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Investigation of Neuroserpin as an Autism Candidate Gene

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00917683
Recruitment Status : Terminated (Lack of enrollment.)
First Posted : June 10, 2009
Last Update Posted : April 19, 2016
Information provided by:
State University of New York - Upstate Medical University

Brief Summary:
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.

Condition or disease

Detailed Description:
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 ( 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)(, a publically available recourse of phenotypic data and bio-materials which provides diagnostic information and DNA from 100's of multiplex ASD families.

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Study Type : Observational
Actual Enrollment : 5 participants
Observational Model: Case Control
Time Perspective: Prospective
Official Title: Investigation of Neuroserpin as an Autism Candidate Gene
Study Start Date : June 2009
Actual Primary Completion Date : April 2012
Actual Study Completion Date : April 2012

Resource links provided by the National Library of Medicine

Autistic patients.
Matched controls

Primary Outcome Measures :
  1. Determine SERPIN1 gene sequence variation in autistic subjects. [ Time Frame: one year ]

Biospecimen Retention:   Samples With DNA
DNA will be isolated from peripheral blood samples.

Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Autistic patients and their first degree relatives

Inclusion Criteria:

  • Autistic patient, or first degree relative of autistic patient

Exclusion Criteria:

  • Less than one year of age.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00917683

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United States, New York
SUNY Upstate Medical University
Syracuse, New York, United States, 13210
Sponsors and Collaborators
State University of New York - Upstate Medical University
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Principal Investigator: Antony E Shrimpton, PhD State University of New York - Upstate Medical University

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Responsible Party: Antony E Shrimpton PhD, Assoc Prof, SUNY Upstate Medical University Identifier: NCT00917683     History of Changes
Other Study ID Numbers: IRB#5811
First Posted: June 10, 2009    Key Record Dates
Last Update Posted: April 19, 2016
Last Verified: April 2016

Additional relevant MeSH terms:
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Autistic Disorder
Autism Spectrum Disorder
Child Development Disorders, Pervasive
Neurodevelopmental Disorders
Mental Disorders
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action