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Cited by 8Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchGenomics and Rare Diseases

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Nonsynonymous Mutations in Intellectual Disability and Autism Spectrum Disorder Gene PTCHD1 Disrupt N-Glycosylation and Reduce Protein Stability

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Xie, Connie T. Y., Pastore, Stephen F., Vincent, John B., Frankland, Paul W., Hamel, Paul A.·2024·Cells
DOI 10.3390/cells13020199PMC PMC10814814

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Abstract

PTCHD1 has been implicated in Autism Spectrum Disorders (ASDs) and/or intellectual disability, where copy-number-variant losses or loss-of-function coding mutations segregate with disease in an X-linked recessive fashion. Missense variants of PTCHD1 have also been reported in patients. However, the significance of these mutations remains undetermined since the activities, subcellular localization, and regulation of the PTCHD1 protein are currently unknown. This paucity of data concerning PTCHD1 prevents the effective evaluation of sequence variants identified during diagnostic screening. Here, we characterize PTCHD1 protein binding partners, extending previously reported interactions with postsynaptic scaffolding protein, SAP102. Six rare missense variants of PTCHD1 were also identified from patients with neurodevelopmental disorders. After modelling these variants on a hypothetical three-dimensional structure of PTCHD1, based on the solved structure of NPC1, PTCHD1 variants harboring these mutations were assessed for protein stability, post-translational processing, and protein trafficking. We show here that the wild-type PTCHD1 post-translational modification includes complex N-glycosylation and that specific mutant proteins disrupt normal N-link glycosylation processing. However, regardless of their processing, these mutants still localized to PSD95-containing dendritic processes and remained competent for complexing SAP102.

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Metadata

Authors
Xie, C. T. Y., Pastore, S. F., Vincent, J. B., Frankland, P. W., & Hamel, P. A.
Affiliations
  • University of Toronto (CA)
  • Centre for Addiction and Mental Health (CA)
Corresponding author
Xie, Connie T. Y.
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2024-01-21
Volume
13
Issue
2
Pages
199
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells13020199
PMC
PMC10814814
OpenAlex
W4391110674
Cited by
8
References
6
Citations by year
2026: 2 · 2025: 4 · 2024: 2
FWCI
2.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • TSpace (University of Toronto) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Canadian Institutes of Health Research (MOP-114952, #PJT-156367)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
intellectual disability, autism spectrum disorder, missense mutations, N-glycosylation, protein stability, SAP102, postsynaptic scaffolding, protein-protein interaction, neurodevelopmental disorders, X-linked recessive inheritance, protein trafficking, PSD-95
MeSH terms
Autism Spectrum Disorder, Glycosylation, Humans, Membrane Proteins, Intellectual Disability, Mutation, Protein Stability

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