Molecular and Regulatory Characterization of the Autism and Intellectual Disability Susceptibility Gene PTCHD1
Notice bibliographique
Résumé
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficiencies, circumscribed patterns of behaviour, stereotypy, and hyper- or hypo-reactivity to sensory stimuli. Nearly half of individuals with ASD exhibit comorbidity with intellectual disability (ID), which is typified by a low intelligence quotient and impairments in adaptive behaviours. Genetics are strongly implicated in the pathoetiologies of both ASD and ID. On Xp22.11, Patched domain-containing 1 (PTCHD1) (OMIM: 300828) has been identified as a highly-penetrant susceptibility gene for ASD and ID, with deleterious alleles consistently transmitted from unaffected maternal carriers to affected males. PTCHD1 contains three exons and two predicted protein-coding transcripts: 1) PTCHD1-a (exons 1-3), expressed in the brain and numerous peripheral tissues; and 2) shorter brain-specific PTCHD1-c (exons 1 and 3). The most prevalent mouse model to study the neurobiological consequences of Ptchd1 loss-of-function involves excision of exon 2 (Ptchd1Δ2), restricting expression to Ptchd1-c. This transcript contains a premature truncating codon in exon 3 (p.Leu118Valfs*51) predicted to disrupt the final 771 amino acids of Ptchd1. Consequently, Ptchd1Δ2 mice exhibit cognitive impairment, motor deficits, and neurobehavioural changes; although notably, they display neither social deficits nor stereotypy. Remarkably, an alternative mouse model developed collaboratively at CAMH and The Hospital for Sick Children in Toronto, containing an indel that disrupts a long open reading frame in exon 3 (Ptchd1Δ3) possesses the same behaviours as Ptchd1Δ2 mice, in addition to presenting with both social deficits and stereotypy. To investigate this, the first chapter of this dissertation attempts to delineate a molecular mechanism to account for this phenotypic disparity between Ptchd1Δ2 and Ptchd1Δ3 mice. Studies of embryonic and early postnatal mice have revealed that expression of Ptchd1 exhibits both brain sub-region and temporal fluctuations during neurodevelopment. Furthermore, several non-coding sequence variants at the PTCHD1 locus have been associated with ASD, suggesting that PTCHD1 may be a dosage-sensitive gene necessary for proper neurodevelopment and neurotransmission. Therefore, the second chapter of this dissertation characterizes regulatory segments and motifs within the Ptchd1 upstream region, as well as identifies and validates a novel downstream regulatory region. In silico analyses predict PTCHD1 to be a polytopic protein that contains 12 transmembrane domains, which are organized into two sterol-sensing domain-like modules, two large lumenal loops, and a C-terminal PDZ-binding domain. Functionally, exogenously expressed PTCHD1 has been observed to localize to the post-synaptic density (PSD) in neurons, and to interact with PSD proteins and bind cholesterol in vitro. Despite these findings, a comprehensive neuronal function of PTCHD1 has yet to be elucidated. From a clinical diagnostic perspective, because of this paucity of functional information, a significant number of PTCHD1 missense variants have been identified in patients with neurodevelopmental disorders, and have been classified as variants of uncertain significance for PTCHD1. Consequently, the third chapter of this dissertation evaluates processing within the rough endoplasmic reticulum, plasma membrane trafficking, and protein-protein interactions of selected clinically reported PTCHD1 missense variants. Collectively, these data have clarified our understanding of presumptive protein production in Ptchd1 loss-of-function mouse models; PTCHD1 neuronal expression and regulation; and the stability, processing, and localization of PTCHD1 missense variants reported by diagnostic clinics.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».