AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 97:136–146 (2000) ARTICLE Prader-Willi and Angelman Syndromes: Sister Imprinted Disorders SUZANNE B. CASSIDY,* ELISABETH DYKENS, AND CHARLES A. WILLIAMS Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically distinct complex disorders mapped to chromosome 15q11-q13. They both have characteristic neurologic, developmental, and behavioral phe- notypes plus other structural and functional abnormalities. However, the cognitive and neurologic impair- ment is more severe in AS, including seizures and ataxia. The behavioral and endocrine disorders are more severe in PWS, including obsessive–compulsive symptoms and hypothalamic insufficiency. Both disorders can result from microdeletion, uniparental disomy, or an imprinting center defect in 15q11-q13, although the abnormality is on the paternally derived chromosome 15 for PWS and the maternally derived 15 for AS because of genomic imprinting. Although the same gene may control imprinting for both disorders, the gene(s) causing their phenotypes differ. AS results from underexpression of a single gene, UBE3A, which codes for E6-AP, a protein that functions to transfer small ubiquitin molecules to certain target proteins, to enable their degradation. The genes responsible for PWS are not determined, although several mater- nally imprinted genes in 15q11-q13 are known. The most likely candidate is SNRPN, which codes for a small nuclear ribonucleoprotein, a ribosome-associated protein that controls gene splicing and thus synthesis of critical proteins in the brain. Animal models exist for both disorders. The genetic relationship between PWS and AS makes them unique and potentially highly instructive disorders that contribute substantially to the population burden of cognitive impairment. Am. J. Med. Genet. (Semin. Med. Genet.) 97:136–146, 2000 ᮊ 2000 Wiley-Liss, Inc. KEY WORDS: Prader-Willi syndrome; Angelman syndrome; genetic imprinting; behavioral phenotype; uniparental disomy; microdeletion; chromosome disorder; mental retardation INTRODUCTION neurologic phenotype. These disorders them thus represents an important occupy an important place in the con- pathogenetic mechanism of cognitive Prader-Willi syndrome (PWS) and An- temporary history of human genetic impairment. gelman syndrome (AS) are two clini- disorders because of their unusual and PWS and AS are different in many cally distinct disorders each with a char- partially shared genetic basis. They are ways. Patients with PWS generally have acteristic cognitive, behavioral, and sometimes called sister disorders be- mild mental retardation, and individuals cause they are both the result of the with AS have severe impairment with absence or lack of expression of one absent speech. Multiple endocrine ab- Suzanne B. Cassidy, M.D., is a medical ge- parent’s contribution to the same re- normalities occur in PWS, whereas sig- neticist who is a Professor of Pediatrics and Director of Human Genetics at Uni- gion of the proximal long arm of chro- nificant neurologic deficits, including versity of California, Irvine. She has a mosome 15q (15q11-q13, the PWS/AS seizures and ataxia, are characteristic of long-standing interest in Prader-Willi region). The absent contribution to this AS. The affect of people with AS is syndrome, and has had a major hand in delineating its clinical, diagnostic, and region is invariably paternal in the case happy, with unprovoked laughter and genetic basis. of PWS and maternal in the case of AS. preference for water play, whereas Elisabeth Dykens, Ph.D., is a behav- ioral psychologist who is an Associate This phenomenon of parent-of-origin those with PWS tend to be relatively Professor of Psychiatry and Biobehav- difference in the expression of genes is discontent and have temper tantrums ioral Sciences at the U.C.L.A. Neuropsy- chiatric Institute. She has played a signifi- the consequence of genomic imprint- and obsessive–compulsive behavior. cant role in the delineation of cognitive ing in this region. Thus, the gene for However, they also share some clinical characteristics and behavioral pheno- types of genetic syndromes. AS and the gene(s) for PWS exhibit dif- findings, including the presence of Charles Williams, M.D., is a medical ferential expression depending on the infantile hypotonia and sometimes hy- geneticist who is Professor of Pediatrics sex of the parent from whom they were popigmentation, and they have in com- at University of Florida. He has been in- strumental in delineating the clinical inherited. Because PWS and AS each mon the presence in each of a distinc- characteristics and genetic basis for An- occurs in approximately 1/10,000– tive (although different) behavioral gelman syndrome. *Correspondence to: Division of 1/15,000 individuals, together they phenotype. In addition, they both dem- Human Genetics, Department of Pediat- represent a substantial contribution to onstrate similar genotype–phenotype rics, UCI Medical Center, Bldg. 2, 101 The City Drive, Orange, CA 92868. cognitive disability, and the nontradi- correlations. Thus, it is appropriate that tional form of inheritance that causes they be discussed together. © 2000 Wiley-Liss, Inc. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 137 The Common Genetic Basis of et al., 1999], although a few patients mechanism is unknown but could be PWS and AS have smaller or larger deletions. The sporadic. All families with recurrence of difference in frequency of UPD be- PWS studied to date have had an im- AS and PWS map to the same genetic tween PWS and AS is, in large part, printing mutation, but this is not true region at 15q11-q13. They each can be presumably because paternal nondis- the result of three shared genetic de- of AS. In AS, approximately 10–15% of junction is much less common than fects: microdeletion, uniparental di- cases are the result of a single gene maternal. Approximately 2–5% of pa- somy (UPD), and imprinting defects. mutation in one gene within 15q11- tients with either disorder have their Also, they share similar diagnostic q13, UBE3A, which codes for a ubiq- deletion or their UPD as a consequence methodologies, including analysis of uitin protein ligase [Kishino et al., of a translocation or other structural ab- the degree of methylation of the gene 1997; Matsuura et al., 1997]. In the re- normality involving chromosome 15. SNRPN within the PWS/AS region. maining 10%, the cause has not yet PWS is known to be caused by been identified. lack of expressed paternally inherited A number of imprinted and non- genes in chromosome 15q11-q13, . [P]atients with UPD imprinted genes have been found to ex- whereas AS is caused by lack of a single or imprinting defects [in ist within the PWS/AS critical region expressed gene, UBE3A, from the ma- (Table II; Figs. 1 and 2) [Nicholls, ternally inherited chromosome 15. In PWS or AS] have milder 1993; Buiting et al., 1994; Glenn et al., this region, the maternally inherited manifestations than those 1997]. However, for none of these genes is it clear how underexpression is genes related to PWS are normally not with deletions. expressed, having been rendered inac- involved in causing the disease pheno- tive because of genetic imprinting; like- types. The major exception is the non- wise, the paternally inherited UBE3A is imprinted P gene [Lee et al., 1994], normally not expressed because of im- Among those with a defect in the im- which codes for a tyrosine transporter printing. Table I reviews the genetic printing process, a proportion have gene whose deficiency results in the mechanisms that are known to cause been shown to have a very small dele- skin and ocular hypopigmentation that these two disorders, and the frequencies tion, mutation, or other abnormality in occur in 50–70% of those with PWS with which they occur. In approxi- the center that controls imprinting and AS with deletions. P protein defi- mately 70% of patients with PWS and a within 15q11-q13, the imprinting cen- ciency also causes strabismus, attribut- comparable number in AS, there is a ter (IC) [Ohta et al., 1999]. Others have able to aberrant chiasmal crossing of op- cytogenetically small deletion in chro- not had a detectable mutation or dele- tic nerve fibers that depend on normal mosome 15 between bands 15q11-q13, tion in the IC but nonetheless have bi- retinal pigment for proper growth and which is paternal in PWS and maternal parental-inheritance and a maternal- routing [Wiesner et al., 1987; King et in AS. In most cases, the same break- only (PWS) or paternal-only (AS) al., 1993]. Although AS is known to points on the chromosome have re- expression pattern [Buiting et al., result from a single gene defect, PWS is sulted in the same 4-Mb deletion 1998]. These individuals are said to caused by at least two genes. The best [Christian et al., 1995; Amos-Landgraf have an imprinting defect, and the candidate gene is SNRPN, discussed below. Upstream of the SNRPN gene, in a region called SNURF (SNRPN up- stream reading frame), is a putative im- TABLE I. Genetic Abnormalities in Prader-Willi (PWS) and printing control element (IC) for the Angelman Syndromes (AS) region [Gray et al., 1999] (Fig. 2). Very Frequency of genetic cause small deletions within it have been Recurrence risk identified in a few patients with AS or PWS (%) AS (%) (%) PWS despite biparental inheritance Deletion 15q11-q13 70 70 <1a [Saitoh et al., 1996]. GABRB3, Uniparental disomy 25–28 (maternal) 3–5 (paternal) <1a GABRA5, and GABRG3, are all non- Imprinting center defect 2–5 2–5 50b imprinted receptor subunit genes for ␥ Translocation within <1 <1 5–50b the neurotransmitter GABA ( -amino PWS/AS critical region butyric acid). There are also several Single gene mutation 0? 10–15 (UBE3A) 50b identified maternally imprinted genes Unknown 0? ∼10 ? and transcripts whose function is un- known. ZNF127 is an imprinted zinc- a Not yet reported.