Clinical Heterogeneity within XerodermaPigmentosum Associated withMutations intheDNA Repair and Transcription GeneERCC3

Summary ThehumanDNA excision repair geneERCC3specifically correctsthenucleotide excision repair (NER)defect ofxeroderma pigmentosum (XP) complementation group B.Inaddition toits function inNER,theERCC3 DNA helicase wasrecently identified asoneofthe componentsofthehumanBTF2/TFIIH transcription factor complex, which isrequired forinitiation oftranscription ofclass IIgenes.Todate, asingle patient (XP11BE) hasbeenassigned tothis XPgroup B(XP-B), withtheremarkable conjunction oftwoautosomal recessive DNA repair deficiency disorders: XPandCockayne syndrome (CS). Theintriguing involvement oftheERCC3protein inthevital processoftranscription may provide an explanation fortherarity, severity, andwide spectrumof clinical features inthis complementation group.Herewe reporttheidentification oftwo new XP-Bpatients: XPCS1BAandXPCS2BA(siblings), bymicroneedle injection ofthecloned ERCC3repair geneaswell asby cell hybridization. Molecular analysis oftheERCC3geneinbothpatients revealed a single basesubstitution causing amissense mutation inaregion that iscompletely conserved inyeast, Drosophila, mouse,andhuman ERCC3.Asinpatient XP11BE, theexpression ofonly one allele (paternal) isdetected. Themutation causesa virtually complete inactivation oftheNERfunction oftheprotein. Despite this severeNERdefect, both patients display alate onsetofneurologic impairment, mild cutaneoussymptoms,andastriking absence ofskin tumorsevenatan ageof>40years.Analysis ofthefrequency ofhprrmutantT-lymphocytes inblood samples suggests arelatively lowinvivomutation frequency inthese patients. Factors inaddition toNERdeficiency may berequired forthedevelopment ofcutaneoustumors.