Phenotypic and functional consequences of haploinsufficiency of genes from exocyst and retinoic acid pathway due to a recurrent microdeletion of 2p13.2.
Phenotypic and functional consequences of haploinsufficiency of genes from exocyst and retinoic acid pathway due to a recurrent microdeletion of 2p13.2.
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DOI：
10.1186/1750-1172-8-100
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发表时间：
2013-07-10
影响因子：
3.7
通讯作者：
Rajcan-Separovic E
中科院分区：
文献类型：
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作者：
Wen J;Lopes F;Soares G;Farrell SA;Nelson C;Qiao Y;Martell S;Badukke C;Bessa C;Ylstra B;Lewis S;Isoherranen N;Maciel P;Rajcan-Separovic E
罕见的、反复发生的基因组失衡促进了基因型与“全身”水平异常的关联。然而，在细胞水平上，对反复出现的基因组异常的功能后果以及它们如何与表型联系起来的研究要少得多。我们报告了对来自 2p13.2 区域（来自 72,140,702-72,924,626）的新的重叠微缺失的两个基因进行功能分析的示例。这些受试者都患有智力障碍（ID）、语言迟缓、多动、面部不对称、耳朵畸形以及脊椎和/或颅面异常。重叠区域包括两个基因，EXOC6B和CYP26B1，它们分别参与胞吐作用/Notch信号传导和视黄酸（RA）代谢，对于早期形态发生、对称性以及颅面、骨骼和大脑发育至关重要。 EXOC6B 的异常功能在患者淋巴母细胞中通过其表达减少以及 Notch 信号通路基因 HES1 和 RBPJ 的表达扰乱来记录，先前指出这是动物和细胞系模型中 EXOC6B 功能障碍的结果。同样，CYP26B1 的功能也受到缺失的影响，因为视黄酸诱导的患者淋巴母细胞中该基因的表达显着低于对照（对照的 8%）。此前在人类中尚未报道过分别参与视黄酸和外囊/Notch 信号通路的 CYP26B1 和 EXOC6B 基因的单倍体不足。考虑到这些基因的已知作用，我们受试者的发育异常和表型特征与这些基因的功能障碍一致。在患者细胞的细胞水平上记录它们的功能障碍增强了我们对有助于临床表型的生物过程的理解。
Rare, recurrent genomic imbalances facilitate the association of genotype with abnormalities at the “whole body” level. However, at the cellular level, the functional consequences of recurrent genomic abnormalities and how they can be linked to the phenotype are much less investigated. We report an example of a functional analysis of two genes from a new, overlapping microdeletion of 2p13.2 region (from 72,140,702-72,924,626). The subjects shared intellectual disability (ID), language delay, hyperactivity, facial asymmetry, ear malformations, and vertebral and/or craniofacial abnormalities. The overlapping region included two genes, EXOC6B and CYP26B1, which are involved in exocytosis/Notch signaling and retinoic acid (RA) metabolism, respectively, and are of critical importance for early morphogenesis, symmetry as well as craniofacial, skeleton and brain development. The abnormal function of EXOC6B was documented in patient lymphoblasts by its reduced expression and with perturbed expression of Notch signaling pathway genes HES1 and RBPJ, previously noted to be the consequence of EXOC6B dysfunction in animal and cell line models. Similarly, the function of CYP26B1 was affected by the deletion since the retinoic acid induced expression of this gene in patient lymphoblasts was significantly lower compared to controls (8% of controls). Haploinsufficiency of CYP26B1 and EXOC6B genes involved in retinoic acid and exocyst/Notch signaling pathways, respectively, has not been reported previously in humans. The developmental anomalies and phenotypic features of our subjects are in keeping with the dysfunction of these genes, considering their known role. Documenting their dysfunction at the cellular level in patient cells enhanced our understanding of biological processes which contribute to the clinical phenotype.