ATYPICAL BACKGROUND SOMATIC MUTANT FREQUENCIES AT THE HPRT LOCUS IN CHILDREN AND ADULTS WITH DOWN-SYNDROME

People with Down syndrome are 10-30 fold more likely to develop leukem ia than the normal population, To date, little is known regarding the molecular mechanisms underlying this phenomenon. We have previously de monstrated that the spontaneous somatic mutant frequency (Mf) at a rep orter gene, hypoxanthine-guanine phosphoribosyl transferase (HPRT), fr om a normal population showed a strict age dependency with an exponent ial increase in Mf from birth to late adolescents with a subsequent li near 2-5% increase per year in adults. In this study, we compared HPRT Mf in children and adults with Down syndrome using the HPRT T-cell cl oning assay. We determined the Mf at the HPRT locus in 27 subjects wit h Down syndrome from ages 6 months to 53.4 years. Results demonstrated that background somatic Mf at the HPRT locus in children and adults w ith Down syndrome are not dependent on age as seen in a normal control population. Results also show that adults with Down syndrome have a s ignificantly lower Mf than normal adults, and that children with Down syndrome have a significantly higher Mf than normal children, although the latter appears to be due to a decreased cloning efficiency (CE), These observations demonstrate that the frequency of spontaneous somat ic mutations in children and adults with Down syndrome are atypical co mpared to normal controls, and suggest that the genetic mechanisms ass ociated with background somatic mutational events in children and adul ts with Down syndrome may be different. (C) 1998 Elsevier Science B.V. All rights reserved.