Genotype, molecular phenotype, and cognitive phenotype: Correlations in fragile X syndrome

The study of the neurobehavioral consequences of mutations of FMR1, the gen e responsible for fragile X syndrome (FraX), has been based largely on corr elations between mutation patterns and cognitive profile. Following the cha racterization of FMRP, the FMR1 gene product, preliminary correlations betw een FMRP levels, and neurologic phenotype have been established. However, m ost of these investigations have focused on individuals at both ends of the genetic and cognitive spectra of FraX, subjects with normal or premutation (PM) alleles or males with the FMR1 full mutation (FM), The present study is designed to characterize FMRP expression and to correlate it with IQ, in a sample representing a wide spectrum of FMR1 mutations, For this purpose we developed a highly sensitive immunoblotting assay using peripheral leuko cytes. Three distinct patterns of FMRP immunoreactivity (-ir) emerged. Indi viduals with normal (n = 28) and PM (n = 8) alleles as well as most females with the FM (n = 14) showed the highest levels with multiple similar to 70 -80 kDa FMRP-ir bands. Males with the FEM (n = 10) demonstrated only a 70 b Da FMRP-ir band, and had significantly lower levels when compared with any previous groups. Males with mosaicism and three of 14 females with FM displ ayed a doublet with equal amounts of the highest and lowest molecular weigh t FMRP-ir bands. Multiple regression models that adjust for the effect of p arental IQ indicated that both activation ratio and FMRP-ir are significant ly correlated to subject IQ, We conclude that FMRP-ir offers promise as an indicator of the impact of FMR1 mutations upon neurologic function. Further more, our unexpected finding of FMRP-ir in all males with FM suggests that most of them are not transcriptionally silent. (C) 1999 Wiley-Liss, Inc.