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.

Autor: Labonne JDJ; Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912, USA., Driessen TM; Department of Genetics, Yale University, New Haven, CT 06510, USA., Harris ME; Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912, USA., Kong IK; Department of Animal Science, Division of Applied Life Science (BK21plus), Institute of Agriculture and Life Science, Gyeongsang National University, Jinju 52828, Korea., Brakta S; Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912, USA., Theisen J; Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912, USA., Sangare M; Faculty of Medicine and Odontostomatology (FMOS), University of Sciences, Techniques and Technologies of Bamako (USTTB), Bamako, Mali., Layman LC; Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912, USA.; Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, GA 30912, USA., Kim CH; Department of Biology, Chungnam National University, Daejeon 34134, Korea., Lim J; Department of Genetics, Yale University, New Haven, CT 06510, USA.; Department of Neuroscience, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale Stem Cell Center, Yale University, New Haven, CT 06510, USA., Kim HG; Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912, USA.; Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, P.O. Box 34110 Doha, Qatar.
Jazyk: angličtina
Zdroj: Journal of clinical medicine [J Clin Med] 2020 Jan 19; Vol. 9 (1). Date of Electronic Publication: 2020 Jan 19.
DOI: 10.3390/jcm9010274
Abstrakt: 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.
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
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