Subject(s)
Diagnostic Errors , Factor VIII/genetics , Genetic Carrier Screening , Hemophilia A/diagnosis , Hemophilia A/genetics , Heterozygote , Exons , Humans , Infant , Male , MutationABSTRACT
Of the 18 missense mutations in the CACNA1A gene, which are associated with familial hemiplegic migraine type 1 (FHM1), only mutations S218L, R583Q and T666M were identified in more than two independent families. Including the four novel families presented here, of which two represent de novo cases, the R1347Q mutation has now been identified in six families. A genotype-phenotype comparison of R1347Q mutation carriers revealed a wide clinical spectrum ranging from (trauma triggered) hemiplegic migraine with and without ataxia, loss of consciousness and epilepsy. R1347Q is the third most frequent mutation in hemiplegic migraine patients and should therefore be screened with priority for confirmation of clinical diagnosis. This study clearly demonstrates that the availability of multiple families better reflects the full clinical spectrum associated with FHM1 mutations.
Subject(s)
Calcium Channels/genetics , Migraine with Aura/genetics , Mutation , Adolescent , Aged , DNA Mutational Analysis , Female , Genotype , Haplotypes , Humans , Male , Middle Aged , Models, Biological , Pedigree , PhenotypeABSTRACT
Pheno- and genotype correlation is attempted in a Dutch cross-sectional study on limb- girdle muscular dystrophy. Sarcoglycans, caveolin-3, calpain-3, and dysferlin were analyzed on muscle tissue. Mutation analysis of the calpain-3, caveolin-3, and fukutin-related protein gene was executed in successive order for all samples. In 51% of all families a classifying diagnosis was made. Several new mutations in LGMD2A, B, and C patients have been found in this population.
Subject(s)
Genetic Predisposition to Disease/genetics , Muscle Proteins/genetics , Muscle, Skeletal/metabolism , Muscular Dystrophies, Limb-Girdle/genetics , Mutation/genetics , Adolescent , Adult , Calpain/genetics , Caveolin 3/genetics , Chromosome Mapping , Cross-Sectional Studies , DNA Mutational Analysis , Dysferlin , Female , Genetic Testing , Genotype , Humans , Male , Membrane Proteins/genetics , Middle Aged , Muscle, Skeletal/physiopathology , Netherlands , Pentosyltransferases , Phenotype , Proteins/geneticsABSTRACT
The receptors for insulin (IR) and epidermal growth factor (EGFR) are members of the tyrosine kinase receptor (TKR) family. Despite homology of their cytosolic TK domains, both receptors induce different cellular responses. Tyrosine phosphorylation of insulin receptor substrate (IRS) molecules is a specific IR post-receptor response. The EGFR specifically activates phospholipase C-gamma1 (PLC-gamma1). Recruitment of substrate molecules with Src homology 2 (SH2) domains or phosphotyrosine binding (PTB) domains to phosphotyrosines in the receptor is one of the factors creating substrate specificity. In addition, it has been shown that the TK domains of the IR and EGFR show preferences to phosphorylate distinct peptides in vitro, suggesting additional mechanisms of substrate recognition. We have examined to what extent the substrate preference of the TK domain contributes to the specificity of the receptor in vivo. For this purpose we determined whether the IR TK domain, in situ, is able to tyrosine-phosphorylate substrates normally used by the EGFR. A chimaeric receptor, consisting of an EGFR in which the juxtamembrane and tyrosine kinase domains were exchanged by their IR counterparts, was expressed in CHO-09 cells lacking endogenous EGFR. This receptor was found to activate PLC-gamma1, indicating that the IR TK domain, in situ, is able to tyrosine phosphorylate substrates normally used by the EGFR. These findings suggest that the IR TK domain, in situ, has a low specificity for selection and phosphorylation of non-cognate substrates.
