Last Updated February 27, 2023
Introduction to Prader-Willi Syndrome
Prader-Willi syndrome (PWS) was first described in 1887 by John Langdon Down who also identified Down syndrome. The full spectrum of PWS was reported in 1956 by Andrea Prader, Alexis Labhart, and Heinrich Willi, hence the current name of the disorder.
Prader-Willi syndrome and Angelman syndrome (AS) were the first diseases associated with the process of genomic imprinting. Although the symptoms of these two disorders are quite different it was shown in 1989 that both are caused by alterations in the pattern of genomic imprinting in the same region of chromosome 15. However, the distinct clinical spectrum of PWS and AS results as a consequence of the parental origin of the chromosome 15 alteration. Chromosomal region 15q11.2–q13 contains a cluster of imprinted genes with relevance to these two distinct neurogenetic disorders.
PWS results from the loss of a group of paternal-specific expressed genes in the chromosome 15q11.2-q13 region, whereas, AS results from loss of a maternal-specific expression, within neurons, of a ubiquitin ligase gene (UBE3A) in the same chromosomal region.
Molecular Biology of Prader-Willi Syndrome
Complex Gene Expression from the 15q11.2-q13 Domain
Analysis of the region of chromosome 15q11.2-q13 has identified several imprinted and non-imprinted genes as well as the AS imprinting control (AS-IC) region and the Prader-Willi imprinting control (PW-IC) region. There are 16 characterized genes in this region of chromosome 15 and a complex locus identified as small nucleolar RNA host gene 14 (SNHG14). Of these 16 genes, 10 are expressed from both the paternal and maternal chromosomes.
The 10 genes expressed from both chromosomes are, in centromere to telomere order, NIPA1 (NIPA magnesium transporter 1, where NIPA=nonimprinted in Prader-Willi/Angelman syndrome), NIPA2 (NIPA magnesium transporter 2), CYFIP1 (cytoplasmic FMR1 interacting protein 1, where FMR1 is the fragile X syndrome gene), TUBGCP5 (tubulin gamma complex associated protein 5), ATP10A (aminophosphoplipid-transporting ATPase), GABRB3 (gamma-aminobutyric acid type A receptor subunit beta3), GABRA5 (gamma-aminobutyric acid type A receptor subunit alpha5), GABRG3 (gamma-aminobutyric acid type A receptor subunit gamma3), OCA2 (OCA2 melanosomal transmembrane protein, where OCA2=oculocutaneous albinism 2), and HERC2 (HECT and RLD domain containing E3 ubiquitin protein ligase 2).
The imprinted genes in the 15q11.2-q13 locus are MKRN3 (makorin ring finger protein 3), MAGEL2 (MAGE-like protein 2, where MAGE family are melanoma antigen proteins), NDN (necdin), NPAP1 (nuclear pore associated protein 1), SNRPN (small nuclear ribonucleoprotein N), and UBE3A (ubiquitin ligase E3A). The MKRN3 encoded protein is a member of a protein family that functions as ubiquitin ligases. Expression of the NDN gene predominates in post mitotic neurons.
All but the UBE3A gene are hypermethylated on the maternal chromosome and as a result are only expressed from the paternal chromosome. The UBE3A gene is only expressed in neurons from the maternal chromosome due to the paternal expression of the SNRPN gene which is transcribed across the SNHG14 locus forming a long non-coding RNA that interferes with paternal expression of the UBE3A gene.
The SNHG14 locus contains 148 exons and undergoes complex alternative splicing. In addition to the transcriptional complexity of the SNHG14 gene, the introns of the SNHG14 locus encode several small nucleolar RNAs (snoRNAs). The promoter region controlling expression of both the SNRPN and the SNHG14 locus is methylated on the maternal chromosome and therefore not expressed.
Molecular Etiology of Prader-Willi Syndrome
Causes of PWS have been shown to be the result of three primary mechanisms. The most common cause (65%-75% of cases) of PWS is deletion of a 5–7 Mb region from the paternal chromosome 15q11.2-q13 domain. The deletions are the result of non-homologous recombination events that are mediated by repetitive sequence elements that define a series of breakpoint cluster regions on either side of the imprinted chromosome 15q11.2-q13 domain. In 20%-30% of PWS patients the disorder is the result of maternal uniparental disomy (UPD). A small percentage (1%-3%) of PWS patients are the result of defects in the Prader-Willi imprinting control region (PW-IC) that controls the imprinting process.
Clinical Spectrum of Prader-Willi Syndrome
PWS is characterized a failure to thrive in the neonatal period accompanied by muscular hypotonia. During early childhood PWS patients exhibit hyperphagia (excessive hunger and abnormally large intake of solid foods), obesity, hypogonadism, sleep apnea, behavior problems, and mild to moderate intellectual impairment. Hypogonadism is present in both males and females. The characteristics of the hypogonadism are genital hypoplasia, incomplete pubertal development, and, in most patients there is infertility. A distinctive behavioral phenotype of PWS is temper tantrums, stubbornness, and manipulative and compulsive behaviors.
Additionally, PWS children have small hands and feet. In prepubertal males the hypogonadism results in sparse body hair, poor development of skeletal muscles, and delay in epiphyseal closure which resulting in long arms and legs. Short stature is common in PWS patients as a result of insufficiency in growth hormone (GH) production and secretion. PWS patients often present with characteristic facial features, strabismus, and scoliosis. The tendency to obesity is highly correlated to the development of type 2 diabetes in PWS patients.