Inherited genetic variants in autism-related CNTNAP2 show perturbed trafficking and ATF6 activation

Giulia Falivelli, Antonella De jaco, Flores Lietta Favaloro, Hyuck Kim, Jennifer Wilson, Noga Dubi, Mark H. Ellisman, Brett S. Abrahams, Palmer Taylor, Davide Comoletti

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Although genetic variations in several genes encoding for synaptic adhesion proteins have been found to be associated with autism spectrum disorders, one of the most consistently replicated genes has been CNTNAP2, encoding for contactin-associated protein-like 2 (CASPR2), a multidomain transmembrane protein of the neurexin superfamily. Using immunofluorescence confocal microscopy and complementary biochemical techniques, we compared wild-type CASPR2 to 12 point mutations identified in individuals with autism. In contrast to the wild-type protein, localized to the cell surface, some of the mutants show altered cellular disposition. In particular, CASPR2-D1129H is largely retained in the endoplasmic reticulum (ER) in HEK-293 cells and in hippocampal neurons. BiP/Grp78, Calnexin and ERp57, key ER chaperones, appear to be responsible for retention of this mutant and activation of one signaling pathway of the unfolded protein response (UPR). The presence of this mutation also lowers expression and activates proteosomal degradation. A frame-shift mutation that causes a form of syndromic epilepsy (CASPR2-1253*), results in a secreted protein with seemingly normal folding and oligomerization. Taken together, these data indicate that CASPR2-D1129H has severe trafficking abnormalities and CASPR2-1253* is a secreted soluble protein, suggesting that the structural or signaling functions of the membrane tethered form are lost. Our data support a complex genetic architecture in which multiple distinct risk factors interact with others to shape autism risk and presentation.

Original languageEnglish (US)
Article numberdds320
Pages (from-to)4761-4773
Number of pages13
JournalHuman Molecular Genetics
Volume21
Issue number21
DOIs
StatePublished - Nov 2012

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Autistic Disorder
Contactins
Proteins
Endoplasmic Reticulum
Calnexin
Unfolded Protein Response
Frameshift Mutation
HEK293 Cells
Fluorescence Microscopy
Point Mutation
Confocal Microscopy
Genes
Epilepsy
Neurons
Mutation
Membranes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Falivelli, G., De jaco, A., Favaloro, F. L., Kim, H., Wilson, J., Dubi, N., ... Comoletti, D. (2012). Inherited genetic variants in autism-related CNTNAP2 show perturbed trafficking and ATF6 activation. Human Molecular Genetics, 21(21), 4761-4773. [dds320]. https://doi.org/10.1093/hmg/dds320

Inherited genetic variants in autism-related CNTNAP2 show perturbed trafficking and ATF6 activation. / Falivelli, Giulia; De jaco, Antonella; Favaloro, Flores Lietta; Kim, Hyuck; Wilson, Jennifer; Dubi, Noga; Ellisman, Mark H.; Abrahams, Brett S.; Taylor, Palmer; Comoletti, Davide.

In: Human Molecular Genetics, Vol. 21, No. 21, dds320, 11.2012, p. 4761-4773.

Research output: Contribution to journalArticle

Falivelli, G, De jaco, A, Favaloro, FL, Kim, H, Wilson, J, Dubi, N, Ellisman, MH, Abrahams, BS, Taylor, P & Comoletti, D 2012, 'Inherited genetic variants in autism-related CNTNAP2 show perturbed trafficking and ATF6 activation', Human Molecular Genetics, vol. 21, no. 21, dds320, pp. 4761-4773. https://doi.org/10.1093/hmg/dds320
Falivelli G, De jaco A, Favaloro FL, Kim H, Wilson J, Dubi N et al. Inherited genetic variants in autism-related CNTNAP2 show perturbed trafficking and ATF6 activation. Human Molecular Genetics. 2012 Nov;21(21):4761-4773. dds320. https://doi.org/10.1093/hmg/dds320
Falivelli, Giulia ; De jaco, Antonella ; Favaloro, Flores Lietta ; Kim, Hyuck ; Wilson, Jennifer ; Dubi, Noga ; Ellisman, Mark H. ; Abrahams, Brett S. ; Taylor, Palmer ; Comoletti, Davide. / Inherited genetic variants in autism-related CNTNAP2 show perturbed trafficking and ATF6 activation. In: Human Molecular Genetics. 2012 ; Vol. 21, No. 21. pp. 4761-4773.
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