A novel interaction between FRMD7 and CASK: evidence for a causal role in idiopathic infantile nystagmus.

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.

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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, Mental Retardation, X-Linked, Cytoskeletal Proteins, Membrane Proteins, Amino Acid Substitution, Protein Structure, Tertiary, Mutation, Missense, Models, Biological, Guanylate Kinases
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:	13 Mar 2024 09:44
DOI:	10.1093/hmg/ddt060
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3179337