Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, USA.
Am J Hum Genet. 2012 Jul 13;91(1):56-72. doi: 10.1016/j.ajhg.2012.05.005. Epub 2012 Jul 5.
Potocki-Shaffer syndrome (PSS) is a contiguous gene disorder due to the interstitial deletion of band p11.2 of chromosome 11 and is characterized by multiple exostoses, parietal foramina, intellectual disability (ID), and craniofacial anomalies (CFAs). Despite the identification of individual genes responsible for multiple exostoses and parietal foramina in PSS, the identity of the gene(s) associated with the ID and CFA phenotypes has remained elusive. Through characterization of independent subjects with balanced translocations and supportive comparative deletion mapping of PSS subjects, we have uncovered evidence that the ID and CFA phenotypes are both caused by haploinsufficiency of a single gene, PHF21A, at 11p11.2. PHF21A encodes a plant homeodomain finger protein whose murine and zebrafish orthologs are both expressed in a manner consistent with a function in neurofacial and craniofacial development, and suppression of the latter led to both craniofacial abnormalities and neuronal apoptosis. Along with lysine-specific demethylase 1 (LSD1), PHF21A, also known as BHC80, is a component of the BRAF-histone deacetylase complex that represses target-gene transcription. In lymphoblastoid cell lines from two translocation subjects in whom PHF21A was directly disrupted by the respective breakpoints, we observed derepression of the neuronal gene SCN3A and reduced LSD1 occupancy at the SCN3A promoter, supporting a direct functional consequence of PHF21A haploinsufficiency on transcriptional regulation. Our finding that disruption of PHF21A by translocations in the PSS region is associated with ID adds to the growing list of ID-associated genes that emphasize the critical role of transcriptional regulation and chromatin remodeling in normal brain development and cognitive function.
波托茨基-沙费尔综合征（PSS）是一种由于 11 号染色体 p11.2 带的染色体间缺失引起的连续基因疾病，其特征为多发性外生骨疣、顶骨孔、智力障碍（ID）和颅面异常（CFA）。尽管已经鉴定出 PSS 中多个外生骨疣和顶骨孔的个别基因，但与 ID 和 CFA 表型相关的基因仍然难以捉摸。通过对具有平衡易位的独立个体进行特征描述，并对 PSS 个体进行支持性比较缺失作图，我们发现证据表明，ID 和 CFA 表型均由 11p11.2 上单个基因 PHF21A 的单倍不足引起。PHF21A 编码一种植物同源域手指蛋白，其鼠类和斑马鱼的同源物均以与神经面和颅面发育功能一致的方式表达，并且后者的抑制导致颅面异常和神经元细胞凋亡。与赖氨酸特异性去甲基酶 1（LSD1）一样，PHF21A 也称为 BHC80，是 BRAF-组蛋白去乙酰化酶复合物的组成部分，可抑制靶基因转录。在两个易位个体的淋巴母细胞系中，PHF21A 分别被各自的断点直接破坏，我们观察到神经元基因 SCN3A 的去抑制和 SCN3A 启动子处 LSD1 占有率的降低，支持 PHF21A 单倍不足对转录调节的直接功能后果。我们发现 PSS 区域的易位破坏 PHF21A 与 ID 有关，这增加了与 ID 相关的基因列表，强调了转录调节和染色质重塑在正常大脑发育和认知功能中的关键作用。
