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Prader–Willi Syndrome: An Example of Genomic Imprinting
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Besides imprinted genes in the 15q11–q13 region, three gamma amino butyric acid receptor genes (GABRB3, GABRA5, and GABRG3) and the P gene for pigment production are located toward the telomere end of the 15q11–q13 region (5). The expression status of the GABA receptor genes has recently been studied with microarray technology and reported to have a paternal bias of expression (more expression from the paternal allele than from the maternal allele) that may impact on the phenotype (24). Mouse models for PWS, whereby the human chromosome equivalent (15q11–q13) located on mouse chromosome 7 is deleted, have also been produced and their phenotypes have also been described (25). By studying the phenotype of these mice with equivalent genetic anomalies seen in humans, a better understanding of the role of specific genes causing PWS will be gained. In addition, studies with animal models (e.g., transgenic knockout mice) involving single genes, such as SNRPN, have shown that loss of a single specific candidate gene does not necessarily correlate with the PWS phenotype. Therefore, PWS is termed a contiguous gene syndrome with several genes involved.
Prader-Willi syndrome and Angelman syndrome: Visualisation of the molecular pathways for two chromosomal disorders
Published in The World Journal of Biological Psychiatry, 2019
Friederike Ehrhart, Kelly J. M. Janssen, Susan L. Coort, Chris T. Evelo, Leopold M. G. Curfs
The last pathway section contains four genes that are involved in PWS as well as in AS (Figure 10). Although, they are not imprinted in the same way as the PWS- and AS-causing genes, which would lead to a complete loss of the gene product, the gene doses are reduced. GABRB3 is the main actor here, as it stimulates the transcription of GABRA5, GABRG3 and OCA2 (Delahanty et al. 2016). GABRB3, GABRA5 and GABRG3 all encode a subunit of the GABA(A) receptor. Expression of GABRB3 was found in embryonic stem cells and neural crest stem cells (Delahanty et al. 2016). These cells are known to give rise to various cells, including melanocytes. What role GABRB3 plays in the differentiation of those stem cells is unknown, visualised by dashed lines in the pathway. A lack of subunit β-3 impairs the function of the GABA(A) receptor, causing problems in rapid inhibitory synaptic transmission in the central nervous system (Homanics et al. 1997). This can lead to epilepsy, cleft palate and hypersensitive behaviour, especially in the case of AS together with the loss of UBE3A induced dysfunction of the GABAergic neurons (Greer et al. 2010; Judson et al. 2016). Loss of GABRA5 and GABRG3 also impair GABA(A) receptor function (and there is recent evidence that the GABA levels are also decreased in PWS patients (Rice et al. 2016)). This mechanism could also play a role in the development of these disorders in humans, but this has not yet been proven. OCA2 encodes the P-protein, which is known to be important in the production of melanin (Delahanty et al. 2016). The loss of GABRB3 alone causes expression of OCA2 to be impaired, leading to hypopigmentation. In PWS and AS, both genes are deleted, probably enhancing that effect.