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U Kuhnle

Publications and source records attributed to U Kuhnle.

At least 37 records · Page 2Linked to original sources
PubMed1995

Pseudohypoaldosteronism: evaluation of type I receptors by radioreceptor assay and by antireceptor antibodies.

We have previously demonstrated a deficiency of mineralocorticoid receptors in pseudohypoaldosteronism, by radioreceptorassay. We now report findings with an antireceptor antibody derived from the immunogenic region of the receptor. Lymphocytes from normal controls and from two cases of pseudohypoaldosteronism previously shown to lack receptor binding were tested. After the plasma membrane of lymphocytes was permeabilized with methanol the cells were incubated with a 1:200 dilution of antibody followed by fluorescent antirabbit immunoglobulin mouse serum. After washing fluorescence was detected by microscopy and cytofluorimetry in both controls and patients with pseudohypoaldosteronism. Recent studies on mineralocorticoid receptor cDNA in pseudohypoaldosteronism have not established a mutation in the sequence. We thus suggest that the pathogenesis of pseudohypoaldosteronism is not related to an abnormality of the receptor but rather due to intracellular factor(s) which can block the binding of aldosterone to its receptor.

Adult↗
PubMed1995

Familial pseudohypoaldosteronism: a review on the heterogeneity of the syndrome.

Pseudohypoaldosteronism is thought to be a rare salt-losing disorder, caused by resistance to the action of aldosterone. Defective aldosterone receptor binding is present in familial as well as sporadic cases and it has been suggested that the pathogenesis is due to a defect in the aldosterone receptor system. To date, however, molecular genetic analysis has been unable to identify a mutation in the aldosterone receptor gene itself. We have reviewed the findings in patients with pseudohypoaldosteronism, for clues which might enable us to identify the underlying pathogenesis. Although aldosterone receptor binding is regularly decreased or absent in monocytes of patients with pseudohypoaldosteronism, in some patients receptor protein can be detected with a fluorescence-labeled antibody. Receptor protein was detected in patients from familial autosomal dominant families and in sporadic cases, but was undetectable in two patients with the familial recessive form. To further elucidate the pattern of inheritance we studied the response of the renin-angiotensin-aldosterone system to the stimulation by sodium depletion in the familial autosomal dominant form and in two families with sporadic cases. In both "sporadic" families investigated, one parent and one sibling had an exaggerated response of renin and aldosterone to sodium depletion indicating a defect of sodium conservation apparent only during stress, leading to reclassification as familial cases. No additional family member in the "classical" autosomal dominant families responded abnormally to sodium depletion. These findings indicate that pseudohypoaldosteronism is unusually heterogeneous in its clinical, biochemical, and genetic presentations and findings and suggest that its pathogenesis is heterogeneous as well.

Genes, Dominant↗
PubMed1995

Exclusion of the locus for autosomal recessive pseudohypoaldosteronism type 1 from the mineralocorticoid receptor gene region on human chromosome 4q by linkage analysis.

Pseudohypoaldosteronism type 1 (PHA1) is an uncommon inherited disorder characterized by salt-wasting in infancy arising from target organ unresponsiveness to mineralocorticoids. Clinical expression of the disease varies from severely affected infants who may die to apparently asymptomatic individuals. Inheritance is Mendelian and may be either autosomal dominant or autosomal recessive. A defect in the mineralocorticoid receptor has been implicated as a likely cause of PHA1. The gene for human mineralocorticoid receptor (MLR) has been cloned and physically mapped to human chromosome 4q31.1-31.2. The etiological role of MLR in autosomal recessive PHA1 was investigated by performing linkage analysis between PHA1 and three simple sequence length polymorphisms (D4S192, D4S1548, and D4S413) on chromosome 4q in 10 consanguineous families. Linkage analysis was carried out assuming autosomal recessive inheritance with full penetrance and zero phenocopy rate using the MLINK program for two-point analysis and the HOMOZ program for multipoint analysis. Lod scores of less than -2 were obtained over the whole region from D4S192 to D4S413 encompassing MLR. This provdes evidence against MLR as the site of mutations causing PHA1 in the majority of autosomal recessive families.

Alleles↗
PubMed1994

True hermaphroditism: geographical distribution, clinical findings, chromosomes and gonadal histology.

We reviewed 283 cases of human true hermaphroditism published from 1980 to 1992. Of the 96 cases described in Africa 96.9% showed a 46,XX karyotype. In Europe 40.5% of 74 cases and 21.0% of the patients in North America had chromosomal mosaicism. The 46,XY karyotype is extremely rare (7%) and equally distributed through Asia, Europe and North America. Of 283 cases 87 were of black or black mixed origin with a 46,XX chromosomal constellation. The most common gonad in patients with true hermaphroditism, an ovotestis, was found in 44.4% of 568 gonads. Gonads with testicular tissue were more frequent on the right side of the body, while pure ovarian tissue was more common on the left. Histologically the testicular tissue was described to be immature and only twice was spermatogenesis reported while the ovarian portion often appeared normal. This coincides with 21 pregnancies reported in ten true hermaphrodites while only one true hermaphrodite apparently has fathered a child. Of the patients 4.6% were reported to have gonadal tumours. Position and type of the genital ducts, frequency of clinical findings such as genital abnormalities and gynaecomastia, correlations between assigned sex and karyotype as well as the age at diagnosis are reported.

Adolescent↗
PubMed1994

[Genetics of human sex determination and its disturbances].

The genetics of human sex determination is considered in view of the various disorders of gonad development. The Y chromosome plays an important role in the induction of sex determination by encoding the testis-determining factor (TDF). However, not all deviations in regular development can be explained by mutations of the TDF as unique factor. Therefore, it is necessary to postulate other mutations in still unknown genes of the cascade for male-specific determination as well as the requirement of an ovary-determining factor for regular female development.

DNA-Binding Proteins↗
PubMed1994

Immunofluorescence of mineralocorticoid receptors in peripheral lymphocytes: presence of receptor-like activity in patients with the autosomal dominant form of pseudohypoaldosteronism, and its absence in the recessive form.

Pseudohypoaldosteronism is a syndrome characterized by salt wasting and a failure to thrive due to the resistance towards the action of aldosterone. Aldosterone levels and plasma renin activity are extremely elevated and aldosterone binding sites in peripheral mononuclear leukocytes have regularly shown to be reduced or absent. Sporadic as well as familial cases have been identified and an autosomal dominant as well as an autosomal recessive mode of inheritance has been described. A defect in the aldosterone receptor has been postulated, however, molecular genetic analysis in selected patients has not revealed a mutation in the sequence of the coding region of the cDNA of the mineralocorticoid receptor gene. In the present study we have used a fluorescence-labeled antibody to detect possible receptor expression in monocytes from patients with various clinical forms of pseudohypoaldosteronism. Patients with the sporadic as well as with the autosomal dominant form were clearly immunopositive despite being negative in terms of aldosterone receptor binding. In contrast in two patients with the autosomal recessive form there was no detectable receptor protein, consistent with the results obtained in the aldosterone binding studies. These results suggest that the pathogenesis of pseudohypoaldosteronism is heterogeneous not only regarding the mode of inheritance but also in terms of receptor binding. Thus, in a subgroup of patients the inability of the receptor to bind ligand may be due to a defect involving other, probably cellular factors rather than a deficiency or a defect in the mineralocorticoid receptor system itself.

Adult↗
PubMed1994

Androgen binding sites in peripheral human mononuclear leukocytes of healthy males and females.

Androgen binding sites have been identified in circulating human mononuclear leukocytes of healthy donors of both sexes. Cells were separated from blood samples on a Ficoll gradient and incubated with different concentrations of [3H]testosterone in the presence or absence of a 400-fold excess of unlabelled testosterone. Binding data were derived from Scatchard analysis. The binding sites fulfil the required criteria for specific steroid binding sites however differ somewhat from the classic androgen receptors from genital skin fibroblast: in fertile adult males (n = 20) the binding sites showed (1) a high affinity for testosterone (1.32 +/- 0.49 nM; mean +/- SD), (2) a saturable capacity (184 +/- 52 binding sites per cell; mean +/- SD), and (3) a characteristic competitive binding profile for other steroid hormones (relative binding affinities: testosterone = dihydrotestosterone > 17 beta-estradiol > progesterone, whereas aldosterone, 17-hydroxy-progesterone and cortisol did not compete appreciably). Furthermore the number of binding sites determined using [3H]dihydrotestosterone, [3H]RU-1881, or [3H]testosterone were comparable. This raises the possibility that androgen receptors in peripheral mononuclear leukocytes differ from those in genital skin fibroblasts. There was no apparent correlation between serum testosterone concentrations and androgen binding sites. In fertile women remarkable changes in androgen binding sites were seen in the course of the menstrual cycle, with a significant increase in the immediate preovulatory period. The presence of androgen receptors in peripheral mononuclear leukocytes provides for the first time the experimental basis for an hypothesis of direct, receptor-mediated effects of androgens on mature immunocompetent cells. The immunological implications of these results are discussed.

Adult↗
PubMed1994

Gonadotropin regulation during puberty in complete androgen insensitivity syndrome with testicles in situ.

This paper describes the time course of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in two patients with the complete androgen insensitivity syndrome (AIS) during puberty and adolescence prior to gonadectomy. In early puberty, LH values were comparable to normal male as well as female standards. At the age of 17 and 18.7 years, respectively, a sudden rise in LH occurred just after the start of estradiol supplementation. These high LH concentrations in the late puberty of our patients are comparable to the values found during early puberty in castrated individuals and children with gonadal dysgenesis. In contrast, FSH concentrations continuously showed levels in the normal male or female range with no rise during adolescence. The sudden increase of LH in late puberty is most probably due to defective testosterone receptors in the pituitary/hypothalamus which apparently can no longer be suppressed by rising testosterone levels and an escape from the negative estradiol feedback. The role of estradiol supplementation might be incidental and further investigation into its role is needed. In contrast to the elevated levels of FSH in patients with defective spermatogenesis, FSH is normal in our patients with AIS and testes in situ. This indicates that FSH secretion is regulated by a combined action of estradiol and gonadal hormones like inhibin.

Adolescent↗
PubMed1994

Abnormality of aldosterone and cortisol late pathways in glucocorticoid-remediable aldosteronism.

Patients with glucocorticoid-remediable aldosteronism (GRA) possess a chimeric gene resulting from fusion of the genes encoding steroid aldosterone synthase and 11 beta-hydroxylase. In the adrenal zona fasciculata, this may lead to ectopic expression under ACTH control of aldosterone synthase activity and increased formation of cortisol C18 oxidation products. We assessed mineralocorticoid and glucocorticoid pathways in three patients with GRA. Baseline plasma progesterone, 17 alpha-hydroxyprogesterone, corticosterone, and cortisol were normal in all patients, whereas 11-deoxycorticosterone, aldosterone, and 11-deoxycortisol were above normal. The ratios of both corticosterone/11-deoxycorticosterone and cortisol/11-deoxycortisol were abnormally low, and decreased further 60 min after administration of ACTH-(1-24) (250 micrograms) as an i.v. bolus. A low corticosterone/11-deoxycorticosterone ratio is consistent with an increased aldosterone synthase activity forming aldosterone by corticosterone. Similarly, a decreased cortisol/11-deoxycortisol ratio could reflect enhanced cortisol C18 oxidation. Our findings are in agreement with a hyperfunction of the 11 beta-hydroxylase/aldosterone synthase complex in the adrenal zona fasciculata of GRA induced by the new chimeric gene.

Adrenocorticotropic Hormone↗
PubMed1993

Familial true hermaphroditism: paternal and maternal transmission of true hermaphroditism (46,XX) and XX maleness in the absence of Y-chromosomal sequences.

We report on 46,XX true hermaphroditism and 46,XX maleness coexisting in the same pedigree, with maternal as well as paternal transmission of the disorder. Molecular genetic analysis showed that both hermaphrodites as well as the 46,XX male were negative for Y-chromosomal sequences. Thus, this pedigree is highly informative and allows the following conclusions: first, the maternal as well as paternal transmission of the disorder allows the possibility of an autosomal dominant as well as an X-chromosomal dominant mode of inheritance; second, testicular determination in the absence of Y-specific sequences in familial 46,XX true hermaphrodites as well as in 46,XX males seems to be due to the varying expression of the same genetic defect; and third, there is incomplete penetrance of the defect.

Adult↗
PubMed1993

Partnership and sexuality in adult female patients with congenital adrenal hyperplasia. First results of a cross-sectional quality-of-life evaluation.

In congenital adrenal hyperplasia affected female patients are born with ambiguous genitalia caused by prenatally elevated circulating androgens from the defective adrenal glands. Surgical correction and life-long medication is needed to enable a normal female life. In contrast to androgen-related behaviour little information is available regarding the psychosocial consequences of genital malformations and lifetime medical treatment on the life of female patients. We report the results regarding partnership and sexuality of a comprehensive quality-of-life evaluation of female patients with congenital adrenal hyperplasia. While there was no significant difference in the first overall evaluation between the various clinical forms of congenital adrenal hyperplasia, patients differed significantly from healthy controls in regard to partnership and sexuality. However, overall analysis suggested, that the patients were able to adjust well to their condition and were able to lead a normal life. Further longitudinal research is needed to more clearly identify problem areas and to improve medical and psychological treatment.

Adolescent↗
PubMed1993

[Hermaphroditism verus: clinical aspects, diagnosis and therapy in adulthood].

A 20-year old woman, who underwent an intersex operation during infancy, was presented for evaluation of the gonads because of suspected true hermaphroditism. The phenotype was female with regular menstruations. Examination revealed an ovarian tumour of 8 cm on the left side and a normal right ovary. During the operation, the tumour was revealed as an endometriosis cyst, which could be excised whilst preserving the ovarian tissue. The right gonad was an ovotestis. The testicular part was removed because of a 4% risk of malignancy. The different combinations of ovary/testis and ovotestis are described. Diagnosis and therapy of true hermaphroditism should be performed as early as possible to obtain an adequate gonadal function and an undisturbed psychosexual development.

Adult↗
PubMed1993

Transient pseudohypoaldosteronism in obstructive renal disease with transient reduction of lymphocytic aldosterone receptors. Results in two affected infants.

We report two patients with transient pseudohypoaldosteronism due to obstructive renal disease. Both patients presented with a salt-losing episode simulating adrenal insufficiency. In one patient, transient reduction of aldosterone receptors could be documented, while in the second patient the clinical and biochemical parameters were consistent with transient pseudohypoaldosteronism. Aldosterone receptors were normal in both patients when studied after the surgical correction of the obstruction.

Humans↗
PubMed1993

True hermaphroditism in a 46,XY individual, caused by a postzygotic somatic point mutation in the male gonadal sex-determining locus (SRY): molecular genetics and histological findings in a sporadic case.

Recently, the gene for the determination of maleness has been identified in the sex-determining region on the short arm of the Y chromosome (SRY) between the Y-chromosomal pseudoautosomal boundary (PABY) and the ZFY gene locus. Experiments with transgenic mice confirmed that SRY is a part of the testis-determining factor (TDF). We describe a sporadic case of a patient with intersexual genitalia and the histological finding of ovotestes in the gonad, which resembles the mixed type of gonadal tissue without primordial follicle structures. The karyotype of the patient was 46,XY. By PCR amplification, we tested for the presence of PABY, SRY, and ZFY by using DNA isolated from peripheral blood leukocytes and for the presence of SRY by using DNA obtained from histological gonadal slices. The SRY products of both DNA preparations were further analyzed by direct sequencing. All three parts of the sex-determining region of the Y chromosome could be amplified from leukocytic DNA. The patient's and the father's SRY sequences were identical with the published sequence. In the SRY PCR product of gonadal DNA, the wild-type and two point mutations were present in the patient's sequence, simulating a heterozygous state of a Y-chromosomal gene: one of the mutations was silent, while the other encoded for a nonconservative amino acid substitution from leucine to histidine. Subcloning procedures showed that the two point mutations always occurred together. The origin of the patient's intersexuality is a postzygotic mutation of the SRY occurring in part of the gonadal tissue. This event caused the loss of the testis-determining function in affected cells.

Adult↗
PubMed1991

Pseudohypoaldosteronism and mineralocorticoid receptor abnormalities.

Pseudohypoaldosteronism is a rare inherited disease characterized by renal salt loss, hyperkalemia and metabolic acidosis despite highly elevated aldosterone values. We previously reported absent or reduced numbers of mineralocorticoid receptors in mononuclear leukocytes and defective effector mechanism as shown by no response in vitro to the incubation of aldosterone in terms of intracellular electrolyte content. We have studied the inheritance of this disorder in ten families and found two different kinds of inheritance: autosomal recessive--often in interrelated families--and autosomal dominant in unrelated families. Parallel studies in the families with the autosomal dominant form of inheritance demonstrated in addition that the effector mechanism of aldosterone is impaired in vitro both in the affected patients and in the carrier relatives characterized by a low number of mineralocorticoid receptors.

Aldosterone↗
PubMed1990

Effects of aldosterone on intralymphocytic sodium and potassium in patients with essential hypertension.

In vitro binding of aldosterone to mineralocorticoid receptors on human mononuclear leukocytes (HML) and its effects on the intracellular sodium and potassium concentrations of HML have already been described. In the present paper this easily accessible human cell model was investigated in 13 patients with essential hypertension. In only four patients sodium in HML without incubation was elevated compared with the range for normal persons. A decrease of intracellular sodium or potassium occurred during incubation without aldosterone (P less than 0.02). The addition of 1.4 nM aldosterone did not prevent this loss of electrolytes as observed in normal persons. Plasma renin activity and aldosterone were not correlated with the electrolyte response and were within the normal limits. The number of mineralocorticoid receptors/cell were within or close to the normal range (n = 9). The independence of intracellular electrolytes from aldosterone despite a normal number of mineralocorticoid receptors may reflect an impairment of the mineralocorticoid effector mechanism in the HML of patients with essential hypertension.

Adolescent↗