Khan S G, Levy H L, Legerski R, Quackenbush E, Reardon J T, Emmert S, Sancar A, Li L, Schneider T D, Cleaver J E, Kraemer K H
Laboratory of Molecular Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892, USA.
J Invest Dermatol. 1998 Nov;111(5):791-6. doi: 10.1046/j.1523-1747.1998.00391.x.
A 4 y old boy of Korean ancestry had xeroderma pigmentosum (XP) with sun sensitivity, multiple cutaneous neoplasms, and inability to speak. Neurologic examination revealed hyperactivity and autistic features without typical XP neurologic abnormalities. Cultured skin fibroblasts (XP22BE) showed decreased post-UV survival, reduced post-UV plasmid host cell reactivation and defective DNA repair (16% of normal unscheduled DNA synthesis in intact cells and undetectable excision repair in a cell free extract). In vitro and in vivo complementation assigned XP22BE to XP group C (XPC) and a markedly reduced level of XPC mRNA was found. Two XPC cDNA bands were identified. One band had a deletion of 161 bases comprising the entire exon 9, which resulted in premature termination of the mutant XPC mRNA. The larger band also had the same deletion of exon 9 but, in addition, had an insertion of 155 bases in its place (exon 9a), resulting in an in-frame XPC mRNA. Genomic DNA analysis revealed a T-->G mutation at the splice donor site of XPC exon 9, which markedly reduced its information content. The 155 base pair XPC exon 9a insertion was located in intron 9 and was flanked by strong splice donor and acceptor sequences. Analysis of the patient's blood showed persistently low levels of glycine (68 microM; NL, 125-318 microM). Normal glycine levels were maintained with oral glycine supplements and his hyperactivity diminished. These data provide evidence of an association of an XPC splice site mutation with autistic neurologic features and hypoglycinemia.
一名4岁的韩裔男孩患有着色性干皮病（XP），对阳光敏感，有多处皮肤肿瘤，且无法说话。神经系统检查显示多动和自闭症特征，但无典型的XP神经系统异常。培养的皮肤成纤维细胞（XP22BE）显示紫外线照射后存活率降低，紫外线照射后质粒宿主细胞再激活减少以及DNA修复缺陷（完整细胞中正常非预定DNA合成的16%，无细胞提取物中无法检测到切除修复）。体外和体内互补分析将XP22BE归为XP C组（XPC），并发现XPC mRNA水平明显降低。鉴定出两条XPC cDNA条带。一条条带缺失161个碱基，包括整个外显子9，导致突变的XPC mRNA提前终止。较大的条带也有相同的外显子9缺失，但此外，在其位置插入了155个碱基（外显子9a），导致框内XPC mRNA。基因组DNA分析显示XPC外显子9的剪接供体位点存在T→G突变，这显著降低了其信息含量。155个碱基对的XPC外显子9a插入位于内含子9中，两侧是强剪接供体和受体序列。对患者血液的分析显示甘氨酸水平持续较低（68微摩尔；正常范围，125 - 318微摩尔）。口服甘氨酸补充剂可维持正常甘氨酸水平，其多动症状减轻。这些数据提供了XPC剪接位点突变与自闭症神经系统特征和低血糖氨酸血症相关联的证据。
