HUTCHINSON-GILFORD-PROGERIA - FAITHFUL DNA MAINTENANCE, INHERITANCE AND ALLELIC TRANSCRIPTION OF BETA(1-4) GALACTOSYLTRANSFERASE

Hutchinson-Gilford progeria syndrome (HGPS) is a fatal segmental aging disorder affecting children. There is a paucity of prior data at the nucleotide level on DNA maintenance in HGPS. We have examined the spec ific nucleotide sequences and production of allelic transcripts from t he locus GGTB2 encoding beta(1-4) galactosyltransferase. Quantitative Northern blots of mRNA from HGPS and control fibroblasts indicated ide ntical mature beta(1-4) galactosyltransferase transcript sizes and amo unts, regardless of their altered glycosylation status. DNA sequencing of cDNA derived from HGPS beta(1-4) galactosyltransferase mRNA popula tions confirmed the encoded amino acid sequence was unaffected. Popula tion studies of 41 unrelated individuals provided allelic frequency es timates for a novel FokI polymorphism, which was identified in two of six progeria cell strains. The polymorphism was faithfully inherited i n a progeria pedigree in a Mendelian manner. Furthermore, the polymorp hism provided direct evidence through sequencing of reverse transcript ion polymerase chain reaction products that both alleles were transcri bed and generated mature mRNA. Any defects in transcripts were below d etectable levels over the lengths of coding sequences examined, despit e multiple replication events from conception leading to the productio n and maintenance of patient-derived cells. These results indicate fai thful transcription in HGPS. (C) 1998 Elsevier Science Ireland Ltd. Al l rights reserved.