 (2005)
Gouya, L. et al. The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH. Nature Genet. 30, 27–28 (2002)
Hartman, J., Gavrik, B. & Hartwell, L. Principles for the buffering of genetic variation. Science 291, 1001–1004 (2001)
Kacser, H. & Burns, J. A. The molecular basis of dominance. Genetics 97, 639–666 (1981)
Acknowledgements
We thank the BBS patients and their families for their continued support and encouragement. We also thank J. Gerdes and A. McCallion for their thoughtful comments on the manuscript. This work was supported by grants from the National Institute of Child Health and Development (N.K.), the National Institute of Diabetes, Digestive and Kidney disorders (N.K.), the National Institute for Arthritis and Musculoskeletal disorders (S.F.), the Polycystic Kidney Disease Foundation (J.L.B. and N.K.), and the Medical Research Council (P.L.B.). R.A.L. is a Senior Scientific Investigator of Research to Prevent Blindness. P.L.B. is a Senior Wellcome Trust Fellow. H.C.D. is an Investigator of the Howard Hughes Medical Institute.
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Supplementary information
Supplementary Table 1
Summary of BBS mutations in families with the MGC1203430T variant. (DOC 19 kb)
Supplementary Figure 1
MGC1203 interacts with BBS4 in yeast and colocalizes with the BBS proteins. (PDF 620 kb)
Supplementary Figure 2
MGC1203 exhibits alternative splicing.. (PDF 8 kb)
Supplementary Figure 3
Expression pattern of mgc1203 and bbs1. (PDF 76 kb)
Supplementary Figure 4
Summary of morphant phenotypes for BBS4, BBS6 and MGC1203. (PDF 16 kb)
Supplementary Figure 5
BBS6 phenotypes of zebrafish embryos. (PDF 103 kb)
Supplementary Figure 6
Suppression of mgc1203 message with a splice blocking morpholino. (PDF 24 kb)
Supplementary Figure 7
mgc1203 interacts genetically with bbs4 and bbs6 in zebrafish. (PDF 14 kb)
Supplementary Methods
A detailed description of material and methods used, including sequence and peptide information. (DOC 43 kb)
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Badano, J., Leitch, C., Ansley, S. et al. Dissection of epistasis in oligogenic Bardet–Biedl syndrome. Nature 439, 326–330 (2006). https://doi.org/10.1038/nature04370
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DOI: https://doi.org/10.1038/nature04370
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