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A meckelin-filamin a interaction mediates ciliogenesis

Adams, Matthew; Simms, Roslyn J.; Abdelhamed, Zakia; Dawe, Helen R.; Szymanska, Katarzyna; Logan, Clare V.; Wheway, Gabrielle; Pitt, Eva; Gull, Keith; Knowles, Margaret A.; Blair, Edward; Cross, Sally H.; Sayer, John A.; Johnson, Colin A.

Authors

Matthew Adams

Roslyn J. Simms

Zakia Abdelhamed

Helen R. Dawe

Katarzyna Szymanska

Clare V. Logan

Gabrielle Wheway Gabrielle.Wheway@uwe.ac.uk
Occasional Associate Lecturer - CHSS - DAS

Eva Pitt

Keith Gull

Margaret A. Knowles

Edward Blair

Sally H. Cross

John A. Sayer

Colin A. Johnson



Abstract

MKS3, encoding the transmembrane receptor meckelin, is mutated in Meckel-Gruber syndrome (MKS), an autosomal-recessive ciliopathy. Meckelin localizes to the primary cilium, basal body and elsewhere within the cell. Here, we found that the cytoplasmic domain of meckelin directly interacts with the actin-binding protein filamin A, potentially at the apical cell surface associated with the basal body. Mutations in FLNA, the gene for filamin A, cause periventricular heterotopias. We identified a single consanguineous patient with an MKS-like ciliopathy that presented with both MKS and cerebellar heterotopia, caused by an unusual in-frame deletion mutation in the meckelin C-terminus at the region of interaction with filamin A. We modelled this mutation and found it to abrogate the meckelin-filamin A interaction. Furthermore, we found that loss of filamin A by siRNA knockdown, in patient cells, and in tissues from Flna Dilp2 null mouse embryos results in cellular phenotypes identical to those caused by meckelin loss, namely basal body positioning and ciliogenesis defects. In addition, morpholino knockdown of flna in zebrafish embryos significantly increases the frequency of dysmorphology and severity of ciliopathy developmental defects caused by mks3 knockdown. Our results suggest that meckelin forms a functional complex with filamin A that is disrupted in MKS and causes defects in neuronal migration and Wnt signalling. Furthermore, filamin A has a crucial role in the normal processes of ciliogenesis and basal body positioning. Concurrent with these processes, the meckelin-filamin A signalling axis may be a key regulator in maintaining correct, normal levels of Wnt signalling. © The Author 2011. Published by Oxford University Press. All rights reserved.

Journal Article Type Article
Acceptance Date Nov 22, 2011
Publication Date Mar 1, 2012
Deposit Date Jun 7, 2016
Journal Human Molecular Genetics
Print ISSN 0964-6906
Electronic ISSN 1460-2083
Publisher Oxford University Press (OUP)
Peer Reviewed Peer Reviewed
Volume 21
Issue 6
Pages 1272-1286
DOI https://doi.org/10.1093/hmg/ddr557
Public URL https://uwe-repository.worktribe.com/output/951166
Publisher URL http://dx.doi.org/10.1093/hmg/ddr557
Contract Date Jun 7, 2016