Androgen insensitivity syndrome encompasses a wide range of phenotypes, which are caused by numerous different mutations in the AR gene. Detailed information on the genotype/phenotype relationship in androgen insensitivity syndrome is important for sex assignment, treatment of androgen insensitivity syndrome patients, genetic counseling of their families, and insight into the functional domains of the AR. The commonly accepted concept of dependence on fetal androgens of the development of Wolffian ducts was studied in complete androgen insensitivity syndrome (CAIS) patients. In a nationwide survey in The Netherlands, all cases (n = 49) with the presumptive diagnosis androgen insensitivity syndrome known to pediatric endocrinologists and clinical geneticists were studied. After studying the clinical phenotype, mutation analysis and functional analysis of mutant receptors were performed using genital skin fibroblasts and in vitro expression studies. Here we report the findings in families with multiple affected cases. Fifty-nine percent of androgen insensitivity syndrome patients had other affected relatives. A total of 17 families were studied, seven families with CAIS (18 patients), nine families with partial androgen insensitivity (24 patients), and one family with female prepubertal phenotypes (two patients). No phenotypic variation was observed in families with CAIS. However, phenotypic variation was observed in one-third of families with partial androgen insensitivity resulting in different sex of rearing and differences in requirement of reconstructive surgery. Intrafamilial phenotypic variation was observed for mutations R846H, M771I, and deletion of amino acid N682. Four newly identified mutations were found. Follow-up in families with different AR gene mutations provided information on residual androgen action in vivo and the development of the prepubertal and adult phenotype. Patients with a functional complete defective AR had some pubic hair, Tanner stage P2, and vestigial Wolffian duct derivatives despite absence of AR expression. Vaginal length was functional in most but not all CAIS patients. The minimal incidence of androgen insensitivity syndrome in The Netherlands, based on patients with molecular proof of the diagnosis is 1:99,000. Phenotypic variation was absent in families with CAIS, but distinct phenotypic variation was observed relatively frequent in families with partial androgen insensitivity. Molecular observations suggest that phenotypic variation had different etiologies among these families. Sex assignment of patients with partial androgen insensitivity cannot be based on a specific identified AR gene mutation because distinct phenotypic variation in partial androgen insensitivity families is relatively frequent. In genetic counseling of partial androgen insensitivity families, this frequent occurrence of variable expression resulting in differences in sex of rearing and/or requirement of reconstructive surgery is important information. During puberty or normal dose androgen therapy, n...
SUMMARYThere are two types of insulin-like growth factor (IGF) receptors. The type I receptor generally binds IGF-I more tightly than IGF-II and also interacts weakly with insulin. The type II receptor prefers IGF-II over IGF-I and does not recognize insulin. The type I receptor is made up of an alpha binding subunit (Mr 130000) and a beta subunit (Mr 95 000) probably organized as a heterotetramer (Oizfh)■ The type II receptor consists of a single binding unit (Mr 250000). IG F stimulates phosphorylation of the beta subunit of the type I receptor in whole cells and solubilized receptor preparations. Tyrosine kinase activity is associated with the type I receptor, resulting in autophosphorylation of the beta subunit and phosphorylation of exogenous substrates. In contrast, phosphorylation of the type II receptor in whole cells is less IGF-dependent, solubilized receptor preparations are not phosphorylated, and purified type II receptors do not exhibit tyrosine kinase activity toward the artificial substrate poly(Glu,Tyr)4:1. There are many similarities between the type I IG F receptor and the insulin receptor; however, different ligand-binding properties, subtle differences in the size of alpha and beta subunits, and immunoreactivity toward anti-receptor antibodies allow us to distinguish between these two receptors. The presence of both IG F receptors as well as insulin receptors on most cells and cross-reactivity of ligands for binding to these receptors present difficulties in assigning a particular biological response to a specific receptor. The type I receptor is down-regulated by ligand while in several cell types the type II receptor is rapidly up-regulated by insulin; the mechanism of up-regulation appears to be a translocation of type II receptors to the cell surface. There are two classes of serum binding proteins for IG F, a M t 150 000 species found in adult blood and a M x 40 000 species, which predominates in foetal blood. Like the type II receptor, IG F binding proteins do not bind insulin. The binding site on the type II receptor can be distinguished from the binding protein sites by a hybrid molecule AjnsuH n-BiGF-i) which recognizes the binding protein but not the type II receptor. Binding proteins produced by cells in culture may cause confusion in the interpretation of experiments that are designed to study the binding of radiolabelled IG F to cell surface receptors in monolayer culture.
The relative contributions of type I and type II insulinlike growth factor (IGF) receptors and IGF carrier proteins to the binding of IGF
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