Ptchd1 exon3 truncating mutations recapitulate more clinically relevant autistic-like traits in mice

PTCHD1: Identification and Neurodevelopmental Contributions of an Autism Spectrum Disorder and Intellectual Disability Susceptibility Gene

“…In order to recapitulate clinical models where CNVs have encompassed just exon 1 or exon 3 of PTCHD1 [ 5 , 6 , 9 , 12 ], exon-specific deletion mice have been generated. Murakami et al generated mice with an exon 1 deletion ( Ptchd1 Δ 1/Y ) [ 48 ], while Ko et al generated mice with an exon 3 deletion ( Ptchd1 Δ 3/Y ) [ 49 ]. Lastly, Roy et al employed Cre-dependent SpCas9 adeno-associated viruses (AAVs) to knockdown Ptchd1 ( Ptchd1 KD ) in specific brain subregions in vivo [ 13 ].…”

“…A multitude of studies investigating the behavioural and neuromotor phenotype of male Ptchd1 -/Y (i.e., Ptchd1 Δ 1/Y , Ptchd1 Δ 2/Y , and Ptchd1 Δ 3/Y ) mice have identified numerous perturbations, many of which recapitulate the clinical symptoms of ASD and/or ADHD. Ptchd1 -/Y mice demonstrate spontaneous hyperactivity, as inferred from an increase in the total distance travelled in a novel environment during an open field test (OFT) [ 48 , 49 ], and elevated locomotor activity [ 31 , 33 ].…”

“… ( A ) Genomic organization of Ptchd1 isoforms a and c and predicted translation products resulting from the Murakami et al [ 48 ] exon 1 knockout mice, Wells et al [ 31 ] and Ung et al [ 33 ] exon 2 knockout mice, and the CRISPR/cas9 knockout mouse generated by Frankland and Vincent [ 49 ]. The PDZ-binding motif is indicated by a red circle.…”

“…However, a preliminary study by Ko et al suggests potential PTCHD1/Ptchd1 involvement in both ASD and ID, with respect to both social abnormalities and learning deficits in mice [ 49 ]. Based on loss CNV and nonsense mutation cases reported in PTCHD1-related ASD patients [ 6 ], they generated Ptchd1 exon 3 truncating mutation mice using CRISPR-Cas9 technology ( Ptchd1 Δ 3/Y ).…”

“…Ptchd1 Δ 3/Y mice exhibited significant reductions in both Ptchd1 full-length (i.e., the transcript derived from exons 1 to 3) and shorter transcripts (i.e., the transcript derived from exons 1 and 3), and social interaction and communication behaviors were abnormal in these mice, as inferred from the reduced male-female interaction time in the three-chambered social interaction assay, the reduced emission of ultrasonic vocalization during the social interaction, and the reduced sniffing behavior in the social odor cue reactivity task, respectively. Furthermore, Ptchd1 Δ 3/Y mice also exhibit impaired learning and memory in contextual fear conditioning [ 49 ]. Given that Ptchd1 Δ 2/Y mice display significant enrichment of the shorter alternatively spliced form of the Ptchd1 transcript ( Ptchd1-c ) and that Ptchd1 Δ 3/Y mice lack expression of both full-length ( Ptchd1-a ) and shorter form ( Ptchd1-c ) transcripts, it seems plausible that the more complete phenotypic picture in the Ptchd1 Δ 3/Y mice (i.e., including social deficits) relates to the loss of both major alternative transcripts ( Ptchd1-a and -c ).…”