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Genetic enhancement of cognition in a kindred with cone-rod dystrophy due to RIMS1 mutation
  1. Sanjay Sisodiya (sisodiya{at}ion.ucl.ac.uk)
  1. Inst of Neurology, UCL, United Kingdom
    1. Pamela Thompson (pam.thompson{at}epilepsynse.org.uk)
    1. Institute of Neurology,UCL, United Kingdom
      1. Anna Need (anna.need{at}duke.edu)
      1. Center for Population Genomics and Pharmacogenetics, Institute for Genome Sciences and Policy, Duke, United States
        1. Sarah Harris
        1. MRC Human Genetics Centre, Edinburgh, United Kingdom
          1. Michael Weale (mweale{at}duke.edu)
          1. Center for Population Genomics and Pharmacogenetics, Institute for Genome Sciences and Policy, Duke, United States
            1. Susan Wilkie (s.wilkie{at}ucl.ac.uk)
            1. Institute of Ophthalmology, UCL, United Kingdom
              1. Michel Michaelides (drmichelmichaelides{at}hotmail.com)
              1. Institute of Ophthalmology, UCL, United Kingdom
                1. Samantha Free (s.free{at}ion.ucl.ac.uk)
                1. Institute of Neurology, UCL, United Kingdom
                  1. Nicole Walley (nicole.walley{at}duke.edu)
                  1. Center for Population Genomics and Pharmacogenetics, Institute for Genome Sciences and Policy, Duke, United States
                    1. Curtis Gumbs
                    1. Center for Population Genomics and Pharmacogenetics, Institute for Genome Sciences and Policy, Duke, United States
                      1. Diane Gerrelli (d.gerrelli{at}ich.ucl.ac.uk)
                      1. ICH, UCL, United Kingdom
                        1. Piers Ruddle
                        1. ICH, UCL, United Kingdom
                          1. Lawrence Whalley
                          1. Department of Mental Health, University of Aberdeen, United Kingdom
                            1. John Starr
                            1. Departments of Psychology and Geriatric Medicine, University of Edinburgh, United Kingdom
                              1. David Hunt
                              1. Institute of Ophthalmology, UCL, United Kingdom
                                1. Goldstein David
                                1. Center for Population Genomics and Pharmacogenetics, Institute for Genome Sciences and Policy, Duke, United States
                                  1. Ian Deary
                                  1. Departments of Psychology and Geriatric Medicine, University of Edinburgh, United Kingdom
                                    1. Anthony Moore
                                    1. Institute of Ophthalmology, UCL, United Kingdom

                                      Abstract

                                      Introduction: The genetic basis of variation in human cognitive abilities is poorly understood. RIMS1 encodes a synapse active zone protein with important roles in maintenance of normal synaptic function: mice lacking this protein have greatly reduced learning ability and memory function. We used an established paradigm examining structural and functional effects of mutations in genes expressed in the eye and the brain 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 studied.

                                      Results: Affected individuals showed significantly enhanced cognitive abilities across a range of domains. Analysis suggests factors other than RIMS1 mutation were unlikely to explain the enhanced cognition. No association with common variation and VIQ 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 human developing brain, but RIMS1 does not appear to have been subject to accelerated evolution in man.

                                      Conclusions: Our preliminary results suggest a possible role for RIMS1 in enhancement of cognitive function at least in this kindred. Whilst further work is clearly required to explore these findings before a role for RIMS1 in human cognition can be formally accepted, the findings suggest genetic mutation may enhance human cognition in some cases.

                                      • RIMS1
                                      • cone-rod dystrophy
                                      • intelligence
                                      • mutation

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