Beyond Epilepsy and Autism: Disruption of GABRB3 Causes Ocular Hypopigmentation

Abstract

Reduced ocular pigmentation is common in Angelman syndrome (AS) and Prader-Willi syndrome (PWS) and long thought to be caused by OCA2 deletion. GABRB3 is located in the 15q11-13 region flanked by UBE3A, GABRA5, GABRG3 and OCA2. Mutations in GABRB3 have been frequently associated with epilepsy and autism, consistent with its role in neurodevelopment. We report here a robust phenotype in the mouse in which deletion of Gabrb3 alone causes nearly complete loss of retinal pigmentation due to atrophied melanosomes, as evidenced by electron microscopy. Using exome and RNA sequencing, we confirmed that only the Gabrb3 gene was disrupted while the Oca2 gene was intact. However, mRNA abundance of Oca2 and other genes adjacent to Gabrb3 is substantially reduced in Gabrb3−/− mice, suggesting complex transcriptional regulation in this region. These results suggest that impairment in GABRB3 downregulates OCA2 and indirectly causes ocular hypopigmentation and visual defects in AS and PWS.

Epigenetics in Prader-Willi Syndrome

“…Furthermore, both transcript and protein levels of GABRB3 were not correlated with copy number in an analysis of PWS, AS, and 15q11.2-13.3 duplication syndrome postmortem brain ( Scoles et al, 2011 ). A recent study on phenotypes and gene expression patterns in a Gabrb3 deletion mouse model is also consistent with complex gene regulation, as neighboring Oca2 expression was reduced and ocular hypopigmentation observed ( Delahanty et al, 2016 ). Dysregulated gene expression of the 15q11.2-13.3 GABA A receptors is expected to have consequences for the balance of inhibitory and excitatory signals that regulate sleep, metabolism, and mood in PWS.…”

Distinguishing patients with idiopathic epilepsy from solitary cysticercus granuloma epilepsy and biochemical phenotype assessment using a serum biomolecule profiling platform

“…Thrombospondin-1 (THBS1) and DNA topoisomerase 3-beta-1 (TOP3B), proteins reported to be associated with various forms of epilepsy [31,33,55], were also overrepresented in SCG patients compared with IE [31,33,55]. Other notable findings included higher observation in the IE group compard to the SCG group of SLIT2 (Slit Guidance Ligand 2 protein), an extracellular matrix protein and member of the SLIT family of proteins which has a role(s) in the blood brain barrier (BBB) integrity [37,56] The mitochondrial protein MT-ND1 with epilepsy background was also found to be observed more in the IE group compared to the SCG group (40).…”

“…A PubMed/Medline literature search showed 53% of these differentially expressed proteins were related to neurological function, 36% to immune/inflammation, and 19% to seizures. Notable epilepsy/seizure related proteins (shaded cells in Table 3) include CACNA2D2 [30], THBS1 [31], VLDLR [30,32], THBS1 [31], VLDLR [32], TOP3B [33], VWF [34,35], KIF1A [36], SLIT2 [37], MT-ND1 [38], EPHB2 [39], OCA2 [40], AKAP11 [41], ADAM11 [42], MAOB [43], and VPS13D [44].…”

Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy

“…We also found that four of the six (66.7%) patients in our cohort showed hypopigmentation, which is commonly seen in PWS but not previously reported in SYS. Hypopigmentation is thought to be caused by a dysfunction of OCA2 or GABRB3 [21], not by MAGEL2, and thus it was not expected. Yet, since our cohort was initially suspected of having PWS, an inclusion bias may be present.…”