Collin, GB;
Marshall, JD;
King, BL;
Milan, G;
Maffei, P;
Jagger, DJ;
Naggert, JK;
(2012)
The Alstrom Syndrome Protein, ALMS1, Interacts with alpha-Actinin and Components of the Endosome Recycling Pathway.
PLOS ONE
, 7
(5)
, Article e37925. 10.1371/journal.pone.0037925.
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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.
| Type: | Article |
|---|---|
| Title: | The Alstrom Syndrome Protein, ALMS1, Interacts with alpha-Actinin and Components of the Endosome Recycling Pathway |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pone.0037925 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pone.0037925 |
| Language: | English |
| Additional information: | © 2012 Collin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. JKN, GBC, and JDM were supported by a grant from the National Institutes of Health (HD036878). DJ was supported by a Royal Society University Research Fellowship (Grant 516002.K5746.KK). PM and GM were funded by Executive Agency for Health and Consumer (EAHC), EURO-WABB, agreement number 2010 12 05. Core services at The Jackson Laboratory were supported by an institutional grant CA34196. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > The Ear Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1358273 |
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