Investigation of Neuroserpin as an Autism Candidate Gene
| Status: | Terminated |
|---|---|
| Conditions: | Neurology, Psychiatric, Autism |
| Therapuetic Areas: | Neurology, Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 1 - Any |
| Updated: | 4/21/2016 |
| Start Date: | June 2009 |
| End Date: | April 2012 |
Previously it has been shown that Familial Encephalopathy with neuroserpin inclusion bodies
(FENIB) patients develop abnormalities that partially overlap with Autism Spectrum disorders
(ASD), confounded with additional features that could be explained by inclusion body
formation not expected in subjects with inclusion body forming SERPINI1 mutations. There is
no described human neuroserpin deficiency phenotype. The neuroserpin knockout mouse
phenotype also suggests a possible overlap with autism. Neuroserpin could contribute
directly at the synapse or through altered neuron migration during early development leading
to the "underconnectivity" that underlies autism by potentially contributing to the excess
of short connections and not enough long ones seen in autistic brains, possibly due to an
imbalance in pruning of neurons and synapses early in life. It is thus proposed to sequence
the neuroserpin gene in initially 20, and subsequently up to 100 idiopathic autistic
patients selected as having the language impairment and perseveration endophenotypes.
(FENIB) patients develop abnormalities that partially overlap with Autism Spectrum disorders
(ASD), confounded with additional features that could be explained by inclusion body
formation not expected in subjects with inclusion body forming SERPINI1 mutations. There is
no described human neuroserpin deficiency phenotype. The neuroserpin knockout mouse
phenotype also suggests a possible overlap with autism. Neuroserpin could contribute
directly at the synapse or through altered neuron migration during early development leading
to the "underconnectivity" that underlies autism by potentially contributing to the excess
of short connections and not enough long ones seen in autistic brains, possibly due to an
imbalance in pruning of neurons and synapses early in life. It is thus proposed to sequence
the neuroserpin gene in initially 20, and subsequently up to 100 idiopathic autistic
patients selected as having the language impairment and perseveration endophenotypes.
It is proposed to perform a pilot study to ask whether genetic variation at SERPINI1 is
contributing to idiopathic autism. To maximize the chance of finding such variants, the
perseveration and language delay endophenotypes (simpler intermediate traits) will be used
to select twenty autistic multiplex (and if necessary singleplex) families with idiopathic
autistic patients who have been evaluated with the Autism Diagnostic Interview-revised
(ADI-R) and their nuclear families ( siblings and their parents) will be identified by Dr.
Liptak and Dr. Lebel with the assistance of Ms Klausner and recruited. Patients with
syndromic autism due to known causes such as fragile X syndrome, Tuberous sclerosis, Down
syndrome, and Neurofibromatosis type I will be excluded. The entire SERPINI1 coding region
(nine exons), one kilobase of promoter region (Chen, 2007) and at least 200 bp of intron
flanking each exon will be sequenced in an index case and the segregation of mutations
identified investigated within the families. All mutations that appear to be good functional
candidates will be compared in frequency amongst autistic and control populations in order
to determine if a case can be made that SERPINI1 could be contributing to autism. In
addition, known neuroserpin SNPs identified through the Hapmap project (www.hapmap.org) will
be investigated and tested for evidence of transmission distortion/disequilibrium by
linkage/association analysis. Depending on the results from this initial experiment it is
proposed to subsequently sequence up to a further 80 local autism patients (maximum of 100
patients). Additional studies would be performed as follow up studies to similarly sequence
the genes of other serpins expressed in the brain; Plasminogen activator 1, PA1, SERPINE1
located at the MLS linkage peak at 7q22.1 seen in IMGSAC study (Lamb, 2002) while Proteinase
nexin 1, PN1 SERPINE2 at 2q36.1,close to previously identified linkage peaks (Autism Genome
Project consortium, 2007) and potentially their putative serine protease targets (tPA at
8p11.21 and uPA at 10q22.2) and the upstream neuroserpin activators (ALK6, AMH and BMP2)
(Lebeurrier, 2008). tPA expression is increased by events that require synaptic plasticity
(Yepes, 2002) and enhances NMDA receptor signaling by cleavage of its NR1 subunit (Pawlack,
2002). All interesting leads will be pursued by obtaining additional samples from the Autism
Genetic Resource Exchange (AGRE)( www.agre.org), a publically available recourse of
phenotypic data and bio-materials which provides diagnostic information and DNA from 100's
of multiplex ASD families.
contributing to idiopathic autism. To maximize the chance of finding such variants, the
perseveration and language delay endophenotypes (simpler intermediate traits) will be used
to select twenty autistic multiplex (and if necessary singleplex) families with idiopathic
autistic patients who have been evaluated with the Autism Diagnostic Interview-revised
(ADI-R) and their nuclear families ( siblings and their parents) will be identified by Dr.
Liptak and Dr. Lebel with the assistance of Ms Klausner and recruited. Patients with
syndromic autism due to known causes such as fragile X syndrome, Tuberous sclerosis, Down
syndrome, and Neurofibromatosis type I will be excluded. The entire SERPINI1 coding region
(nine exons), one kilobase of promoter region (Chen, 2007) and at least 200 bp of intron
flanking each exon will be sequenced in an index case and the segregation of mutations
identified investigated within the families. All mutations that appear to be good functional
candidates will be compared in frequency amongst autistic and control populations in order
to determine if a case can be made that SERPINI1 could be contributing to autism. In
addition, known neuroserpin SNPs identified through the Hapmap project (www.hapmap.org) will
be investigated and tested for evidence of transmission distortion/disequilibrium by
linkage/association analysis. Depending on the results from this initial experiment it is
proposed to subsequently sequence up to a further 80 local autism patients (maximum of 100
patients). Additional studies would be performed as follow up studies to similarly sequence
the genes of other serpins expressed in the brain; Plasminogen activator 1, PA1, SERPINE1
located at the MLS linkage peak at 7q22.1 seen in IMGSAC study (Lamb, 2002) while Proteinase
nexin 1, PN1 SERPINE2 at 2q36.1,close to previously identified linkage peaks (Autism Genome
Project consortium, 2007) and potentially their putative serine protease targets (tPA at
8p11.21 and uPA at 10q22.2) and the upstream neuroserpin activators (ALK6, AMH and BMP2)
(Lebeurrier, 2008). tPA expression is increased by events that require synaptic plasticity
(Yepes, 2002) and enhances NMDA receptor signaling by cleavage of its NR1 subunit (Pawlack,
2002). All interesting leads will be pursued by obtaining additional samples from the Autism
Genetic Resource Exchange (AGRE)( www.agre.org), a publically available recourse of
phenotypic data and bio-materials which provides diagnostic information and DNA from 100's
of multiplex ASD families.
Inclusion Criteria:
- Autistic patient, or first degree relative of autistic patient
Exclusion Criteria:
- Less than one year of age.
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