TheGeneEncoding p44,a Subunit oftheTranscription Factor TFIIH, IsInvolved inLarge-Scale Deletions Associated withWerdnig- Hoffmann Disease

Summary Mutations ofthesurvival motorneurone gene(SMN) areassociated withspinal muscular atrophy (SMA), a frequent lethal autosomal recessive disorder. Inspite of this, nophenotype-genotype correlation wasobserved, since theSMNgeneislacking inthemajority ofpatients affected with either thesevere form(type I)orthemilder forms (types IIandIl). Here, weshowthat thegene encoding p44,asubunit ofthebasal transcription factor TFHH,isduplicated intheSMA region andthat the p44gene products (p44t andp44c) differ bythree amino acid changes. Geneanalysis ofatotal of94unrelated SMApatients revealed that thep44tgeneisinvolved in large-scale deletions associated withWerdnig-Hoffmanndisease (type I). TheTFIIHpolypeptide composition aswell astranscription andDNA repair activities arenormal inpatients lacking thep44tgeneonboth mutant chromosomes, suggesting that thep44tgeneis notcritical forthedevelopment ofSMA.