Prader-Willi syndrome: clinical genetics, cytogenetics and molecular biology

Abstract

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder that arises from lack of expression of paternally inherited genes known to be imprinted and located in the chromosome 15q11-q13 region. PWS is considered the most common syndromal cause of life-threatening obesity and is estimated at 1 in 10,000 to 20,000 individuals. A de novo paternally derived chromosome 15q11-q13 deletion is the cause of PWS in about 70% of cases, and maternal disomy 15 accounts for about 25% of cases. The remaining cases of PWS result either from genomic imprinting defects (microdeletions or epimutations) of the imprinting centre in the 15q11-q13 region or from chromosome 15 translocations. Here, we describe the clinical presentation of PWS, review the current understanding of causative cytogenetic and molecular genetic mechanisms, and discuss future directions for research.

Figures

Figure 1.. Ideogram of chromosome 15, showing genes located in the typical deletion region of Prader–Willi syndrome.

The locations of genes in this region, 15q11-q13, and their imprinting statuses are shown. The gene order is based on the UCSC Genome Bioinformatics website (http://genome.ucsc.edu). Approximately 40% of subjects with the typical deletion have the type I deletion, and approximately 60% have the type II deletion. Abbreviations: Cen, centromere; Tel, telomere; BP, breakpoint; IC, imprinting centre; snoRNA, small nucleolar RNA.

Figure 2.. Microsatellite patterns representing different Prader–Willi syndrome genetic subtypes.

Microsatellite patterns are generated by PCR amplification of specific highly polymorphic regions of the genome. The amplified fragments contain a fluorescent tag that is detected after capillary electrophoresis to separate the fragments based on size. The microsatellite patterns are from three different Prader–Willi syndrome (PWS) families. (a) Individuals with type I deletions have only one DNA peak with genotyping analysis using the proximally placed microsatellite marker D15S1035 located between breakpoints BP1 and BP2, indicating the chromosome break occurred at BP1. (b) Individuals with type II deletions have two DNA peaks for D15S1035 but only one peak for a second DNA marker, D15S822, located in the middle of the PWS critical region, indicating the deletion breakpoints at BP2 and BP3. (c) Individuals with maternal heterodisomy have two maternally derived DNA peaks for microsatellite markers from the 15q11-q13 region (e.g. D15S822) and no paternally derived peaks since the paternally derived chromosome is absent.

Figure 3.. Speculative diagram illustrating possible interconnected and interactive mechanisms leading to Prader–Willi syndrome.

Chromosome 15q11-q13 abnormalities in Prader–WIlli syndrome (PWS) lead to altered or lack of expression of genes in the region grouped into three categories (imprinted, biased or biallelic). In addition, expression of an interactive network of downstream genes is affected as a result of trans effects (for example due to loss of expression of 15q11-q13 genes involved in RNA processing) and cis effects (for example due to loss of or reduced expression of SGNE1, which might lead to poor transport and processing of proteins such as vasopressin). Many of these perturbations of gene expression might impact on RNA and/or protein processing/trafficking of neuroregulators/hormones. This in turn might lead to misregulation of neuronal development and endocrine dysfunction. The disruption of the expression of other genes, such as those encoding NDN (a cell cycle regulator), the GABA receptors (GABRB3, GABRA5) and olfactory receptors (OR4N4), might have more direct effects on neuronal function, and P (OCA2) disruption directly affects pigmentation. Representative examples of genes grouped according to their expression pattern and their presumed role in the clinical outcome are shown in the figure. Abbreviations: GABR, gamma aminobutyric acid receptor; Gpr15, G-protein-coupled receptor 15; HERC2, hect domain and RLD (renal cell carcinoma-like domain) 2; IPW, imprinted in Prader–Willi; MAGEL2, Mage-like 2; NDN, Necdin; NIPA1, not imprinted in PWS A1; OR4N4, olfactory receptor, family 4, subfamily N, member 4; P (OCA2), oculocutaneous albinism II; POMC, pro-opiomelanocortin; SGNE1, secretory granule neuroendocrine protein 1; snoRNAs, small nucleolar RNAs; SNRPN, small nuclear ribonucleoprotein N; SNURF, SNRPN upstream reading frame; Tcerg1, transcription elongation regulator 1.