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Dissection of epistasis in oligogenic Bardet–Biedl syndrome

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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Figure 1: MGC1203 interacts and colocalizes with BBS proteins.
Figure 2: Epistasis and splice defects of the 430T variant.
Figure 3: Genetic interaction of mgc1203 with bbs4 in zebrafish.
Figure 4: Potent interaction between mgc1203 and bbs1.

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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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Correspondence to Nicholas Katsanis.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

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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