+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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



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



American Journal of Medical Genetics 83(4): 286-295



The study of the neurobehavioral consequences of mutations of FMR1, the gene responsible for fragile X syndrome (FraX), has been based largely on correlations between mutation patterns and cognitive profile. Following the characterization of FMRP, the FMR1 gene product, preliminary correlations between FMRP levels, and neurologic phenotype have been established. However, most 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 leukocytes. Three distinct patterns of FMRP immunoreactivity (-ir) emerged. Individuals 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 approximately 70-80 kDa FMRP-ir bands. Males with the FM (n = 10) demonstrated only a 70 kDa FMRP-ir band, and had significantly lower levels when compared with any previous groups. Males with mosaicism and three of 14 females with FM displayed a doublet with equal amounts of the highest and lowest molecular weight FMRP-ir bands. Multiple regression models that adjust for the effect of parental IQ indicated that both activation ratio and FMRP-ir are significantly correlated to subject IQ. We conclude that FMRP-ir offers promise as an indicator of the impact of FMR1 mutations upon neurologic function. Furthermore, our unexpected finding of FMRP-ir in all males with FM suggests that most of them are not transcriptionally silent.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 010713342

Download citation: RISBibTeXText

PMID: 10208163

DOI: 10.1002/(sici)1096-8628(19990402)83:4<286::aid-ajmg10>3.0.co;2-h


Related references

Genotype and molecular phenotype in fragile X syndrome. American Journal of Human Genetics 61(4 Suppl. ): A175, 1997

Genotype/phenotype correlations in the fragile X syndrome Comparison of FMR1 DNA patterns in lymphocytes, lymphoblasts and fibroblasts. American Journal of Human Genetics 55(3 Suppl. ): A214, 1994

A multicenter study on genotype-phenotype correlations in the fragile X syndrome, using direct diagnosis with probe StB12.3: the first 2,253 cases. American Journal of Human Genetics 55(2): 225-237, 1994

New insights into Fragile X syndrome. Relating genotype to phenotype at the molecular level. Febs Journal 272(3): 872-878, 2005

Medical genetics: advances in brief: A multicenter study on genotype-phenotype correlations in the fragile X syndrome, using direct diagnosis with probe StB12.3: the first 2,253 cases. Journal of Medical Genetics 31(10): 818-818, 1994

Genotype/phenotype correlations among the 5 molecular classes of Angelman syndrome. American Journal of Human Genetics 67(4 Suppl. 2): 351, 2000

Ion channel mechanisms related to sudden cardiac death in phenotype-negative long-QT syndrome genotype-phenotype correlations of the KCNQ1(S349W) mutation. Journal of Cardiovascular Electrophysiology 22(2): 193-200, 2011

Ethylmalonic aciduria/SCAD deficiency There are correlations between genotype and metabolic and enzymatic phenotype, but not between genotype and clinical phenotype. Journal of Inherited Metabolic Disease 25(Suppl. 1): 65, 2002

Identification of novel deletions of 15q11q13 in Angelman syndrome by array-CGH: molecular characterization and genotype-phenotype correlations. European Journal of Human Genetics 15(9): 943-949, 2007

Choline Acetyltransferase Mutations Causing Congenital Myasthenic Syndrome: Molecular Findings and Genotype-Phenotype Correlations. Human Mutation 36(9): 881-893, 2016

SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. Human Mutation 32(7): 760-772, 2011

Accurate description of the phenotype: the clinician's contribution to the clarification of genotype-phenotype correlations. Orvosi Hetilap 147(23): 1059-1061, 2006

Genotype-phenotype correlations: assessing the influence of sequence variants on the clinical phenotype. Clinical Chemistry 51(1): 8, 2004

Genotype-phenotype correlations in Darier disease: A focus on the neuropsychiatric phenotype. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 177(8): 717-726, 2018

NBAS pathogenic variants: Defining the associated clinical and facial phenotype and genotype-phenotype correlations. Human Mutation 2019, 2019