FitzPatrick David R, Carr Ian M, McLaren Lorna, Leek Jack P, Wightman Patrick, Williamson Kathy, Gautier Philippe, McGill Niolette, Hayward Caroline, Firth Helen, Markham Alex F, Fantes Judy A, Bonthron David T
Cell and Molecualr Genentics, MRC Human Genetics Unit, Western General Hospital, Edinburgh, EH4 2XU, UK.
Hum Mol Genet. 2003 Oct 1;12(19):2491-501. doi: 10.1093/hmg/ddg248. Epub 2003 Jul 29.
Cytogenetic evidence, in the form of deletions and balanced translocations, points to the existence of a locus on 2q32-q33, for which haploinsufficiency results in isolated cleft palate (CPO). Here we show by high-resolution FISH mapping of two de novo CPO-associated translocations involving 2q32-q33 that one breakpoint interrupts the transcription unit of the gene encoding the DNA-binding protein SATB2 (formerly KIAA1034). The breakpoint in the other translocation is located 130 kb 3' to the SATB2 polyadenylation signal, within a conserved region of non-coding DNA. The SATB2 gene is transcribed in a telomeric to centromeric direction and lies in a gene-poor region of 2q32-q33; the nearest confirmed gene is 1.26 Mb centromeric to the SATB2 polyadenylation signal. SATB2-encoding transcripts are assembled from 11 exons that span 191 kb of genomic DNA. They encode a protein of 733 amino acids that has two CUT domains and a homeodomain and shows a remarkable degree of evolutionary conservation, with only three amino acid substitutions between mouse and human. This protein belongs to the same family as SATB1, a nuclear matrix-attachment region binding protein implicated in transcriptional control and control of chromatin remodelling. There are also sequence similarities to the Drosophila protein DVE. Whole mount in situ hybridization to mouse embryos shows site- and stage-specific expression of SATB2 in the developing palate. Despite the strong evidence supporting an important role for SATB2 in palate development, mutation analysis of 70 unrelated patients with CPO did not reveal any coding region variants.
细胞遗传学证据，以缺失和平衡易位的形式，表明在2q32 - q33存在一个位点，该位点的单倍体不足会导致孤立性腭裂（CPO）。在此我们通过对两个涉及2q32 - q33的新生CPO相关易位进行高分辨率荧光原位杂交定位显示，一个断点打断了编码DNA结合蛋白SATB2（以前称为KIAA1034）的基因的转录单元。另一个易位中的断点位于SATB2多聚腺苷酸化信号下游130 kb处，在非编码DNA的保守区域内。SATB2基因以端粒到着丝粒的方向转录，位于2q32 - q33基因贫乏区域；最近确认的基因位于SATB2多聚腺苷酸化信号着丝粒方向1.26 Mb处。编码SATB2的转录本由跨越191 kb基因组DNA的11个外显子组装而成。它们编码一个733个氨基酸的蛋白质，该蛋白质有两个CUT结构域和一个同源结构域，并且显示出高度的进化保守性，小鼠和人类之间只有三个氨基酸替换。该蛋白质与SATB1属于同一家族，SATB1是一种与转录调控和染色质重塑控制有关的核基质附着区域结合蛋白。它与果蝇蛋白DVE也有序列相似性。对小鼠胚胎进行的全胚胎原位杂交显示SATB2在发育中的腭部有位点和阶段特异性表达。尽管有强有力的证据支持SATB2在腭部发育中起重要作用，但对70名无关的CPO患者进行的突变分析未发现任何编码区变体。
