GENOMIC IMPRINTING - POTENTIAL FUNCTION AND MECHANISMS REVEALED BY THE PRADER-WILLI AND ANGELMAN SYNDROMES

The Prader-Willi (PWS) and Angelman (AS) syndromes are two clinically distinct syndromes which result from lack of expression of imprinted g enes within chromosome 15q11-q13. These two syndromes result from 15q1 1-q13 deletions, chromosome 15 uniparental disomy (UPD), imprinting ce ntre mutations and, for AS, probable mutations in a single gene. The d ifferential phenotype results from a paternal genetic deficiency in PW S patients and a maternal genetic deficiency in AS patients. Within 15 q11-q13, four genes (SNRPN, IPW, ZNF127, FNZ127) and two expressed seq uence tags (PAR1 and PAR5) have been found to be expressed only from t he paternally inherited chromosome, and therefore all must be consider ed candidate genes involved in the pathogenesis of PWS. A candidate AS gene (UBE3A) has very recently been identified. The mechanisms of imp rinted gene expression are not yet understood, but it is clear that DN A methylation is involved in both somatic cell expression and inherita nce of the imprint. The presence of DNA methylation imprints that dist inguish the paternally and maternally inherited alleles is a common ch aracteristic of all known imprinted genes which have been studied exte nsively, including SNRPN and ZNF127. Recently, several PWS and AS pati ents have been found that have microdeletions in a region upstream of the SNRPN gene referred to as the imprinting centre, or IC. Paternal I C deletions in PWS patients and maternal IC deletions in AS patients r esult in uniparental DNA methylation and uniparental gene expression a t biparentally inherited loci. The IC is a novel genetic element which controls initial resetting of the parental imprint in the germline fo r all imprinted gene expression over a 1.5-2.5 Mb region within chromo some 15q11-q13.