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Role of ciliary genes in the development and maintenance of hearing

Summary

Cilia are antenna-like membrane-associated structures which play essential roles during development, and during the normal function of many cells throughout the body. Dysfunction of these organelles can lead to serious illnesses, involving deafness and blindness, as well as life-threatening complications such as kidney and liver disease, diabetes, respiratory problems, and obesity. These so-called “ciliopathies” are usually genetically inherited, and at present there are few, if any cures.

Following a successful collaboration with Phil Beales (Institute of Child Health, UCL) investigating the role of cilia in the development of hair cells, we are continuing to work in the field of human ciliary diseases. We recently characterized the causes of deafness in a poorly understood ciliopathy called Alström Syndrome, working with Jan Marshall’s group at the Jackson Labs to describe the cochlear pathology in a mouse model of the disease. In this work we found that mutations of the Alms1 gene that cause Alström Syndrome lead to developmental peculiarities within the outer hair cell stereociliary bundle. In addition to accelerated hair cell death, we also demonstrated pathological cell loss within stria vascularis.

In related public engagement projects I have been working with several ciliopathy patient support groups to describe our lab work, and to explain the causes of genetic hearing loss. Since 2008 I have been a member of the Board of Directors at Alström Syndrome UK (www.alstrom.org.uk), and was appointed Chair in 2009. I work with the clinical teams at Torbay Hospital, QEH Birmingham, and the Children’s Hospital Birmingham who specialize in the syndrome. In 2010 I helped to co-found the Ciliopathy Alliance (www.ciliopathyalliance.org), which acts to promote awareness of these debilitating diseases, and to encourage novel research to improve the lives of patients. The Alliance is currently organizing the first international conference on the role of cilia in health and disease (www.cilia2012.org).

Relevant Publications

  • Jagger D, Collin G, Kelly J, Towers E, Nevill G, Longo-Guess C, Benson J, Halsey K, Dolan D, Marshall J, Naggert J, Forge A. Alström Syndrome protein ALMS1 localizes to basal bodies of cochlear hair cells and regulates cilium-dependent planar cell polarity. Human Molecular Genetics 20, 466-481, 2011.
  • Jagger DJ & Forge A . Assessing PCP in the cochlea of mammalian ciliopathy models. Methods in Molecular Biology vol. 839 (in press).
  • May-Simera HL, Ross A, Rix S, Forge A, Beales PL, Jagger DJ. Patterns of expression of Bardet-Biedl syndrome proteins in the mammalian cochlea suggest noncentrosomal functions. Journal of Comparative Neurology 514, 174-188, 2009.
  • Ross AJ, May-Simera H, Eichers ER, Kai M, Hill J, Jagger DJ, Leitch CC, Chapple JP, Munro PM, Fisher S, Tan PL, Phillips HM, Leroux MR, Henderson DJ, Murdoch JN, Copp AJ, Eliot MM, Lupski JR, Kemp DT, Dollfus H, Tada M, Katsanis N, Forge A, Beales PL. Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nature Genetics 37, 1135-1140, 2005.
Ciliopathy ASUK Cilia 2012

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