PTCHD1 is an X-linked gene, and disease-associated mutations that have been reported in males are typically inherited from unaffected carrier mothers, or occasionally occur de novo. PTCHD1 is listed on the SFARI Gene site as an autism gene with a SFARI gene score of 1 (High confidence; criteria 1.1), with multiple lines of evidence. Copy number loss mutations encompassing all or part of the coding region of PTCHD1, as well as loss-of-function single nucleotide variants within the coding region, are likely to be pathogenic. Many missense variants have been identified in subjects with related phenotypes, however, without supporting co-segregation data or functional assay, the vast majority of these remain as variants of uncertain significance.
The main clinical features associated with PTCHD1 deficiency are autism spectrum disorder or autism-related traits; mild to moderate global developmental delay, variable degrees of intellectual disability; orofacial hypotonia and mild motor incoordination are also common.
The protein encoded by PTCHD1 is predicted to be an 888 amino acid 12-pass transmembrane protein, including two putative sterol-sensing domains, two external loops, and a C-terminal PDZ-binding domain. Evidence using exogenously expressed protein suggests binding to post-synaptic scaffold proteins such as SAP102, also a component of the SNARE complex of proteins required for docking and fusion of synaptic vesicles called SNAPIN (also known as SNAPAP), membrane protein trafficking molecules SNX27, and VPS35, and retromer complex component VPS26B. No SHH signalling pathway activity has been reported for PTCHD1, yet it has been reported that PTCHD1 is able to bind cholesterol molecules.
Several mouse knockout models have been explored, mainly involving excision of the second (of three) exon. A mouse model with exon 1 removed has also been reported. Various phenotypes have been reported in these mice that correspond to clinical phenotypes in PTCHD1 patients, including cognitive deficit, and motor deficits, however none of the studies using these models reported any disruption of social/communication behaviour or any increase in repetitive grooming (as a stereotypic behaviour). It should be noted that removal of exon 2 leads to a massive increase in expression of a smaller, more brain-specific transcript, termed Ptchd1-c. This transcript contains a number of C-terminal open reading frames, the largest encoding a 542 amino acid protein that includes 8 of the 12 transmembrane domains, the PDZ-binding domain, one of the two external loops, and the majority of the sterol sensing domain. Human PTCHD1-c present in brain regions such as cerebellum, cortex, hippocampus, substantia nigra, pons, and spinal cord, but not in any of the peripheral tissues tested, whereas PTCHD1-a is found in these same brain regions, but also in spleen, small intestine, heart, kidney, and lung.
A third mouse model has also been developed that has a truncating mutation early in exon 3. This would terminate the protein after the first 5 transmembrane domains and first loop of Ptchd1-a, and would prevent translation of Ptchd1-c. Reports indicate that these mouse share the cognitive and motor deficits reported for the exon 2 knockout mice, but also show a clear social deficit, communication/vocalization deficit, as well as repetitive grooming.
It should also be noted that there is a long non-coding RNA, antisense to PTCHD1, which is called PTCHD1-AS. Transcription initiation for PTCHD1-AS (at least for some transcripts) occurs at or around the PTCHD1 promoter/upstream region. A knockout mouse model for Ptchd1-AS has been generated and studied, but shows generally milder phenotypes in comparison to the Ptchd1 knockouts, and does not appear to influence expression of the sense gene, Ptchd1. Importantly, the Ptchd1 exon 1 deletion mouse model reported by Murakami et al, 2019, also deletes the putative promoter/regulatory regions for Ptchd1-as, and, as such, is likely a knockout for both genes.
PTCHD1