ORIGINAL ARTICLE

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

Sanjay M Sisodiya¹, Pamela J Thompson¹, Anna Need², Sarah E Harris³, Michael E Weale², Susan E Wilkie⁴, Michel Michaelides⁴, Samantha L Free¹, Nicole Walley², Curtis Gumbs², Dianne Gerrelli⁵, Piers Ruddle⁵, Lawrence J Whalley⁶, John M Starr⁷, David M Hunt⁴, David B Goldstein², Ian J Deary³, Anthony T Moore⁴

¹ Department of Clinical and Experimental Epilepsy, Institute of Neurology, UCL, Queen Square, London, UK
² Center for Population Genomics and Pharmacogenetics, Institute for Genome Sciences and Policy, Duke University, North Carolina, USA
³ Department of Psychology, University of Edinburgh, Edinburgh, UK
⁴ Institute of Ophthalmology, UCL, London, UK
⁵ Human Developmental Biology Resource, Institute of Child Health, UCL, London, UK
⁶ Department of Mental Health, University of Aberdeen, Aberdeen, UK
⁷ Department of Geriatric Medicine, University of Edinburgh, Edinburgh, UK

Correspondence to:
S M Sisodiya
Department of Clinical and Experimental Epilepsy, National Hospital for Neurology and Neurosurgery, Box 29, Queen Square, London WC1N 3BG, UK; sisodiya{at}ion.ucl.ac.uk

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.

Abbreviations: LBC, Lothian birth cohort; LOD, logarithm of odd; SNP, single-nucleotide polymorphism; VIQ, verbal IQ

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