A meckelin-filamin A interaction mediates ciliogenesis

Adams, M., Simms, R.J., Abdelhamed, Z., Dawe, H.R., Szymanska, K., Logan, C.V., Wheway, G., Pitt, E., Gull, K., Knowles, M.A., Blair, E., Cross, S.H., Sayer, J.A., and Johnson, C.A.
Human molecular genetics   21(6): 1272-1286 (Journal)
Registered Authors
MeSH Terms
  • Animals
  • Blotting, Western
  • Ciliary Motility Disorders/genetics
  • Ciliary Motility Disorders/metabolism*
  • Ciliary Motility Disorders/pathology*
  • Contractile Proteins/antagonists & inhibitors
  • Contractile Proteins/genetics
  • Contractile Proteins/metabolism*
  • Female
  • Filamins
  • Fluorescent Antibody Technique
  • Humans
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Male
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism*
  • Mice
  • Microfilament Proteins/antagonists & inhibitors
  • Microfilament Proteins/genetics
  • Microfilament Proteins/metabolism*
  • Mutation/genetics*
  • Phenotype
  • RNA, Small Interfering/genetics
  • Two-Hybrid System Techniques
  • Zebrafish/embryology
22121117 Full text @ Hum. Mol. Genet.

MKS3, encoding the transmembrane receptor meckelin, is mutated in Meckel-Gruber syndrome (MKS), an autosomal recessive ciliopathy. Meckelin localises to the primary cilium, basal body and elsewhere within the cell. Here, we found 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 loss of filamin A by siRNA knockdown, in patient cells, and in tissues from FlnaDilp2 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 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.

Genes / Markers
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Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes