Ptchd1, or Patched domain-containing 1, is a gene located in Xp22.11. It has been implicated as a susceptibility gene for autism spectrum disorder (ASD) and intellectual disability (ID), and is mainly expressed in the developing and adult brain tissues [1,3]. Structurally similar to Patched family proteins, it may be involved in sterol transport, and has been shown to bind cholesterol [4]. However, it does not seem to be part of the canonical Hedgehog signalling as it does not bind Sonic Hedgehog nor repress Smoothened like Patched 1 (PTCH1) [4].

Animal models, especially Ptchd1 knockout (KO) mouse models, have been crucial in understanding its functions. Ptchd1 KO mice recapitulate some ASD-and ID-related symptoms. Ptchd1 deficiency in male mice induces global changes in synaptic gene expression, affects the expression of immediate-early genes Egr1 and Npas4, impairs excitatory synaptic structure and neuronal excitatory activity in the hippocampus, leading to cognitive dysfunction, motor disabilities and hyperactivity [5]. Additionally, Ptchd1 has been found to play an evolutionarily conserved role in protecting the μ-opioid receptor against overstimulation. Loss of Ptchd1 in mice reduced opioid-induced desensitization of neurons in several brain regions and the peripheral nervous system, and Ptchd1 KO mice fail to develop analgesic tolerance and have greatly diminished somatic withdrawal [2].

In conclusion, Ptchd1 plays important roles in neurodevelopment and cognitive function, as well as in opioid tolerance. The use of Ptchd1 KO mouse models has significantly contributed to understanding its functions in the context of ASD, ID and opioid-related physiological responses. These findings provide a foundation for exploring therapeutic interventions for individuals with ASD and ID, as well as for better understanding opioid-related phenomena [1,2,3,5].

References:

1. Pastore, Stephen F, Ko, Sangyoon Y, Frankland, Paul W, Hamel, Paul A, Vincent, John B. 2022. PTCHD1: Identification and Neurodevelopmental Contributions of an Autism Spectrum Disorder and Intellectual Disability Susceptibility Gene. In Genes, 13, . doi:10.3390/genes13030527. https://pubmed.ncbi.nlm.nih.gov/35328080/

2. Maza, Nycole, Wang, Dandan, Kowalski, Cody, Grill, Brock, Martemyanov, Kirill A. 2022. Ptchd1 mediates opioid tolerance via cholesterol-dependent effects on μ-opioid receptor trafficking. In Nature neuroscience, 25, 1179-1190. doi:10.1038/s41593-022-01135-0. https://pubmed.ncbi.nlm.nih.gov/35982154/

3. Montanaro, Federica Alice Maria, Mandarino, Alessandra, Alesi, Viola, Vicari, Stefano, Alfieri, Paolo. 2024. PTCHD1 gene mutation/deletion: the cognitive-behavioral phenotyping of four case reports. In Frontiers in psychiatry, 14, 1327802. doi:10.3389/fpsyt.2023.1327802. https://pubmed.ncbi.nlm.nih.gov/38288059/

4. Hiltunen, Mimmu K, Timmis, Alex J, Thomsen, Maren, Goldman, Adrian, Riobo-Del Galdo, Natalia A. 2023. PTCHD1 Binds Cholesterol but Not Sonic Hedgehog, Suggesting a Distinct Cellular Function. In International journal of molecular sciences, 24, . doi:10.3390/ijms24032682. https://pubmed.ncbi.nlm.nih.gov/36769003/

5. Ung, D C, Iacono, G, Méziane, H, Hérault, Y, Laumonnier, F. 2017. Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse. In Molecular psychiatry, 23, 1356-1367. doi:10.1038/mp.2017.39. https://pubmed.ncbi.nlm.nih.gov/28416808/