Disruption of a ciliary B9 protein complex causes meckel syndrome

William E. Dowdle, Jon F. Robinson, Kneist Andreas Kneist, M. Salomé Sirerol-Piquer, Suzanna G.M. Frints, Kevin C. Corbit, Norran A. Zaghloul, Gesina Van Lijnschoten, Leon Mulders, Dideke E. Verver, Klaus Zerres, Randall R. Reed, Tania Attié-Bitach, Colin A. Johnson, José Manuel García-Verdugo, Nicholas Katsanis, Carsten Bergmann, Jeremy F. Reiter

Research output: Contribution to journalArticle

Abstract

Nearly every ciliated organism possesses three B9 domain-containing proteins: MKS1, B9D1, and B9D2. Mutations in human MKS1 cause Meckel syndrome (MKS), a severe ciliopathy characterized by occipital encephalocele, liver ductal plate malformations, polydactyly, and kidney cysts. Mouse mutations in either Mks1 or B9d2 compromise ciliogenesis and result in phenotypes similar to those of MKS. Given the importance of these two B9 proteins to ciliogenesis, we examined the role of the third B9 protein, B9d1. Mice lacking B9d1 displayed polydactyly, kidney cysts, ductal plate malformations, and abnormal patterning of the neural tube, concomitant with compromised ciliogenesis, ciliary protein localization, and Hedgehog (Hh) signal transduction. These data prompted us to screen MKS patients for mutations in B9D1 and B9D2. We identified a homozygous c.301A>C (p.Ser101Arg) B9D2 mutation that segregates with MKS, affects an evolutionarily conserved residue, and is absent from controls. Unlike wild-type B9D2 mRNA, the p.Ser101Arg mutation failed to rescue zebrafish phenotypes induced by the suppression of b9d2. With coimmunoprecipitation and mass spectrometric analyses, we found that Mks1, B9d1, and B9d2 interact physically, but that the p.Ser101Arg mutation abrogates the ability of B9d2 to interact with Mks1, further suggesting that the mutation compromises B9d2 function. Our data indicate that B9d1 is required for normal Hh signaling, ciliogenesis, and ciliary protein localization and that B9d1 and B9d2 are essential components of a B9 protein complex, disruption of which causes MKS.

Original languageEnglish (US)
Pages (from-to)94-110
Number of pages17
JournalAmerican journal of human genetics
Volume89
Issue number1
DOIs
StatePublished - Jul 15 2011

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Dowdle, W. E., Robinson, J. F., Andreas Kneist, K., Sirerol-Piquer, M. S., Frints, S. G. M., Corbit, K. C., Zaghloul, N. A., Van Lijnschoten, G., Mulders, L., Verver, D. E., Zerres, K., Reed, R. R., Attié-Bitach, T., Johnson, C. A., García-Verdugo, J. M., Katsanis, N., Bergmann, C., & Reiter, J. F. (2011). Disruption of a ciliary B9 protein complex causes meckel syndrome. American journal of human genetics, 89(1), 94-110. https://doi.org/10.1016/j.ajhg.2011.06.003