title: Genetic enhancement of cognition in a kindred with cone-rod dystrophy due to RIMS1 mutation.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Clinical and Experimental Epilepsy, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. sisodiya@ion.ucl.ac.uk
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Sisodiya
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Thompson
authors.forename: Anna
authors.initials: A
authors.lastname: Need
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Harris
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weale
authors.forename: Susan E
authors.initials: SE
authors.lastname: Wilkie
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Free
authors.forename: Nicole
authors.initials: N
authors.lastname: Walley
authors.forename: Curtis
authors.initials: C
authors.lastname: Gumbs
authors.forename: Dianne
authors.initials: D
authors.lastname: Gerrelli
authors.forename: Piers
authors.initials: P
authors.lastname: Ruddle
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Whalley
authors.forename: John M
authors.initials: JM
authors.lastname: Starr
authors.forename: David M
authors.initials: DM
authors.lastname: Hunt
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D003071:Cognition; D019143:Evolution, Molecular; D005124:Eye Abnormalities / Q000235:genetics*; D005190:Family; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D024861:Genetic Enhancement; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009483:Neuropsychological Tests; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000473:pathology
chemical_list: D009419:Nerve Tissue Proteins; C491492:RIMS1 protein, human; D012333:RNA, Messenger; C491490:Rims1 protein, mouse; D019204:GTP-Binding Proteins