Prader-Willi and Angelman syndromes: Sister imprinted disorders

Abstract

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 phenotypes plus other structural and functional abnormalities. However, the cognitive and neurologic impairment 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 maternally 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.

A new diagnostic workflow for patients with mental retardation and/or multiple congenital abnormalities: test arrays first

“…52 UPD, which arises when an individual inherits two copies of a chromosome pair from one parent and no copy of the other parent, can result in rare recessive disorders, or developmental problems because of the effects of imprinting. 53 Examples of genetic diseases linked to UPD include the Prader -Willi syndrome (MIM 176270), Angelman syndrome (MIM 105830), BeckwithWiedemann syndrome (MIM 130650) and Silver -Russell syndrome (MIM 180860). SNP array analysis is able to detect uniparental isodisomy and uniparental heterodisomy (when both parents are included in the experiment), but the interpretation of new UPD regions is difficult and further research is required to confirm the clinical consequences.…”

“…However, more recent studies have already mentioned the partial replacement of conventional karyotyping by molecular karyotyping. 53,57 In addition, Koolen et al 29 described a workflow for the clinical interpretation of CNVs in individuals with MR. Our results show that high-density SNP arrays can be successfully used as a tool for the detection of CNVs, low-level mosaicism and copy number neutral abnormalities. Their high resolution and commercial availability make them attractive to implement in a routine diagnostic setting.…”

The behavioural phenotype of Angelman syndrome

“…Table 1 here++++++++++++ Within a number of the studies, some reported clinical characteristics such as speech difficulties, ataxic gait and protruding tongue were often placed in different categories. For example ataxic gait has been categorised as a musculoskeletal (Zori, Hendrickson, Woolven, Whidden, Gray & Williams, 1992) or neurological phenomenon (Dorries, Spohr & Kunze, 1988) or behaviour characteristic (Cassidy, Dykens, Williams, 2000). For the purpose of this review, speech difficulties, ataxic gait and protruding tongue will not be categorised as behaviours, consistent with studies by Zori et al, (1992), Clayton-Smith and Laan (2003), and Clayton-Smith (1992).…”

The four Rs of RNA-directed evolution

“…One consequence of repeat deletion is failure to assemble and correctly segregate chromosomes during meiosis and mitosis 79 . Microdeletion in areas of SAT overlap, such as those observed in 70% of human Angelman and Prater-Willi syndromes 80 , may have a similar basis, as may chromosomal loss during oncogenesis. Deletion of retroelements from inverted repeats, such as those found in the human Y chromosome 81 , may be favored by the enhanced transcription and chromatin remodeling occurring during spermatogenesis 82 .…”