Polymorphisms in CRYBB2 encoding alpha-B2-crystallin are associated with sensorimotor gating and memory function

Introduction alpha-B2-crystallin (gene symbol: Crybb2/CRYBB2) was first described as a structural protein of the ocular lens before it was detected in various brain regions of the mouse, including the hippocampus and the cerebral cortex. Mutations in the mouse Crybb2 gene lead to alterations of sensorimotor gating measured as prepulse inhibition (PPI) and reduced hippocampal size, combined with an altered number of parvalbumin-positive GABAergic interneurons. Both are endophenotypes that typically occur in schizophrenia. The aim of this study was to investigate, whether CRYBB2 variants are associated with schizophrenia and schizophrenia related endophenotypes.

Methods 27 single nucleotide polymorphisms (SNPs) within the CRYBB2 gene and its flanking regions were genotyped using Matrix-assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) in a sample of 510 schizophrenia patients and 1322 healthy controls. CRYBB2 mRNA expression in lymphocytes, PPI, antisaccades, memory and working memory including functional magnetic resonance imaging were investigated. Association analyses between multimarker haplotypes and endophenotypes were calculated using the R software package “haplo.score”.

Results In the case-control study, no association with schizophrenia was found. However, a haplotype at the 3′-end of CRYBB2 was associated with reduced sensorimotor gating, measured as P50-ratio. Two other haplotypes were associated with a decreased mRNA expression of CRYBB2, poorer antisaccade task performance, and altered working memory-linked functional magnetic resonance imaging signals. These results were not schizophrenia-specific, but could be detected in patients and healthy controls separately as well as in the combined group.

Conclusion This is the first study to demonstrate the importance of bB2-crystallin for sensorimotor gating and memory function in humans and therefore provides implications for bB2-crystallin function in the human brain. Replication and functional studies are needed to better understand the role of CRYBB2 in the human brain.