title: 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 is 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 frequently been 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.
authors.affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37212, USA; Department of Human Genetics, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Delahanty
authors.affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
authors.forename: Terry Jo
authors.initials: TJ
authors.lastname: Bichell
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
authors.forename: Wangzhen
authors.initials: W
authors.lastname: Shen
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
authors.forename: Kelienne
authors.initials: K
authors.lastname: Verdier
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37212, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212, USA; Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Macdonald
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Xu
authors.affiliation: Pathology Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
authors.forename: Kelli
authors.initials: K
authors.lastname: Boyd
authors.affiliation: Vanderbilt Electron Microscopy Core, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Williams
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA; Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN 37212, USA. Electronic address: jingqiong.kang@vanderbilt.edu.
authors.forename: Jing-Qiong
authors.initials: JQ
authors.lastname: Kang
mesh_terms: D017204:Angelman Syndrome / Q000150:complications / Q000235:genetics / Q000473:pathology; D000818:Animals; D001321:Autistic Disorder / Q000150:complications / Q000235:genetics* / Q000473:pathology; D004827:Epilepsy / Q000150:complications / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D018392:Genomic Imprinting; D006801:Humans; D017496:Hypopigmentation / Q000235:genetics* / Q000473:pathology; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D009154:Mutation; D011218:Prader-Willi Syndrome / Q000150:complications / Q000235:genetics / Q000473:pathology; D011963:Receptors, GABA-A / Q000235:genetics*
chemical_list: C546273:GABRB3 protein, human; C546270:Gabrb3 protein, mouse; D026901:Membrane Transport Proteins; C489600:OCA2 protein, human; D011963:Receptors, GABA-A
keywords: Angelman syndrome; GABA(A) receptors; GABRB3; OCA2; UBE3A; autism; deletion; epilepsy; eye; hypopigmentation