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Resequencing and association analysis of PTPRA, a possible susceptibility gene for schizophrenia and autism spectrum disorders.

Xing J, Wang C, Kimura H, Takasaki Y, Kunimoto S, Yoshimi A, Nakamura Y, Koide T, Banno M, Kushima I, Uno Y, Okada T, Aleksic B, Ikeda M, Iwata N, Ozaki N - PLoS ONE (2014)

Bottom Line: Eight rare mutations, including 3 novel variants, were identified during the mutation-screening phase.Additionally, a novel duplication in the 3'UTR region, 174620_174623dupTGAT, was predicted to be located within a Musashi Binding Element.No evidence was seen for the association of rare, missense mutations in the PTPRA gene with schizophrenia or autism spectrum disorders; however, we did find some rare variants with possibly damaging effects that may increase the susceptibility of carriers to the disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.

ABSTRACT

Background: The PTPRA gene, which encodes the protein RPTP-α, is critical to neurodevelopment. Previous linkage studies, genome-wide association studies, controlled expression analyses and animal models support an association with both schizophrenia and autism spectrum disorders, both of which share a substantial portion of genetic risks.

Methods: We sequenced the protein-encoding areas of the PTPRA gene for single nucleotide polymorphisms or small insertions/deletions (InDel) in 382 schizophrenia patients. To validate their association with the disorders, rare (minor allele frequency <1%), missense mutations as well as one InDel in the 3'UTR region were then genotyped in another independent sample set comprising 944 schizophrenia patients, 336 autism spectrum disorders patients, and 912 healthy controls.

Results: Eight rare mutations, including 3 novel variants, were identified during the mutation-screening phase. In the following association analysis, L59P, one of the two missense mutations, was only observed among patients of schizophrenia. Additionally, a novel duplication in the 3'UTR region, 174620_174623dupTGAT, was predicted to be located within a Musashi Binding Element.

Major conclusions: No evidence was seen for the association of rare, missense mutations in the PTPRA gene with schizophrenia or autism spectrum disorders; however, we did find some rare variants with possibly damaging effects that may increase the susceptibility of carriers to the disorders.

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Related in: MedlinePlus

Structure of the PTPRA gene, RPTP-α, and position of discovered rare missense mutations.
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pone-0112531-g001: Structure of the PTPRA gene, RPTP-α, and position of discovered rare missense mutations.

Mentions: The human PTPRA gene is located at Chromosome 20: 2,844,830–3,019,320 and has a total of 28 exons (Ensembl release 73; Genome assembly: GRCh37; Transcript: ENST00000380393) (Fig. 1). We included only coding regions and 3′UTR (exons 8–28) (Fig. 2). Genomic DNA was extracted from whole blood or saliva using QIAGEN QIAamp DNA blood kit or tissue kit (QIAGEN Ltd. Hilden, Germany). Primers for 10 amplicons ranging from lengths of 700 to 3000 bps covering all the target exons were designed with the Primer-BLAST tool by NCBI (http://www.ncbi.nlm.nih.gov/tools/primer-blast/) and tested for validity with UCSC In-Silico PCR (http://genome.ucsc.edu/cgi-bin/hgPcr). The Takara LA taq Kit (Takara Bio Inc. Shiga, Japan) was used for PCR amplification, and products were cleaned up with Illustra Exonuclease I and Alkaline Phosphatase (GE Healthcare & Life Science, Little Chalfont, United Kingdom). After that, Sanger sequencing was performed using the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, California, United States). Upon the initial discovery, for all variants, we used Sanger sequencing to confirm the detection. Sequenced samples were read on an Applied Biosystems 3130xL Genetic Analyzer. Mutation detection was performed with Mutation Surveyor (Softgenetics, State College, PA, USA). The mutation calls were then revalidated for confidence.


Resequencing and association analysis of PTPRA, a possible susceptibility gene for schizophrenia and autism spectrum disorders.

Xing J, Wang C, Kimura H, Takasaki Y, Kunimoto S, Yoshimi A, Nakamura Y, Koide T, Banno M, Kushima I, Uno Y, Okada T, Aleksic B, Ikeda M, Iwata N, Ozaki N - PLoS ONE (2014)

Structure of the PTPRA gene, RPTP-α, and position of discovered rare missense mutations.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231042&req=5

pone-0112531-g001: Structure of the PTPRA gene, RPTP-α, and position of discovered rare missense mutations.
Mentions: The human PTPRA gene is located at Chromosome 20: 2,844,830–3,019,320 and has a total of 28 exons (Ensembl release 73; Genome assembly: GRCh37; Transcript: ENST00000380393) (Fig. 1). We included only coding regions and 3′UTR (exons 8–28) (Fig. 2). Genomic DNA was extracted from whole blood or saliva using QIAGEN QIAamp DNA blood kit or tissue kit (QIAGEN Ltd. Hilden, Germany). Primers for 10 amplicons ranging from lengths of 700 to 3000 bps covering all the target exons were designed with the Primer-BLAST tool by NCBI (http://www.ncbi.nlm.nih.gov/tools/primer-blast/) and tested for validity with UCSC In-Silico PCR (http://genome.ucsc.edu/cgi-bin/hgPcr). The Takara LA taq Kit (Takara Bio Inc. Shiga, Japan) was used for PCR amplification, and products were cleaned up with Illustra Exonuclease I and Alkaline Phosphatase (GE Healthcare & Life Science, Little Chalfont, United Kingdom). After that, Sanger sequencing was performed using the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, California, United States). Upon the initial discovery, for all variants, we used Sanger sequencing to confirm the detection. Sequenced samples were read on an Applied Biosystems 3130xL Genetic Analyzer. Mutation detection was performed with Mutation Surveyor (Softgenetics, State College, PA, USA). The mutation calls were then revalidated for confidence.

Bottom Line: Eight rare mutations, including 3 novel variants, were identified during the mutation-screening phase.Additionally, a novel duplication in the 3'UTR region, 174620_174623dupTGAT, was predicted to be located within a Musashi Binding Element.No evidence was seen for the association of rare, missense mutations in the PTPRA gene with schizophrenia or autism spectrum disorders; however, we did find some rare variants with possibly damaging effects that may increase the susceptibility of carriers to the disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.

ABSTRACT

Background: The PTPRA gene, which encodes the protein RPTP-α, is critical to neurodevelopment. Previous linkage studies, genome-wide association studies, controlled expression analyses and animal models support an association with both schizophrenia and autism spectrum disorders, both of which share a substantial portion of genetic risks.

Methods: We sequenced the protein-encoding areas of the PTPRA gene for single nucleotide polymorphisms or small insertions/deletions (InDel) in 382 schizophrenia patients. To validate their association with the disorders, rare (minor allele frequency <1%), missense mutations as well as one InDel in the 3'UTR region were then genotyped in another independent sample set comprising 944 schizophrenia patients, 336 autism spectrum disorders patients, and 912 healthy controls.

Results: Eight rare mutations, including 3 novel variants, were identified during the mutation-screening phase. In the following association analysis, L59P, one of the two missense mutations, was only observed among patients of schizophrenia. Additionally, a novel duplication in the 3'UTR region, 174620_174623dupTGAT, was predicted to be located within a Musashi Binding Element.

Major conclusions: No evidence was seen for the association of rare, missense mutations in the PTPRA gene with schizophrenia or autism spectrum disorders; however, we did find some rare variants with possibly damaging effects that may increase the susceptibility of carriers to the disorders.

Show MeSH
Related in: MedlinePlus