Genetic enhancement of cognition in a kindred with cone-rod dystrophy due to RIMS1 mutation

Background

The genetic basis of variation in human cognitive abilities is poorly understood. RIMS1 encodes a synapse active‐zone protein with important roles in the maintenance of normal synaptic function: mice lacking this protein have greatly reduced learning ability and memory function.

Objective

An established paradigm examining the structural and functional effects of mutations in genes expressed in the eye and the brain was used to study a kindred with an inherited retinal dystrophy due to RIMS1 mutation.

Materials and methods

Neuropsychological tests and high‐resolution MRI brain scanning were undertaken in the kindred. In a population cohort, neuropsychological scores were associated with common variation in RIMS1. Additionally, RIMS1 was sequenced in top‐scoring individuals. Evolution of RIMS1 was assessed, and its expression in developing human brain was studied.

Results

Affected individuals showed significantly enhanced cognitive abilities across a range of domains. Analysis suggests that factors other than RIMS1 mutation were unlikely to explain enhanced cognition. No association with common variation and verbal IQ was found in the population cohort, and no other mutations in RIMS1 were detected in the highest scoring individuals from this cohort. RIMS1 protein is expressed in developing human brain, but RIMS1 does not seem to have been subjected to accelerated evolution in man.

Conclusions

A possible role for RIMS1 in the enhancement of cognitive function at least in this kindred is suggested. Although further work is clearly required to explore these findings before a role for RIMS1 in human cognition can be formally accepted, the findings suggest that genetic mutation may enhance human cognition in some cases.A genetic contribution to variation in human intelligence is well established, but the identities of the genes responsible remain elusive. Many mutations are associated with impaired cognition:¹ no definite genetic causes of enhanced cognition are established,² and there are no known cognition‐enhancing “gain‐of‐function” mutations in genes otherwise associated with cognitive impairment. Therapeutic possibilities deriving from the discovery of any such genes or variants are potentially important: cognitive decline reduces the quality of life,³ and low intelligence test scores are associated with increased morbidity and shorter life‐span.⁴ Accelerated evolution of genes subserving neurodevelopment figures in molecular explanations of the advance of the human nervous system: many of the identified genes regulate brain size and behaviour, some encoding critical synaptic proteins.⁵To identify genes influencing human brain development and function, including cognitive function, we use a paradigm evaluating cerebral structure and function in individuals with known mutations in genes co‐expressed in the lineage‐sharing eye and brain, ascertained by their obvious ocular phenotype, but in whom a neurological phenotype was not fully appreciated. Using this paradigm, we demonstrated roles for the genes PAX6, PITX2, SOX2 and OTX2 in human brain development, cognitive function and memory.^{6,7,8,9,10,11}We now report on the functional and structural effects of mutation in the eye‐ and brain‐expressed gene RIMS1, through the study of individuals from a family already reported to have retinal dystrophy caused by RIMS1 mutation.^12,13 To our knowledge, this is the only family so far reported with such a mutation: the eye phenotype is homogeneous in the family, and has been documented in detail.¹³ The orthologous murine Rim1α encodes a synaptic active‐zone protein necessary for preserving the normal probability of synaptic neurotransmitter release and for long‐term presynaptic potentiation.^14,15Rim1α is also expressed in retinal ribbon synapses.¹⁶ Mice lacking Rim1α protein show severely impaired learning and memory.¹⁷ In our kindred, RIMS1 mutation (Arg844His) causes a late‐onset dominantly inherited cone–rod dystrophy (CORD7; OMIM 603649), leading to varying degrees of visual loss starting from the third decade onwards.¹³ Because RIMS1/Rim1α is also expressed in the brain, we hypothesised that this RIMS1 mutation would produce a structural and functional neurological phenotype.