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.


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.
Sisodiya
Sanjay M
SM
Department of Clinical and Experimental Epilepsy, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. sisodiya@ion.ucl.ac.uk
Thompson
Pamela J
PJ
Need
Anna
A
Harris
Sarah E
SE
Weale
Michael E
ME
Wilkie
Susan E
SE
Michaelides
Michel
M
Free
Samantha L
SL
Walley
Nicole
N
Gumbs
Curtis
C
Gerrelli
Dianne
D
Ruddle
Piers
P
Whalley
Lawrence J
LJ
Starr
John M
JM
Hunt
David M
DM
Goldstein
David B
DB
Deary
Ian J
IJ
Moore
Anthony T
AT
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
D009419:Nerve Tissue Proteins; C491492:RIMS1 protein, human; D012333:RNA, Messenger; C491490:Rims1 protein, mouse; D019204:GTP-Binding Proteins