XERODERMA-PIGMENTOSUM GROUP-C SPLICE MUTATION ASSOCIATED WITH AUTISM AND HYPOGLYCINEMIA

A 4 y old boy of Korean ancestry had xeroderma pigmentosum (XP) with s un sensitivity, multiple cutaneous neoplasms, and inability to speak. Neurologic examination revealed hyperactivity and autistic features wi thout typical XP neurologic abnormalities, Cultured skin fibroblasts ( XP22BE) showed decreased post-UV survival, reduced post-UV plasmid hos t cell reactivation and defective DNA repair (16% of normal unschedule d DNA synthesis in intact cells and undetectable excision repair in a cell free extract). In vitro and in vivo complementation assigned XP22 BE to XP group C (XPC) and a markedly reduced level of XPC mRNA was fo und, Two XPC cDNA hands were identified. One band had a deletion of 16 1 bases comprising the entire exon 9, which resulted in premature term ination of the mutant XPC mRNA. The larger band also had the same dele tion 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 analys is 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 sp lice donor and acceptor sequences. Analysis of the patient's blood sho wed persistently low levels of glycine (68 mu M; NL, 125-318 mu M). No rmal glycine levels mere maintained with oral glycine supplements and his hyperactivity diminished. These data provide evidence of an associ ation of an XPC splice site mutation with autistic neurologic features and hypoglycinemia.