Polymorphisms in CRYBB2 encoding βB2-crystallin are associated with antisaccade performance and memory function

Abstract

βB2-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. Decreased PPI and alterations of parvalbumin-positive interneurons are also endophenotypes that typically occur in schizophrenia. To verify the results found in mice, we genotyped 27 single nucleotide polymorphisms (SNPs) within the CRYBB2 gene and its flanking regions and investigated different schizophrenia typical endophenotypes in a sample of 510 schizophrenia patients and 1322 healthy controls. In the case-control study, no association with schizophrenia was found. However, 3 of the 4 investigated haplotype blocks indicated a decreased CRYBB2 mRNA expression. Two of these blocks were associated with poorer antisaccade task performance and altered working memory-linked functional magnetic resonance imaging signals. For the two haplotypes associated with antisaccade performance, suggestive evidence was found with visual memory and in addition, haplotype block 4 showed a nominally significant association with reduced sensorimotor gating, measured as P50 ratio. These results were not schizophrenia-specific, but could be detected in a combined sample of patients and healthy controls. This is the first study to demonstrate the importance of βB2-crystallin for antisaccade performance and memory function in humans and therefore provides implications for βB2-crystallin function in the human brain.

Insights into the biochemical and biophysical mechanisms mediating the longevity of the transparent optics of the eye lens

“…(1) Embryologically, the lens begins as a placode of a few elongated and swollen cells at the periphery of the neural ectoderm in the trilaminar embryo. It is unsurprising that many important molecular components are common to both neurons and elongated lens fiber cells (35)(36)(37). (2) Lens development begins at approximately 50 days embryonic age, and all cells are retained for its lifetime.…”

Physiological and pathological functions of βB2-crystallins in multiple organs: a systematic review

“…Mutations in the mouse Crybb2 gene give rise to alterations in prepulse inhibition (PPI; an operational measurement of sensorimotor gating) and reduce hippocampal size, i.e., features typical of patients with schizophrenia [55,93,94]. Studies in mutant Crybb2 Philly , Crybb2 Aey2 , and Crybb2 O377 mice revealed C-terminal mutations of the βB2crystallin protein, likely associated with abnormal Ca 2+ binding, which correlated with consistent alterations in adult behavior and evolution of neuropsychiatric disorders [56,93,95].…”

“…Gene analysis of a dominant cataract mouse model unmasked a crybb2 mutation and revealed that βB2crystallin is expressed within distinct regions of the brain [22]. The Crybb2 transcript was best detected in the brain during postnatal development and through adolescence and was expressed predominantly in neurons of the olfactory bulb (mitral cell layer and glomerular layer), hippocampus (pyramidal cells of the CA1, CA2, and CA3 regions and granule cells of the dentate gyrus), cerebral cortex (pyramidal cells throughout all layers), and cerebellum (Purkinje cells and stellate cells of the molecular layers) [22,55,56]. As illustrated in animal models of optic nerve injury and axonal regeneration, mounting evidence highlights βB2-crystallin as a momentous factor that operates through autocrine and paracrine mechanisms to support axonal growth and repair, at least in part by accelerating the production of ciliary neurotrophic factor (CNTF) [49,51,57].…”