Prader-Willi syndrome: are we any closer to better help affected children?

Prader-Willi syndrome phenotype, at 15 years of age . Note absence of typical PWS facial features and presence of mild truncal obesity (Author: Schüle B et al via Wikimedia).

May was a Prader-Willi Syndrome awareness month and these days are an ideal time to learn more about this devastating genetic disease, its molecular background and scientific endeavors to find targeted treatments to help affected children.

Prader–Willi syndrome (PWS) is a complex neurodevelopmental disorder that occurs in 1 to 15,000 – 30,000 births worldwide. In Slovenia we have 1-2 births per year.

Although considered a “rare” disorder, PWS is one of the most commonly diagnosed genetic diseases and the most frequent genetic cause of obesity. Immediately after birth, PWS babies are severely hypotonic and have feeding problems. During first years of life they fail to thrive and their development is delayed. They also have breathing defects and gradually acquire multiple endocrine dysfunctions and specific behavioral traits. In particular, at 2-4 years of age they drastically change their feeding behavior and become hyperphagic what leads to quick weight gain and severe obesity (Figure 1). In addition, PWS children exhibit several other behavioral problems, including skin picking, repetitive behaviors, difficulty with routine changes and great emotional lability. Several PWS children are also diagnosed as autists. Children with PWS and their families face many challenges and frequently require medical care and special assistance.

FIGURE 1: By Fanny Cortés M1, M. Angélica Alliende R1,a, Andrés Barrios R1,2, Bianca Curotto L1,b, Lorena Santa María V1,c, Ximena Barraza O3, Ledia Troncoso A2, Cecilia Mellado S4,6, Rosa Pardo V [CC BY 4.0 (], via Wikimedia Commons.

The culprit of this genetic disease lies in a small region of chromosome 15, referred to q11-q13 (Figure 2). This region is imprinted what means that genes have to be expressed from father’s chromosome. PWS occurs when one or more genes in this specific region are not expressed. There are 3 common ways that this can happen: 1) deletion of the paternal chromosome 15 (found in about 70% of patients); 2) loss of the entire paternal chromosome 15 and instead there are two chromosomes 15 inherited from mother, which is called maternal uniparental disomy 15 (25%); or 3) deficiency in the normal expression of the relevant genes due to an imprinting defect (found in 5% or less). The multigenic nature of PWS has complicated studies and our understanding of the contribution of individual genes to the PWS phenotypes as most patients have lost expression of all these genes. Consequently, the molecular mechanisms behind the symptoms are mostly unknown and current therapies are predominantly symptomatic from hormone replacement to behavior management.

Recently, a few cases have provided insights into which genes within the region may account for specific phenotypes. MAGEL2 is one of the 6 protein-coding genes in this maternally imprinted PWS region (Figure 2).

FIGURE 2: Schematic representation of the genetic architecture within the PWS cluster in human Chromosome 15. In the PWS region, there are several paternal-only expressed protein coding genes (blue and red) and non-coding RNAs (in gray). 

Recently, children with nonsense mutations in the paternal copy of MAGEL2 have been identified with a PWS-like syndrome, now known as Schaaf-Yang syndrome (SHFYNG). SHFYNG kids have several symptoms typically seen in PWS, but they don’t develop severe hyperphagia and morbid obesity and have instead some symptoms not typically seen in classic PWS, such as joint contractures and higher prevalence of autism spectrum disorder (ASD). Interestingly, mice with a targeted deletion of Magel2 recapitulate fundamental aspects of PWS and SHFYNG, additionally implying an important role of MAGEL2 in the pathogenesis of these disorders.

MAGEL2 is a member of a protein family called melanoma antigens (MAGEs), proteins that are often expressed in cancer.

On molecular level these proteins regulate E3 ubiquitin ligases and control ubiquitination of proteins in cells (Figure 3). Ubiquitin is a small protein that labels other proteins for specific destiny in cell. Ubiquitination is carried out in three steps by ubiquitin-activating (E1s), ubiquitin-conjugating (E2s), and ubiquitin ligase enzymes (E3s) that finally attach ubiquitin to the target proteins. Diverse ubiquitin codes tag proteins for different functions or direct them for degradation. MAGE proteins regulate this process by different ways to specify target proteins and enhance the ubiquitination reaction.

FIGURE 3: MAGE proteins regulate RING E3 ubiquitin ligases and control ubiquitination of the proteins. 

MAGEL2 binds to E3 ubiquitin ligase TRIM27 and enables translocation of TRIM27 to the endosomes where ubiquitination reaction takes place (Figure 4). At the endosomes, MAGEL2-TRIM27 regulate proper intracellular sorting of selected membrane proteins. Endosome is a major protein-sorting hub in cells. It consists of interconnected network of membranous compartments which receive and sort proteins to proper location in cell. MAGE-L2 is essential for recycling of membrane proteins from endosomes back to the plasma membrane and thus prevents them from being degraded in the lysosome and lost (Figure 4).

FIGURE 4: In hypothalamic neurons MAGEL2 facilitates endosomal protein sorting and recycling of proteins to plasma membrane. Disruption of MAGEL2 in PWS and SHFYNG results in aberrant protein degradation in lysosomes. Loss of hypothalamic proteins leads to disrupted hypothalamic function and symptoms seen in PWS and SHFYNG children. Restoring MAGEL2 function may represent novel therapeutic options for patients.

MAGE-L2 is highly expressed in the brain, specifically in the hypothalamus that controls several important physiological functions, such as growth, appetite and behavior. Currently it is not know exactly which proteins are recycled by the MAGEL2. However, several symptoms and phenotypes seen in patients and mice suggest improper level and function of numerous hypothalamic hormones and neurotransmitters (such as serotonin, orexin, leptin and oxytocin). Now, research efforts are focused towards identifying these proteins that rely on MAGEL2 for proper function and try to save them from degradation. This will open new therapeutic options for more targeted treatments to improve quality of life of PWS and SHFYNG children.

For references see:

  1. Fon Tacer K. and Potts, R.P. Cellular and disease functions of the Prader–Willi Syndrome gene MAGEL2. Biochemical Journal 2017. In press.
  3. Sabina Konkolič, Prader-Willijev sindrom: vzgojno-izobraževalni profil. Magistrsko delo. Pedagoška fakulteta Univerze v Ljubljani. 2014.
Več od Klementina Fon Tacer

Prader-Willi syndrome: are we any closer to better help affected children?

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