Several studies have found rare single gene mutations, including deletions and missense mutations, in the PTCHD1 gene that have associations with autism. For example, Marshall et al. (2008) found a 160kb deletion that results in a null mutation for the PTCHD1 gene.
Molecular Function
PTCHD1 is suggested to be a transmembrane protein containing a patched-related domain with twelve transmembrane helices, highly related to the Hedgehog (Hh) receptors PATCHED1 (PTCH1) and PTCH2 as well as to Niemann-Pick Type C1 protein (NPC1).
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Structural variation of chromosomes in autism spectrum disorder.
Ptchd1 null mice (males with Ptchd1 knocked out are also null) have increased hyperactivity, aggression and impaired learning in fear conditioning and passive avoidance paradigms. The null mice show abnormalities attributed to the thalamic nuclei networks, including changes in NREMS sleep pattern and sensory-evoked inhibition. Specific changes in neurophysiology of thalamic reticular and geniculate neurons is also reported.
References
Type
Title
Author, Year
Primary
Thalamic reticular impairment underlies attention deficit in Ptchd1(Y/-) mice.
Model Type:
Genetic
Model Genotype:
Hemizygous
Mutation:
Ptchd1 conditional knockouts were generated by targeting lox P sites to flank exon 2 of the Ptchd1 gene and a neomycin selection cassette. After successful germline transmission the F1 mice were mated to C57BL/6 Beta actin Flp mice to excise the Neo cassette. The floxed mice were backcrossed to C57Bl/6 mice for 5 generations and then speed congenic genotyping PCR was used to select mice with >95% C57Bl/6 background for subsequent matings. For generating Ptchd1 hemizygous males, null for Ptchd1, the floxed mice were mated to C57Bl/6J Beta actin Cre mice to produce germline knockout of the floxed allele on X chromosome. Authors in Wells et al Nature 2016 note that the behavioral phenotypes in this background are similar regardless of background, as they test the same construct in a C57BL/6* 129 Sv background.
Allele Type: Knockout
Strain of Origin: 129X1/SvJ and 129S1/SV-+p+Tyr-cKitlSl-J/+
Genetic Background: C57BL/6
ES Cell Line: R1
Mutant ES Cell Line: Model Source: 27007844
Model Type:
Genetic
Model Genotype:
Hemizygous
Mutation:
Conditional deletion of exon 2 of the Ptchd1 gene using SST-cre, in somatostatin expressing interneurons
Allele Type: Conditional loss-of-function
Strain of Origin: 129X1/SvJ and 129S1/SV-+p+Tyr-cKitlSl-J/+
Genetic Background: C57BL/6
ES Cell Line: R1
Mutant ES Cell Line: Model Source: 27007844
Model Type:
Genetic
Model Genotype:
Hemizygous
Mutation:
Ptchd1 KO mice with exon 2 deleted on a mixed genetic background of C57BL/6 *129
Allele Type: Knockout
Strain of Origin: 129X1/SvJ and 129S1/SV-+p+Tyr-cKitlSl-J/+
Genetic Background: C57BL/6 * 129
ES Cell Line: R1
Mutant ES Cell Line: Model Source: 27007844
Model Type:
Genetic
Model Genotype:
Hemizygous
Mutation:
Ptched1 hemizygous male mice (-/y) were generated by Cre mediated excision of the critical exon 2 using a targeting vector purchased from KOMP containing a flipped STOP cassette that includes an engrailed2 splice acceptor, an IRES sequence, a lacz cDNA and a floxed human beta-actin promoter driven Neo casette.
Allele Type: Knockout
Strain of Origin: BALB/cN*C57BL/6N
Genetic Background: BALB/cN*C57BL/6N
ES Cell Line: C57BL/6N
Mutant ES Cell Line: Model Source: 28416808
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Ptched1 homozygous knockout female mice (-/-) were generated by Cre mediated excision of the critical exon 2 using a targeting vector purchased from KOMP containing a flipped STOP cassette that includes an engrailed2 splice acceptor, an IRES sequence, a lacz cDNA and a floxed human beta-actin promoter driven Neo casette.
Allele Type: Knockout
Strain of Origin: BALB/cN*C57BL/6N
Genetic Background: BALB/cN*C57BL/6N
ES Cell Line: C57BL/6N
Mutant ES Cell Line: Model Source: 28416808
Model Type:
Genetic
Model Genotype:
Hemizygous
Mutation:
To test whether ad dysfunction plays a role in memory deficits in a ptchd1 model, we took advantage of our finding that ad, but not av, projects to presub. optimized circuit-based crispr-cas9 viral approach included a retrograde rv-expressing cre (rvdgl-cre) injected in presub and a virus expressing target guide rnas (aav9-sgrna-mch) combined with a cre-dependent spcas9 virus (aav9-dio-spcas9) injected in ad, to knock down ptchd1 in ad
Allele Type: Knockdown
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: 34197733
Description: Ptchd1 knockouts have decreased number of bouts of sleep or fragmented sleep even if the duration is the same as wild type controls
Exp Paradigm: NA
Description: Ptchd1 knockout mice have increased distance traveled in the open field test compared to controls indicating hyperactivity throughout the test
Exp Paradigm: NA
Description: Burst firing is decreased in thalamic reticular neurons indicating an impairment in either calcium or potassium currents through t type or sk channels, repectively
Exp Paradigm: NA
Description: K currents are reduced by 50% in thalamic reticular neurons through sk channels compared to wild type, leading to insufficient potassium mediated hyperpolarization
Exp Paradigm: NA
Description: The transient inhibitory chloride currents in the thalamic laternal geniculate nucleus, in response to visual stimulation, are found to be reduced in the ptchd1 knockout mice, impaired inhibition is observed in response to trains of stimuli as well
Exp Paradigm: NA
Description: In the altered operant conditioning paradigm that includes a distractor in the anticipatory phase ptchd1 knockout mice perform significantly worse, with increased number of errors, compared to wild type controls
Exp Paradigm: NA
Description: Calcium ion concentration is reduced in the resting state neuron, assessed using ratiometric calcium indicator fura-2 am from acute brain slices
Exp Paradigm: NA
Description: Ptchd1 sstn knockout mice also have poor suppression of distraction as introduction of a distractor in the anticipation phase impairs their performance significantly more than it does for wild type mice
Exp Paradigm: NA
Description: Ptchd1 knockout mice, on mixed background, have increased distance traveled in the open field test compared to controls indicating hyperactivity throughout the test
Exp Paradigm: NA
Cued or contextual fear conditioning: passive avoidance1
Decreased
Description: Ptchd1 knockouts on mixed background also have decreased latency to enter the chamber they received a shock compared to wild type controls
Exp Paradigm: NA
Description: Mutants show increased locomotion during the diurnal cycle, including the habituation phase and the light and dark phases, compared to controls.
Exp Paradigm: Locomotor activity was measured in a circadian activity test over 35 hr and totaled for each phase of the cycle.
Description: Mutants show an increase in total distance travelled in the open field and total number of object box entries in the social recognition test, compared to controls.
Exp Paradigm: Open field test
Description: Mutants show an increase in total distance travelled in the open field and total number of object box entries in the social recognition test, compared to controls.
Exp Paradigm: Social recognition test
Description: Mutants show decreased paired pulse ratio in the schaeffer collateral axons, the main excitatory input onto ca1 pyramidal neurons, compared to controls, indicating an increased release probability at these synapses.
Exp Paradigm: NA
Miniature post synaptic current frequency: excitatory1
Decreased
Description: Mutants show increase in mepsc frequency in the hippocampal ca1 pyramidal neurons compared to controls.
Exp Paradigm: Mepscs were recorded at -70mv in the presence of tetrodotoxin and picrotoxin.
Description: Mutants spend more time in the center of the open field and show increased number of entries and time spent in the open arms of the elevated plus maze, compared to controls.
Exp Paradigm: Open field test
Description: Mutants spend more time in the center of the open field and show increased number of entries and time spent in the open arms of the elevated plus maze, compared to controls.
Exp Paradigm: Elevated plus maze test
Description: Mutants showed decreased recognition index of an object 3 hours after the acquisition trial and spent more time exploring the novel object, compared to controls.
Exp Paradigm: NA
Description: Mutants show absence of the full length ptchd1 transcript and weak expression of the alternatively spliced transcript that skips exon2, compared to controls.
Exp Paradigm: NA
Description: Mutants show abnormal gene expression for a number of hippocampal genes compared to controls. mutants show an aberrant upregulation of a number of psd associated genes (dlg4, shank1,2,3), presynaptic genes (synt1, bsn, vamp2), and transcription factors (egr1, npas4) compared to controls.
Exp Paradigm: NA
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
decreased
Description: Observed a lack of cfc-training-induced synaptic strengthening (ampa/nmda ratio) in the ad/rsc circuit of kd mice
Exp Paradigm: ex vivo electrophysiology; additional Cre-dependent ChR2-eYFP virus (AAV9-DIO-ChR2-eYFP) injected in AD, to knock down PTCHD1 in AD and determine whether PTCHD1 KD has any impact on CFC-training induced AMPA/NMDA ratio increases in the AD/RSC circuit
Description: Increased neuronal excitability of ad neurons in home cage (before cfc training) and post-cfctraining conditions, using mch control and ptchd1 kd groups
Exp Paradigm: ex vivo electrophysiology
