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Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31

We report a genomic and phenotypic delineation for two chromosome regions with candidate genes for syndromic intellectual disability at 12q12 and Xp22.31, segregating independently in one family with four affected members. Fine mapping of three affected members, along with six unreported small infor...

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Autores principales: Labonne, Jonathan D. J., Driessen, Terri M., Harris, Marvin E., Kong, Il-Keun, Brakta, Soumia, Theisen, John, Sangare, Modibo, Layman, Lawrence C., Kim, Cheol-Hee, Lim, Janghoo, Kim, Hyung-Goo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019335/
https://www.ncbi.nlm.nih.gov/pubmed/31963867
http://dx.doi.org/10.3390/jcm9010274
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author Labonne, Jonathan D. J.
Driessen, Terri M.
Harris, Marvin E.
Kong, Il-Keun
Brakta, Soumia
Theisen, John
Sangare, Modibo
Layman, Lawrence C.
Kim, Cheol-Hee
Lim, Janghoo
Kim, Hyung-Goo
author_facet Labonne, Jonathan D. J.
Driessen, Terri M.
Harris, Marvin E.
Kong, Il-Keun
Brakta, Soumia
Theisen, John
Sangare, Modibo
Layman, Lawrence C.
Kim, Cheol-Hee
Lim, Janghoo
Kim, Hyung-Goo
author_sort Labonne, Jonathan D. J.
collection PubMed
description We report a genomic and phenotypic delineation for two chromosome regions with candidate genes for syndromic intellectual disability at 12q12 and Xp22.31, segregating independently in one family with four affected members. Fine mapping of three affected members, along with six unreported small informative CNVs, narrowed down the candidate chromosomal interval to one gene LRRK2 at 12q12. Expression studies revealed high levels of LRRK2 transcripts in the whole human brain, cerebral cortex and hippocampus. RT-qPCR assays revealed that LRRK2 transcripts were dramatically reduced in our microdeletion patient DGDP289A compared to his healthy grandfather with no deletion. The decreased expression of LRRK2 may affect protein–protein interactions between LRRK2 and its binding partners, of which eight have previously been linked to intellectual disability. These findings corroborate with a role for LRRK2 in cognitive development, and, thus, we propose that intellectual disability and autism, displayed in the 12q12 microdeletions, are likely caused by LRRK2. Using another affected member, DGDP289B, with a microdeletion at Xp22.31, in this family, we performed the genomic and clinical delineation with six published and nine unreported cases. We propose HDHD1 and PNPLA4 for X-linked intellectual disability in this region, since their high transcript levels in the human brain substantiate their role in intellectual functioning.
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spelling pubmed-70193352020-03-09 Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31 Labonne, Jonathan D. J. Driessen, Terri M. Harris, Marvin E. Kong, Il-Keun Brakta, Soumia Theisen, John Sangare, Modibo Layman, Lawrence C. Kim, Cheol-Hee Lim, Janghoo Kim, Hyung-Goo J Clin Med Article We report a genomic and phenotypic delineation for two chromosome regions with candidate genes for syndromic intellectual disability at 12q12 and Xp22.31, segregating independently in one family with four affected members. Fine mapping of three affected members, along with six unreported small informative CNVs, narrowed down the candidate chromosomal interval to one gene LRRK2 at 12q12. Expression studies revealed high levels of LRRK2 transcripts in the whole human brain, cerebral cortex and hippocampus. RT-qPCR assays revealed that LRRK2 transcripts were dramatically reduced in our microdeletion patient DGDP289A compared to his healthy grandfather with no deletion. The decreased expression of LRRK2 may affect protein–protein interactions between LRRK2 and its binding partners, of which eight have previously been linked to intellectual disability. These findings corroborate with a role for LRRK2 in cognitive development, and, thus, we propose that intellectual disability and autism, displayed in the 12q12 microdeletions, are likely caused by LRRK2. Using another affected member, DGDP289B, with a microdeletion at Xp22.31, in this family, we performed the genomic and clinical delineation with six published and nine unreported cases. We propose HDHD1 and PNPLA4 for X-linked intellectual disability in this region, since their high transcript levels in the human brain substantiate their role in intellectual functioning. MDPI 2020-01-19 /pmc/articles/PMC7019335/ /pubmed/31963867 http://dx.doi.org/10.3390/jcm9010274 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Labonne, Jonathan D. J.
Driessen, Terri M.
Harris, Marvin E.
Kong, Il-Keun
Brakta, Soumia
Theisen, John
Sangare, Modibo
Layman, Lawrence C.
Kim, Cheol-Hee
Lim, Janghoo
Kim, Hyung-Goo
Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31
title Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31
title_full Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31
title_fullStr Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31
title_full_unstemmed Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31
title_short Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31
title_sort comparative genomic mapping implicates lrrk2 for intellectual disability and autism at 12q12, and hdhd1, as well as pnpla4, for x-linked intellectual disability at xp22.31
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019335/
https://www.ncbi.nlm.nih.gov/pubmed/31963867
http://dx.doi.org/10.3390/jcm9010274
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