Xeroderma pigmentosum group C splice mutation associated with autism and hypoglycinemia

被引:52
作者
Khan, SG
Levy, HL
Legerski, R
Quackenbush, E
Reardon, JT
Emmert, S
Sancar, A
Li, L
Schneider, TD
Cleaver, JE
Kraemer, KH
机构
[1] NCI, Mol Carcinogenesis Lab, Bethesda, MD 20892 USA
[2] Childrens Hosp, Genet Serv, Boston, MA 02115 USA
[3] MD Anderson Hosp & Tumor Inst, Houston, TX USA
[4] Ctr Blood Res, Boston, MA 02115 USA
[5] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC USA
[6] NCI, Lab Expt & Computat Biol, Frederick, MD 21701 USA
[7] Univ Calif San Francisco, Dept Radiobiol, San Francisco, CA 94143 USA
关键词
alternative splicing; amino acid metabolism; DNA repair; skin cancer;
D O I
10.1046/j.1523-1747.1998.00391.x
中图分类号
R75 [皮肤病学与性病学];
学科分类号
100206 ;
摘要
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 hands 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 mu M; NL, 125-318 mu M). Normal glycine levels mere 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.
引用
收藏
页码:791 / 796
页数:6
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