Watkins, Rachel J, Patil, Rajashree, Goult, Benjamin T 
ORCID: 0000-0002-3438-2807, Thomas, Mervyn G ORCID: 0000-0002-4630-1234, Gottlob, Irene and Shackleton, Sue
(2013)
A novel interaction between FRMD7 and CASK: evidence for a causal role in idiopathic infantile nystagmus.
Human molecular genetics, 22 (10).
pp. 2105-2118.
ISSN 0964-6906, 1460-2083
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A novel interaction between FRMD7 and CASK evidence for a causal role in idiopathic infantile nystagmus.pdf - Open Access published version Download (1MB) | Preview |
Abstract
Idiopathic infantile nystagmus (IIN) is a genetically heterogeneous disorder of eye movement that can be caused by mutations in the FRMD7 gene that encodes a FERM domain protein. FRMD7 is expressed in the brain and knock-down studies suggest it plays a role in neurite extension through modulation of the actin cytoskeleton, yet little is known about its precise molecular function and the effects of IIN mutations. Here, we studied four IIN-associated missense mutants and found them to have diverse effects on FRMD7 expression and cytoplasmic localization. The C271Y mutant accumulates in the nucleus, possibly due to disruption of a nuclear export sequence located downstream of the FERM-adjacent domain. While overexpression of wild-type FRMD7 promotes neurite outgrowth, mutants reduce this effect to differing degrees and the nuclear localizing C271Y mutant acts in a dominant-negative manner to inhibit neurite formation. To gain insight into FRMD7 molecular function, we used an IP-MS approach and identified the multi-domain plasma membrane scaffolding protein, CASK, as a FRMD7 interactor. Importantly, CASK promotes FRMD7 co-localization at the plasma membrane, where it enhances CASK-induced neurite length, whereas IIN-associated FRMD7 mutations impair all of these features. Mutations in CASK cause X-linked mental retardation. Patients with C-terminal CASK mutations also present with nystagmus and, strikingly, we show that these mutations specifically disrupt interaction with FRMD7. Together, our data strongly support a model whereby CASK recruits FRMD7 to the plasma membrane to promote neurite outgrowth during development of the oculomotor neural network and that defects in this interaction result in nystagmus.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Neurites, Cell Line, Cell Membrane, Cell Nucleus, Humans, Nystagmus, Congenital, Cytoskeletal Proteins, Membrane Proteins, Amino Acid Substitution, Protein Structure, Tertiary, Mutation, Missense, Models, Biological, Guanylate Kinases, X-Linked Intellectual Disability |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 13 Mar 2024 09:44 |
| Last Modified: | 12 Apr 2025 09:21 |
| DOI: | 10.1093/hmg/ddt060 |
| Related Websites: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3179337 |
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