The ADGRB3 gene encodes a member of the adhesion-G protein-coupled receptor family, which includes proteins having a pivotal role in the development and maintenance of the central nervous system, particularly as regulators of synaptic development and plasticity (summary by Scuderi et al., 2019).

Shiratsuchi et al. (1997) identified 2 novel human genes homologous to BAI1 (602682), an angiogenesis inhibitor that is a candidate for involvement in development of glioblastoma. Like BAI1, these 2 genes, designated BAI2 (602683) and BAI3, were specifically expressed in brain, and are likely to be expressed in the same type of cells. However, in spite of similar tissue specificity among the 3 BAI genes, only BAI1 is transcriptionally regulated by p53. BAI3 expression was absent in 2 of 9 glioblastoma cell lines examined and was significantly reduced in 3 of the remaining 7. These findings suggested that BAI3 may play an important role in suppression of glioblastoma.

ADGRB3 is almost exclusively expressed in the brain, where it localizes to excitatory synapses (summary by Scuderi et al., 2019).

Shiratsuchi et al. (1997) mapped the BAI3 gene to 6q12 by fluorescence in situ hybridization.

By immunoprecipitation analysis, Bolliger et al. (2011) showed that all 4 mouse C1ql proteins (see 615227) interacted with human BAI3. The interactions required divalent cations, most likely Ca(2+). Binding was mediated by the gC1q domains of the C1ql proteins and the thrombospondin repeats of BAI3.

In 2 sibs, born of consanguineous parents, with cerebellar ataxia and a complex neurobehavioral disorder, Scuderi et al. (2019) identified a homozygous biallelic intragenic duplication within the ADGRB3 gene. The duplication breakpoints mapped to intron 3 and intron 17 and resulted in a direct duplication involving exons 4 to 17. The duplication, which was identified by a combination of FISH, SNP/CGH array, MLPA assay, and Sanger sequencing, was found in the heterozygous state in each parent. Since ADGRB3 is almost exclusively expressed in the brain, it was not possible to characterize the abnormal transcript. However, the duplication was predicted to result in a frameshift, premature termination, and most likely nonsense-mediated mRNA decay with a loss of function. The sibs, who were 36 and 32 years of age at the time of the report, had mild developmental delay in early childhood. Features included delayed walking with an unstable gait, tremor, speech delay, and strabismus. In the teenage years, the patients showed cerebellar ataxia, intellectual disability, memory difficulties, and affective emotional issues, such as anxiety and mood instability. One sib, who developed seizures at age 11 during an infection, had a more severe phenotype with prominent psychiatric symptoms, such as inappropriate laughing, social closure, and hallucinations, and severe intellectual disability (IQ of 41). Additional features in both patients included dysarthria or scanning speech, nystagmus, postural and intention tremor, dysmetria, dysdiadochokinesia, ataxic gait, poor coordination, mild muscle weakness with hyperreflexia, scapular winging, lumbar hyperlordosis, dorsal hyperkyphosis, and flat feet. Brain imaging showed moderate cerebral and cerebellar atrophy, with predominant vermis atrophy. The parents had a milder phenotype with normal cognitive function: the father presented with hallucinations, mood alterations, aggression, psychomotor agitation, and insomnia in his forties, whereas the mother had an anxious/depressive disorder and restless legs syndrome. Brain imaging in the parents showed white matter signal abnormalities, moderate cerebral atrophy, and mild cerebellar vermis atrophy. Scuderi et al. (2019) noted that ADGRB3 had been shown to regulate excitatory synapse connectivity and formation during mouse cerebellum development, and also to play a role in the regulation of synaptic density in the hippocampus.