Multiple imprinted genes associated with Prader-Willi syndrome and location of an imprinting control element.

Abstract

Our studies aim to identify the mechanisms and genes involved in genomic imprinting in mammalian development and human disease. Imprinting refers to an epigenetic modification of DNA that results in parent-of-origin specific expression during embryogenesis and in the adult. This imprint is reset at each generation, depending on the sex of the parental gametogenesis. Prader-Willi (PWS) and Angelman (AS) syndromes are excellent models for the study of genomic imprinting in humans, since these distinct neurobehavioural disorders are both associated with genetic abnormalities (large deletions, uniparental disomy, and imprinting mutations) of inheritance in chromosome 15q11-q13, dependent on the parental origin (reviewed in ref. 1). Some AS patients have biparental inheritance, consistent with a single imprinted gene (active on the maternal chromosome), whereas similar PWS patients are not found suggesting that at least two imprinted genes (active on the paternal allele) may be necessary for classical PWS. We have previously shown that the small ribonucleoprotein associated protein SmN gene (SNRPN), located in the PWS critical region [2], is only expressed from the paternal allele and is differentially methylated on parental alleles [3]. Therefore, SNRPN may have a role in PWS. Methylation imprints have also been found at two other loci in 15q11-q13, PW71 [4] and D15S9 [5], which map 120 kb and 1.5 Mb proximal to SNRPN, respectively. We have now characterized in detail the gene structure and expression from two imprinted loci within 15q11-q13, SNRPN and D15S9, which suggests that both loci are surprisingly complex, with important implications for the pathogenesis of PWS.