Mutations in the gene encoding CADM1 are associated with autism spectrum disorder

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Abstract

The unified idea on the molecular pathogenesis of Autism Spectrum Disorder (ASD) is still unknown although mutations in genes encoding neuroligins and SHANK3 have been shown in a small part of the patients. RA175/SynCAM1/CADM1(CADM1), a member of immunoglobulin superfamily, is another synaptic cell adhesion molecule. To clarify the idea that impaired synaptogenesis underlies the pathogenesis of ASD, we examined the relationship between mutations in the CADM1 gene and ASD. We found two missense mutations, C739A(H246N) and A755C(Y251S), in the CADM1 gene of male Caucasian ASD patients and their family members. Both mutations were located in the third immunoglobulin domain, which is essential for trans-active interaction. The mutated CADM1 exhibited less amount of high molecular weight with the matured oligosaccharide, defective trafficking to the cell surface, and more susceptibility to the cleavage and or degradation. Our findings provide key support for the unified idea that impaired synaptogenesis underlies the pathogenesis of ASD.

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Materials and methods

Patients. We obtained the DNA of 195 Caucasian patients, 170 males and 25 females, from the Autism Genetic Resource Exchange (AGRE) Consortium (Cure Autism Now, Los Angels, CA). All samples were from familial cases of Autism Spectrum Disorder (ASD) or Pervasive Developmental Disorder—not otherwise specified (PDD-nos). Caucasian control samples were obtained from the Coriell Institute (Camden, NJ). The study was approved by the Committee of Ethics at Jichi Medical University.

PCR amplification.

Results

We screened mutations in the CADM1 gene of Caucasian DNA samples from the Autism Genetic Resource Exchange (AGRE) Consortium and detected two missense mutations, C739A (H246N) and A755C (Y251S), in the CADM1 gene of male patients AU014803 and AU078704, respectively (Fig. 1A). These mutations were located in the third immunoglobulin (Ig3) domain (Fig. 1B), which is essential for homophilic or heterophilic transactive interaction [8]. However, these mutations were not detected in 197 control

The relationship between the mutation of CADM1 and the pathogenesis of ASD

The prevalence of CADM1 mutations in the DNA samples evaluated in this study is reasonable considering the prevalence of NLGN mutations in Autism patients; three percent have missense mutations in the conserved region of NLGN4, but no changes in NLGN3 [13]. The H246N and Y251S mutations were also detected in the other affected members of these two families (Fig. 2). In addition to the affected patients, however, mutations were detected in the non-manifesting sister (AU014804) and mother

Acknowledgments

We express our deepest sympathy at the untimely passing of an excellent neuroscientist, Dr. El-Husseini A. This work was supported by the Ministry of Education Science, and Sport research Grant (18700333, 19790739, 19500305). We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. The Autism Genetic Resource Exchange is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the

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