TY - JOUR
T1 - Inherited genetic variants in autism-related CNTNAP2 show perturbed trafficking and ATF6 activation
AU - Falivelli, Giulia
AU - De jaco, Antonella
AU - Favaloro, Flores Lietta
AU - Kim, Hyuck
AU - Wilson, Jennifer
AU - Dubi, Noga
AU - Ellisman, Mark H.
AU - Abrahams, Brett S.
AU - Taylor, Palmer
AU - Comoletti, Davide
N1 - Funding Information:
We are grateful to Dr Giudo Gaietta for helpful advice in the use of the confocal microscope and to Ms Eva N. Rubio-Marrero for the technical help during the resubmission process. We would like to thank the Robert Wood Johnson Foundation (grant # 67038) for their support of the Child Health Institute of New Jersey.
Funding Information:
This work was supported by National Institutes of Health grants, P42-ES10337-08 and RO1-GM18360-39 to P.T.; RO1-MH092906-01 and Autism Speaks #2617 to D.C.; Com-pagnia San Paolo Bando in Neuroscienze to ADJ; Confocal microscopy employed the facilities of the National Center for Imaging and Microscopy (NCMIR) at UCSD supported by NIH P41 RR004050 and P41GM103412 (MHE). BSA was supported by a New Investigator Development Award, a Human Genetics Pilot Award and a Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (P30HD071593) Pilot Award from the Albert Einstein College of Medicine.
PY - 2012/11
Y1 - 2012/11
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/dds320
DO - 10.1093/hmg/dds320
M3 - Article
C2 - 22872700
AN - SCOPUS:84867837982
SN - 0964-6906
VL - 21
SP - 4761
EP - 4773
JO - Human molecular genetics
JF - Human molecular genetics
IS - 21
M1 - dds320
ER -