Investigation of Neuroserpin as an Autism Candidate Gene

The recruitment status of this study is unknown because the information has not been verified recently.
Verified February 2010 by State University of New York - Upstate Medical University.
Recruitment status was  Not yet recruiting
Sponsor:
Information provided by:
State University of New York - Upstate Medical University
ClinicalTrials.gov Identifier:
NCT00917683
First received: June 8, 2009
Last updated: February 26, 2010
Last verified: February 2010
  Purpose

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
Autism

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Prospective
Official Title: Investigation of Neuroserpin as an Autism Candidate Gene

Resource links provided by NLM:


Further study details as provided by State University of New York - Upstate Medical University:

Primary Outcome Measures:
  • Determine SERPIN1 gene sequence variation in autistic subjects. [ Time Frame: one year ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA

DNA will be isolated from peripheral blood samples.


Estimated Enrollment: 100
Study Start Date: June 2009
Estimated Study Completion Date: June 2013
Estimated Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Groups/Cohorts
1
Autistic patients.
2
Matched controls

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 (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.

  Eligibility

Ages Eligible for Study:   1 Year and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Autistic patients and their first degree relatives

Criteria

Inclusion Criteria:

  • Autistic patient, or first degree relative of autistic patient

Exclusion Criteria:

  • Less than one year of age.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00917683

Contacts
Contact: Antony E Shrimpton, PhD 315 464 6807 shrimpta@upstate.edu

Locations
United States, New York
SUNY Upstate Medical University Not yet recruiting
Syracuse, New York, United States, 13210
Contact: Antony E Shrimpton, PhD    315-464-6807    shrimpta@upstate.edu   
Sub-Investigator: Robert Lebel, MD         
Sub-Investigator: Gregory Liptak, MD         
Sponsors and Collaborators
State University of New York - Upstate Medical University
Investigators
Principal Investigator: Antony E Shrimpton, PhD State University of New York - Upstate Medical University
  More Information

No publications provided

Responsible Party: Antony E Shrimpton PhD, Assoc Prof, SUNY Upstate Medical University
ClinicalTrials.gov Identifier: NCT00917683     History of Changes
Other Study ID Numbers: IRB#5811
Study First Received: June 8, 2009
Last Updated: February 26, 2010
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Autistic Disorder
Child Development Disorders, Pervasive
Mental Disorders Diagnosed in Childhood
Mental Disorders
Neuroserpin
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 19, 2014