ReviewMouse models of Prader–Willi Syndrome: A systematic review
Highlights
► First comprehensive summary of phenotypes of all know PWS mouse models. ► Comparison of differences on single gene mutant models. ► Highlighting the similarities of single gene mutant mice to the human PWS features.
Introduction
Prader–Willi Syndrome (PWS) is a complex neurogenetic disorder with a worldwide prevalence of 1 in 15,000–30,000 (Cassidy and Driscoll, 2009). It is caused by loss of expression of imprinted, paternally inherited genes located on human chromosome 15q11-q13. Genomic imprinting is an epigenetic phenomenon that results in the expression of some genes from only one of the two parental chromosomes, thus leading to silencing of the other copy (Reik and Walter, 2001). Approximately 70% of the individuals with PWS have large deletions (∼4 Mb) of their paternal 15q11-q13 region, while 25% have maternal uniparental disomy and 3% show mutations involving the Imprinting Center (IC, 3%) (Butler, 2011, Ohta et al., 1999). Clinically, there are two stages in the typical course of PWS: an early stage characterised by neonatal hypotonia with poor suck leading to failure to thrive, often necessitating assisted feeding, and a second stage with onset in early childhood, marked by hyperphagia, which, if uncontrolled, leads to the development of morbid obesity with consequent complications such as diabetes and the metabolic syndrome. Other cardinal features of PWS are short stature with small hands and feet due to GH-deficiency, typical dysmorphic facial features, hypogonadism and poor developed genitalia, pain insensitivity, intellectual disability with abnormal behaviours like skin picking, obsessive–compulsive traits and stubbornness (Butler, 2011). Indeed, some of these features (hypogonadism, GH-deficiency and hyperphagia) are suspected to be related to a functional defect at hypothalamic level, although the mechanisms leading to the typical eating behaviour are not yet fully understood (Cassidy, 1997; Goldstone, 2004).
The PWS imprinted cluster in human chromosome 15q11-q13 has its orthologous locus on mouse chromosome 7C (Nicholls et al., 1998) (Fig. 1). This region contains all the corresponding protein-coding homologous genes with the exception of the presence of the Frat3 gene in the mouse, and the absence of the C15ORF2 gene and the non-coding snoRNA genes SNORD108 and SNORD109A/B (Relkovic and Isles, 2011). The genes are in the same order in human and mouse, but reversed with respect to the centromere. This almost identical PWS gene cluster in the mouse genome opened up the opportunity to dissect out and identify the critical genes responsible for this condition. Several multiple gene as well as single gene knockout models have been developed in the last two decades, resulting in a wide range of phenotypes, each one bearing some of the features of the human PWS phenotype. This review will specifically focus on these mouse models and what we have learned about their role in the pathogenesis of this multisystem syndrome.
Section snippets
Mouse models with large deletion at the PWS locus
In humans with PWS, the size of the deletion in the PWS locus on chromosome 15q11q13 is variable, but it almost always encompasses multiple genes, suggesting that it is a contiguous gene syndrome. Based on this observation, some mouse models bearing a deletion of the entire PWS critical region have been generated. The very first PWS mouse model was generated by Cattanach et al. (1992) using intercrosses between mice harbouring translocations to derive progeny with maternal duplication of the
Single gene knockout mouse models
Human studies have showed that deletions in PWS patients can differ considerably in size and location. However, some genes are regarded as critical since their deletion is commonly observed in molecular studies of humans with PWS: these are the SNURF-SNRPN gene and the adjacent Imprinting Center, the MAGEL2 and the NECDIN gene, and the SNORD116 gene cluster. Specific knockout mouse models have been generated accordingly for each of these genes.
Conclusion
Mouse models of PWS have considerably improved our knowledge about this complex disorder, although many questions still remain unanswered. The results of the studies conducted on these models also confirmed that the human PWS phenotype is a consequence of the loss of expression of multiple, rather than single genes. Hence, it is not surprising that, although each one of the single gene knockout models shows some features reminiscent of the human PWS phenotype, none of them reproduces the
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