Departments of Psychiatry & Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Int J Mol Sci. 2020 May 6;21(9):3296. doi: 10.3390/ijms21093296.
The 15q11.2 BP1-BP2 microdeletion () syndrome is emerging as the most frequent pathogenic copy number variation (CNV) in humans associated with neurodevelopmental disorders with changes in brain morphology, behavior, and cognition. In this study, we explored functions and interactions of the four protein-coding genes in this region, namely , , , and , and elucidate their role, in solo and in concert, in the causation of neurodevelopmental disorders. First, we investigated the STRING protein-protein interactions encompassing all four genes and ascertained their predicted Gene Ontology (GO) functions, such as biological processes involved in their interactions, pathways and molecular functions. These include magnesium ion transport molecular function, regulation of axonogenesis and axon extension, regulation and production of bone morphogenetic protein and regulation of cellular growth and development. We gathered a list of significantly associated cardinal maladies for each gene from searchable genomic disease websites, namely MalaCards.org: HGMD, OMIM, ClinVar, GTR, Orphanet, DISEASES, Novoseek, and GeneCards.org. Through tabulations of such disease data, we ascertained the cardinal disease association of each gene, as well as their expanded putative disease associations. This enabled further tabulation of disease data to ascertain the role of each gene in the top ten overlapping significant neurodevelopmental disorders among the disease association data sets: (1) Prader-Willi Syndrome (PWS); (2) Angelman Syndrome (AS); (3) 15q11.2 Deletion Syndrome with Attention Deficit Hyperactive Disorder & Learning Disability; (4) Autism Spectrum Disorder (ASD); (5) Schizophrenia; (6) Epilepsy; (7) Down Syndrome; (8) Microcephaly; (9) Developmental Disorder, and (10) Peripheral Nervous System Disease. The cardinal disease associations for each of the four contiguous 15q11.2 BP1-BP2 genes are - Spastic Paraplegia 6; -Angelman Syndrome and Prader-Willi Syndrome; -Fragile X Syndrome and Autism; -Prader-Willi Syndrome. The four genes are individually associated with PWS, ASD, schizophrenia, epilepsy, and Down syndrome. Except for , the other three genes are associated with AS. Unlike the other genes, is also not associated with attention deficit hyperactivity disorder and learning disability, developmental disorder, or peripheral nervous system disease. was the only gene not associated with microcephaly but was the only gene associated with developmental disorders. Collectively, all four genes were associated with up to three-fourths of the ten overlapping neurodevelopmental disorders and are deleted in this most prevalent known pathogenic copy number variation now recognized among humans with these clinical findings.
15q11.2 BP1-BP2 微缺失（）综合征是一种新兴的与神经发育障碍相关的最常见致病性拷贝数变异（CNV），其与大脑形态、行为和认知改变有关。在这项研究中，我们探索了该区域四个蛋白编码基因的功能和相互作用，即、、、和，并阐明了它们在神经发育障碍病因中的单独和协同作用。首先，我们研究了涵盖所有四个基因的 STRING 蛋白质-蛋白质相互作用，并确定了它们的预测基因本体论（GO）功能，例如它们相互作用涉及的生物过程、途径和分子功能。这些功能包括镁离子运输的分子功能、轴突发生和轴突延伸的调节、骨形态发生蛋白的调节和细胞生长发育的调节。我们从可搜索的基因组疾病网站（如 MalaCards.org：HGMD、OMIM、ClinVar、GTR、Orphanet、DISEASES、Novoseek 和 GeneCards.org）中为每个基因收集了一份显著相关的主要疾病清单。通过对这些疾病数据的制表，我们确定了每个基因的主要疾病关联，以及它们扩展的潜在疾病关联。这使我们能够进一步对疾病数据进行制表，以确定每个基因在十大重叠显著神经发育障碍中的作用，这些障碍是从疾病关联数据集中确定的：（1）普拉德-威利综合征（PWS）；（2）安格曼综合征（AS）；（3）15q11.2 缺失综合征伴注意力缺陷多动障碍和学习障碍；（4）自闭症谱系障碍（ASD）；（5）精神分裂症；（6）癫痫；（7）唐氏综合征；（8）小头畸形；（9）发育障碍；（10）周围神经系统疾病。四个 15q11.2 BP1-BP2 连续基因的主要疾病关联分别为-痉挛性截瘫 6；-安格曼综合征和普拉德-威利综合征；-脆性 X 综合征和自闭症；-普拉德-威利综合征。四个基因分别与 PWS、ASD、精神分裂症、癫痫和唐氏综合征有关。除了之外，其他三个基因都与 AS 有关。与其他基因不同的是，与注意力缺陷多动障碍和学习障碍、发育障碍或周围神经系统疾病无关。是唯一与小头畸形无关的基因，但它是唯一与发育障碍有关的基因。总的来说，所有四个基因都与十种重叠神经发育障碍中的四分之三有关，并且在现在在具有这些临床发现的人类中识别到的最常见的致病性拷贝数变异中缺失。
