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The Alström Syndrome Protein, ALMS1, Interacts with α-Actinin and Components of the Endosome Recycling Pathway

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  • Gayle B Collin
  • Jan D Marshall
  • Benjamin L King
  • Gabriella Milan
  • Pietro Maffei
  • Daniel J Jagger
  • Jürgen K Naggert

Abstract

Alström syndrome (ALMS) is a progressive multi-systemic disorder characterized by cone-rod dystrophy, sensorineural hearing loss, childhood obesity, insulin resistance and cardiac, renal, and hepatic dysfunction. The gene responsible for Alström syndrome, ALMS1, is ubiquitously expressed and has multiple splice variants. The protein encoded by this gene has been implicated in ciliary function, cell cycle control, and intracellular transport. To gain better insight into the pathways through which ALMS1 functions, we carried out a yeast two hybrid (Y2H) screen in several mouse tissue libraries to identify ALMS1 interacting partners. The majority of proteins found to interact with the murine carboxy-terminal end (19/32) of ALMS1 were α-actinin isoforms. Interestingly, several of the identified ALMS1 interacting partners (α-actinin 1, α-actinin 4, myosin Vb, rad50 interacting 1 and huntingtin associated protein1A) have been previously associated with endosome recycling and/or centrosome function. We examined dermal fibroblasts from human subjects bearing a disruption in ALMS1 for defects in the endocytic pathway. Fibroblasts from these patients had a lower uptake of transferrin and reduced clearance of transferrin compared to controls. Antibodies directed against ALMS1 N- and C-terminal epitopes label centrosomes and endosomal structures at the cleavage furrow of dividing MDCK cells, respectively, suggesting isoform-specific cellular functions. Our results suggest a role for ALMS1 variants in the recycling endosome pathway and give us new insights into the pathogenesis of a subset of clinical phenotypes associated with ALMS.

Suggested Citation

  • Gayle B Collin & Jan D Marshall & Benjamin L King & Gabriella Milan & Pietro Maffei & Daniel J Jagger & Jürgen K Naggert, 2012. "The Alström Syndrome Protein, ALMS1, Interacts with α-Actinin and Components of the Endosome Recycling Pathway," PLOS ONE, Public Library of Science, vol. 7(5), pages 1-9, May.
  • Handle: RePEc:plo:pone00:0037925
    DOI: 10.1371/journal.pone.0037925
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    References listed on IDEAS

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    1. Elisabetta Zulato & Francesca Favaretto & Caterina Veronese & Stefano Campanaro & Jan D Marshall & Sara Romano & Anna Cabrelle & Gayle B Collin & Barbara Zavan & Anna S Belloni & Enrica Rampazzo & Jür, 2011. "ALMS1-Deficient Fibroblasts Over-Express Extra-Cellular Matrix Components, Display Cell Cycle Delay and Are Resistant to Apoptosis," PLOS ONE, Public Library of Science, vol. 6(4), pages 1-13, April.
    2. Jens S. Andersen & Christopher J. Wilkinson & Thibault Mayor & Peter Mortensen & Erich A. Nigg & Matthias Mann, 2003. "Proteomic characterization of the human centrosome by protein correlation profiling," Nature, Nature, vol. 426(6966), pages 570-574, December.
    3. Joon Kim & Ji Eun Lee & Susanne Heynen-Genel & Eigo Suyama & Keiichiro Ono & KiYoung Lee & Trey Ideker & Pedro Aza-Blanc & Joseph G. Gleeson, 2010. "Functional genomic screen for modulators of ciliogenesis and cilium length," Nature, Nature, vol. 464(7291), pages 1048-1051, April.
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