Heterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders.

Inherited and de novo genomic imbalances at chromosome 16p11.2 are associated with autism spectrum disorders (ASD), but the causative genes remain unknown. Among the genes located in this region, PRRT2 codes for a member of the synaptic SNARE complex that allows the release of synaptic vesicles. PRR...

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Autores principales:	Guillaume Huguet, Caroline Nava, Nathalie Lemière, Etienne Patin, Guillaume Laval, Elodie Ey, Alexis Brice, Marion Leboyer, Pierre Szepetowski, Christopher Gillberg, Christel Depienne, Richard Delorme, Thomas Bourgeron
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/391d3f07547743f5ace953f1ef854c18
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spelling	oai:doaj.org-article:391d3f07547743f5ace953f1ef854c182021-11-18T08:30:12ZHeterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders.1932-620310.1371/journal.pone.0088600https://doaj.org/article/391d3f07547743f5ace953f1ef854c182014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24594579/?tool=EBIhttps://doaj.org/toc/1932-6203Inherited and de novo genomic imbalances at chromosome 16p11.2 are associated with autism spectrum disorders (ASD), but the causative genes remain unknown. Among the genes located in this region, PRRT2 codes for a member of the synaptic SNARE complex that allows the release of synaptic vesicles. PRRT2 is a candidate gene for ASD since homozygote mutations are associated with intellectual disability and heterozygote mutations cause benign infantile seizures, paroxysmal dyskinesia, or hemiplegic migraine. Here, we explored the contribution of PRRT2 mutations in ASD by screening its coding part in a large sample of 1578 individuals including 431 individuals with ASD, 186 controls and 961 individuals from the human genome Diversity Panel. We detected 24 nonsynonymous variants, 1 frameshift (A217PfsX8) and 1 in-frame deletion of 6 bp (p.A361_P362del). The frameshift mutation was observed in a control with no history of neurological or psychiatric disorders. The p.A361_P362del was observed in two individuals with autism from sub-Saharan African origin. Overall, the frequency of PRRT2 deleterious variants was not different between individuals with ASD and controls. Remarkably, PRRT2 displays a highly significant excess of nonsynonymous (pN) vs synonymous (pS) mutations in Asia (pN/pS = 4.85) and Europe (pN/pS = 1.62) compared with Africa (pN/pS = 0.26; Asia vs Africa: P = 0.000087; Europe vs Africa P = 0.00035; Europe vs Asia P = P = 0.084). We also showed that whole genome amplification performed through rolling cycle amplification could artificially introduce the A217PfsX8 mutation indicating that this technology should not be performed prior to PRRT2 mutation screening. In summary, our results do not support a role for PRRT2 coding sequence variants in ASD, but provide an ascertainment of its genetic variability in worldwide populations that should help researchers and clinicians to better investigate the role of PRRT2 in human diseases.Guillaume HuguetCaroline NavaNathalie LemièreEtienne PatinGuillaume LavalElodie EyAlexis BriceMarion LeboyerPierre SzepetowskiChristopher GillbergChristel DepienneRichard DelormeThomas BourgeronPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 3, p e88600 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Guillaume Huguet Caroline Nava Nathalie Lemière Etienne Patin Guillaume Laval Elodie Ey Alexis Brice Marion Leboyer Pierre Szepetowski Christopher Gillberg Christel Depienne Richard Delorme Thomas Bourgeron Heterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders.
description	Inherited and de novo genomic imbalances at chromosome 16p11.2 are associated with autism spectrum disorders (ASD), but the causative genes remain unknown. Among the genes located in this region, PRRT2 codes for a member of the synaptic SNARE complex that allows the release of synaptic vesicles. PRRT2 is a candidate gene for ASD since homozygote mutations are associated with intellectual disability and heterozygote mutations cause benign infantile seizures, paroxysmal dyskinesia, or hemiplegic migraine. Here, we explored the contribution of PRRT2 mutations in ASD by screening its coding part in a large sample of 1578 individuals including 431 individuals with ASD, 186 controls and 961 individuals from the human genome Diversity Panel. We detected 24 nonsynonymous variants, 1 frameshift (A217PfsX8) and 1 in-frame deletion of 6 bp (p.A361_P362del). The frameshift mutation was observed in a control with no history of neurological or psychiatric disorders. The p.A361_P362del was observed in two individuals with autism from sub-Saharan African origin. Overall, the frequency of PRRT2 deleterious variants was not different between individuals with ASD and controls. Remarkably, PRRT2 displays a highly significant excess of nonsynonymous (pN) vs synonymous (pS) mutations in Asia (pN/pS = 4.85) and Europe (pN/pS = 1.62) compared with Africa (pN/pS = 0.26; Asia vs Africa: P = 0.000087; Europe vs Africa P = 0.00035; Europe vs Asia P = P = 0.084). We also showed that whole genome amplification performed through rolling cycle amplification could artificially introduce the A217PfsX8 mutation indicating that this technology should not be performed prior to PRRT2 mutation screening. In summary, our results do not support a role for PRRT2 coding sequence variants in ASD, but provide an ascertainment of its genetic variability in worldwide populations that should help researchers and clinicians to better investigate the role of PRRT2 in human diseases.
format	article
author	Guillaume Huguet Caroline Nava Nathalie Lemière Etienne Patin Guillaume Laval Elodie Ey Alexis Brice Marion Leboyer Pierre Szepetowski Christopher Gillberg Christel Depienne Richard Delorme Thomas Bourgeron
author_facet	Guillaume Huguet Caroline Nava Nathalie Lemière Etienne Patin Guillaume Laval Elodie Ey Alexis Brice Marion Leboyer Pierre Szepetowski Christopher Gillberg Christel Depienne Richard Delorme Thomas Bourgeron
author_sort	Guillaume Huguet
title	Heterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders.
title_short	Heterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders.
title_full	Heterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders.
title_fullStr	Heterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders.
title_full_unstemmed	Heterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders.
title_sort	heterogeneous pattern of selective pressure for prrt2 in human populations, but no association with autism spectrum disorders.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/391d3f07547743f5ace953f1ef854c18
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Heterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders.

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