Partial Androgen Insensitivity

Amrhein, James A.; Klingensmith, Georgeanna J.; Walsh, Patrick C.; McKusick, Victor A.; Migeon, Claude J.

doi:10.1056/nejm197708182970703

Cited by 99 publications

(18 citation statements)

References 35 publications

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“…Earlier, Wilson (16) had observed that the rate of DHT formation from testosterone was greater in fibroblast monolayers grown from foreskin and scrotal skin than in fibroblasts from nongenital skin sites. The finding of this specialized metabolic function in skin fibroblasts of different anatomical origin was also reported by Pinsky et al (21), Mulay et al (15) and by our laboratory (22) (Fig. 3).…”

Section: 5e~-reductase Activity In Normal Skin Fibroblastssupporting

confidence: 90%

Cultured human skin fibroblasts: a model for the study of androgen action

Brown

Migeon

1981

Mol Cell Biochem

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Human skin may be considered as a target organ for androgens, as are male sex accessory organs, since all events involved in testosterone action have been observed in this tissue. As a corollary, the mechanism of androgen action can be studied in vitro in cultured skin fibroblasts. The advantages of this system are that studies can be performed with intact human cells under carefully controlled conditions, differentiated genetic and biochemical characteristics of the cells are faithfully preserved and the biological material is renewable from a single biopsy specimen. The metabolism of androgens, in particular the 5 alpha-reduction of testosterone to the active metabolite, dihydrotestosterone, the intracellular binding of androgen to its specific receptor protein and its subsequent translocation to the nucleus have been studied in skin fibroblasts. The intracellular androgen receptor content of genital skin fibroblasts is higher than that from nongenital skin sites. In addition, the androgen receptor has been characterized as a specific macromolecule with properties of high affinity and low capacity similar to that of other steroid hormone receptors. The pathophysiology of three genetic mutations which alter normal male sexual development and differentiation has been identified in the human skin fibroblast system. In 5 alpha-reductase deficiency, an autosomal recessive disorder in which dihydrotestosterone formation is impaired, virilization of the Wolffian ducts is normal but the external genitalia and urogenital sinus derivatives are female in character. At least two types of X-linked disorders of the androgen receptor exist such that the actions of both testosterone and dihydrotestosterone are impaired and developmental abnormalities may involve both Wolffian derivatives and the external genitalia as well. These two forms of androgen insensitivity result from either the absence of androgen receptor binding activity (receptor (-) form) or apparently normal androgen receptor binding with absence of an appropriate biological response (receptor (+) form). In addition, studies with human skin fibroblasts may also be of value in defining the cellular mechanisms underlying the broad spectrum of partial defects in virilization. In summary, we have correlated our studies of the molecular mechanism of androgen action in human genital skin fibroblasts with those of other investigators as these studies contribute to our understanding of male sexual development and differentiation.

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Section: 5e~-reductase Activity In Normal Skin Fibroblastssupporting

confidence: 90%

Cultured human skin fibroblasts: a model for the study of androgen action

Brown

Migeon

1981

Mol Cell Biochem

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“…The evidence for X chromosome linkage in man is based on transmission of the mutation in families segregating androgen insensitivity and observations ofmutant-type cells that do not bind the androgen dihydrotestosterone in the heterozygous female (6). Furthermore, there is heterogeneity with regard to mutations associated with androgen insensitivity in man (7,8). In some families the dihydrotestosterone receptor activity is lacking (ar-), whereas in others receptor activity with respect to androgen binding is not obviously abnormal (7).…”

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“…These translocation chromosomes lack different segments ofthe X chromosome, but each has the distal portion of the long arm that contains the gene for HPRT. Only hybrid cells that retain the human X chromosome can proliferate in nutrient medium that makes HPRT essential (8). Those hybrids having HPRT and other appropriate human X chromosome markers were assayed for androgen binding activity.…”

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confidence: 99%

Studies of the locus for androgen receptor: localization on the human X chromosome and evidence for homology with the Tfm locus in the mouse.

Migeon¹,

Brown²,

Axelman³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

116

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We have established a cell line from mouse kidney cells expressing the tfin mutation and showed that these cells lack androgen binding activity. A subclone of these simian virus 40 (SV40)-transformed cells (6TGR-SV-0tn) selected in 6-thioguanine and lacking hypoxanthine phosphoribosyltransferase was used to produce a series of mouse-human hybrids containing the normal human X chromosome or various X autosome-translocation chromosomes (expressing only segments of the human X chromosome). When the androgen receptor locus (AR) was present in the hybrid, the number of receptor sites and kinetics of binding were similar to that in the human parental cells. Analysis of hybrids with partial human X chromosomes by using assays for X chromosome-linked enzymes and for the androgen receptor protein indicate that the AR locus on the human X chromosome is near the centromere between Xql3 and Xpll and is proximal to the locus for phosphoglycerate kinase. Hybrids derived from 6TGR-SV-tfm mouse cells and human labial fibroblasts from an XY individual with the ar-form of androgen insensitivity have no binding activity. The lack ofcomplementation indicates that the X chromosome-linked mutations in mouse and man affect homologous loci and supports the evolutionary conservation ofX chromosomal loci in mammals; however, the position of the locus on the human X chromosome indicates that intrachromosomal rearrangement has occured.

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“…2). Examples include the androgen receptor in testicular feminization (3) and other forms of androgen resistance (4,5) and the low density lipoprotein receptor in familial hypercholesteremia (6).…”

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confidence: 99%

“…Secondary derangements of insulin receptors have been reported on circulating cells and adipocytes in several states of insulin resistance and hyperinsulinemia including obesity (8), glucocorticoid excess (9), acromegaly (10), adultonset diabetes mellitus (11), in some patients with lipoatrophic diabetes (12,13), and in two groups of patients with circulating immunoglobulins directed against their insulin receptorsnamely, patients with extreme insulin resistance type B (14,15) and with ataxia telangiectasia (16). Skin fibroblasts propagated in culture are not subject to in vivo humoral influences such as hyperinsulinemia or antireceptor antibodies and more faithfully reflect the genetic endowment of the donor (3)(4)(5)(6). Fibroblast cultures established from skin from normal volunteers possess insulin receptors with the characteristic specificity for insulins of different biological potencies seen in other insulin receptors (17).…”

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confidence: 99%

Primary defect of insulin receptors in skin fibroblasts cultured from an infant with leprechaunism and insulin resistance.

Schilling¹,

Rechler²,

Grünfeld³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

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Insulin binding to insulin receptors on skin fibroblasts established in culture from an infant with insulin resistance and clinical features of leprechaunism was markedly decreased in comparison with cultures from an age-matched control. By contrast, the binding of epidermal growth factor, a polypeptide growth factor chemically unrelated to insulin, to patient's and control fibroblasts was indistinguishable. The selective defect in insulin binding to patient's fibroblasts was reflected in an impaired ability of insulin to stimulate 2-deoxyglucose uptake. These results most likely indicate a primary genetic defect of insulin receptors.The binding of a hormone to its receptor is thought to be the first step in hormone action (1). Strong support for this concept has come from the direct demonstration that certain genetic syndromes of hormone resistance in humans are associated with primary abnormalities of receptors (reviewed in ref.2). Examples include the androgen receptor in testicular feminization (3) and other forms of androgen resistance (4, 5) and the low density lipoprotein receptor in familial hypercholesteremia (6).This report describes a primary defect of insulin receptors occurring in an infant with leprechaunism (7) and insulin resistance. Secondary derangements of insulin receptors have been reported on circulating cells and adipocytes in several states of insulin resistance and hyperinsulinemia including obesity (8), glucocorticoid excess (9), acromegaly (10), adultonset diabetes mellitus (11), in some patients with lipoatrophic diabetes (12, 13), and in two groups of patients with circulating immunoglobulins directed against their insulin receptorsnamely, patients with extreme insulin resistance type B (14, 15) and with ataxia telangiectasia (16). Skin fibroblasts propagated in culture are not subject to in vivo humoral influences such as hyperinsulinemia or antireceptor antibodies and more faithfully reflect the genetic endowment of the donor (3-6). Fibroblast cultures established from skin from normal volunteers possess insulin receptors with the characteristic specificity for insulins of different biological potencies seen in other insulin receptors (17). In the present study, we demonstrate a profound, selective deficit of insulin receptors and impaired stimulation of glucose uptake by insulin in skin fibroblasts established in culture from an insulin-resistant patient with leprechaunism. § MATERIALS AND METHODS Case Description. A complete clinical description of the patient will be reported elsewhere. $ In brief, the patient was a Canadian Indian male infant who weighed 2.41 kg (3rd percentile) at birth. His parents were first cousins once removed. His physical appearance was considered to be typical of leprechaunism: emaciation, absence of subcutaneous fat, decreased muscle mass, hirsutism, and low-set, poorly developed ears. The clinical course was marked by failure to thrive, pneumonia of unknown etiology, and sudden death at 47 days of age. Additional clinical findings included tac...

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Partial Androgen Insensitivity

Cited by 99 publications

References 35 publications

Cultured human skin fibroblasts: a model for the study of androgen action

Cultured human skin fibroblasts: a model for the study of androgen action

Studies of the locus for androgen receptor: localization on the human X chromosome and evidence for homology with the Tfm locus in the mouse.

Primary defect of insulin receptors in skin fibroblasts cultured from an infant with leprechaunism and insulin resistance.

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