scholarly journals Phenotypic Diversity and Testosterone-Induced Normalization of Mutant L712F Androgen Receptor Function in a Kindred with Androgen Insensitivity*

2000 ◽  
Vol 85 (9) ◽  
pp. 3245-3250 ◽  
Author(s):  
Paul-Martin Holterhus ◽  
Gernot H. G. Sinnecker ◽  
Olaf Hiort
Keyword(s):  
Androgen Receptor ◽  
Phenotypic Diversity ◽  
Binding Capacity ◽  
Phenotypic Variability ◽  
External Genitalia ◽  
Androgen Insensitivity Syndrome ◽  
Physiological Concentration ◽  
Androgen Insensitivity ◽  
Low Concentrations ◽  
In Trans

Abstract Molecular causes of phenotypic diversity in androgen insensitivity syndrome, occurring even in the same family, have rarely been identified. We report on a family with four affected individuals, three brothers (B1–3) and their uncle, displaying strikingly different external genitalia: B1, ambiguous; B2, severe micropenis; B3, slight micropenis; and uncle, micropenis and penoscrotal hypospadias. All had been assigned a male gender. We detected the same L712F mutation of the androgen receptor (AR) gene in each subject. Methyltrienolone binding on cultured genital skin fibroblasts of B2 suggested moderate impairment of the ligand-binding domain [maximal binding capacity, 38.2 fmol/mg protein (normal); Kd, 0.21 nmol/L; normal range, 0.03–0.13 nmol/L]. In trans-activation assays, the mutant 712F-AR showed considerable deficiency at low concentrations of testosterone (0.01–0.1 nmol/L) or dihydrotestosterone (0.01 nmol/L). Remarkably, this could be fully neutralized by testosterone concentrations greater than 1.0 nmol/L. Hence, the 712F-AR could switch its function from subnormal to normal within the physiological concentration range of testosterone. This was reflected by an excellent response to testosterone therapy in B1, B2, and the uncle. Taking into account the well documented individual and time-dependent variation in testosterone concentration in early fetal development, our observations clearly illustrate the potential impact of varying ligand concentrations for distinct cases of phenotypic variability in androgen insensitivity syndrome.

The subcellular defects in the androgen insensitivity syndrome

1986 ◽  
Vol 113 (4_Suppl) ◽  
pp. S396-S402
Author(s):  
W. SWOBODA ◽  
K. HERKNER
Keyword(s):  
Binding Capacity ◽  
Kinetic Method ◽  
External Genitalia ◽  
Androgen Insensitivity Syndrome ◽  
Normal Female ◽  
Androgen Insensitivity ◽  
Wide Range ◽  
Group A ◽  
Group B ◽  
Tissue Specimens

ABSTRACT The androgen insensitivity syndrome (AIS) was studied with consideration of the complexity of mechanisms involved on the intracellular level: testosterone (T) and dihydrotestosterone (DHT) receptors and the androgen-5α-reductase (A5R). Five children with "normal" female external genitalia (group A) and three patients with variable forms of ambiguity (group B), ages 1 to 18 years, were studied. Tissue specimens from genital skin were analysed for the Kd- and Nmaxvalues of the cytosolic and nuclear T- and DHT-receptors, as well as for the Km- and Vmax-data of the tissue specific A5R. The enzyme analyses were performed with a kinetic method. Results show that patients from group A mainly lack action of the nuclear DHT receptor, combined with reduces binding capacity in the cytosol. T binding was poor in both, cytosolic and nuclear fractions, respectively. Results of group B proved to be more inhomogenous, ranging from total absence of a DHT receptor to normal binding capacities in the nuclear fractions, accompanied by decreased cytosolic Nmax values for that ligand. T binding was poor in all patients of group B in the cytosolic and nuclear fractions, respectively. A5R was qualitatively normal in all patients examined, except one, but decreased enzyme activities could be observed in a wide range. In summary, the study confirms the complex mechanisms, presenting as AIS clinically. Moreover a close relationship between abnormalities of androgen receptor function and changes in A5R activity could be evaluated, thus confirming the recent theories about intracellular androgen action.

scholarly journals A Novel Mutation of the AR Androgen Receptor Gene

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A694-A694
Author(s):  
Abdullah Abdulruhman Aljasser
Keyword(s):  
Androgen Receptor ◽  
Novel Mutation ◽  
Receptor Gene ◽  
External Genitalia ◽  
Androgen Receptor Gene ◽  
Androgen Insensitivity Syndrome ◽  
Loss Of Function ◽  
Androgen Insensitivity ◽  
Androgen Synthesis ◽  
Voice Changes

Abstract Androgen insensitivity syndrome (AIS), formerly known as testicular feminization, is an X-linked recessive condition resulting in a failure of normal masculinization of the external genitalia in chromosomally male individuals. The basic etiology of androgen insensitivity syndrome is a loss-of-function mutation in the androgen receptor (AR) gene. Loss of AR function means that, despite normal levels of androgen synthesis, the typical postreceptor events that mediate the effects of hormones on tissues do not occur. This results in the phenotype of prenatal undervirilization of external genitalia, absence of pubic and axillary hair, lack of acne, and absence of voice changes at puberty We present This baby reffered at age of 2 months from pediatric surgery as a case of bilateral inguinal hernia and chromosomes 46xy. Phenotypically female no male structures no phallus and single opening and visible labia, both test are in the inguinal canals. HCG stimulation test shows: Testosterone: the level at (0) time: 0.8 nmol/l then 3 days: 31.4 nmol/l. DHT dihydrotetostrerone: the level at (0) time: 13 NG/L then 3 days: 485 The baby was given 3 doses of Testosterone injections 150mg but no response at the genetalia. Radiological investigations shows ultrasound both tests at the inguinal canals and no uterus Also MRI of pelvis shows absence of uterus and both test at the inguinal canals Molecular genetics analysis for Androgen receptor gene: Exon 7 c.2512 G >A hem. P.Glu838lys missense, novel VUS,likely pathogenic. The segregations analysis test in the process. Her we present a novel mutation of the AR gene not reported yet in literature.

scholarly journals The FKBP4 Gene, Encoding a Regulator of the Androgen Receptor Signaling Pathway, Is a Novel Candidate Gene for Androgen Insensitivity Syndrome

2020 ◽  
Vol 21 (21) ◽  
pp. 8403
Author(s):  
Erkut Ilaslan ◽  
Renata Markosyan ◽  
Patrick Sproll ◽  
Brian J. Stevenson ◽  
Malgorzata Sajek ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Signaling Pathway ◽  
Gene Mutation ◽  
Gene Mutations ◽  
Androgen Insensitivity Syndrome ◽  
Homologous Gene ◽  
Gene Encoding ◽  
Androgen Insensitivity ◽  
Disorder Of Sexual Development ◽  
Partial Androgen Insensitivity Syndrome

Androgen insensitivity syndrome (AIS), manifesting incomplete virilization in 46,XY individuals, is caused mostly by androgen receptor (AR) gene mutations. Therefore, a search for AR mutations is a routine approach in AIS diagnosis. However, some AIS patients lack AR mutations, which complicates the diagnosis. Here, we describe a patient suffering from partial androgen insensitivity syndrome (PAIS) and lacking AR mutations. The whole exome sequencing of the patient and his family members identified a heterozygous FKBP4 gene mutation, c.956T>C (p.Leu319Pro), inherited from the mother. The gene encodes FKBP prolyl isomerase 4, a positive regulator of the AR signaling pathway. This is the first report describing a FKBP4 gene mutation in association with a human disorder of sexual development (DSD). Importantly, the dysfunction of a homologous gene was previously reported in mice, resulting in a phenotype corresponding to PAIS. Moreover, the Leu319Pro amino acid substitution occurred in a highly conserved position of the FKBP4 region, responsible for interaction with other proteins that are crucial for the AR functional heterocomplex formation and therefore the substitution is predicted to cause the disease. We proposed the FKBP4 gene as a candidate AIS gene and suggest screening that gene for the molecular diagnosis of AIS patients lacking AR gene mutations.

Prenatal prediction of androgen insensitivity syndrome using exon 1 polymorphism of the androgen receptor gene

1992 ◽  
Vol 43 (7) ◽  
pp. 659-663 ◽  
Author(s):  
Jean Marc Lobaccaro ◽  
Serge Lumbroso ◽  
Françoise Carré Pigeon ◽  
Jean-Louis Chaussain ◽  
Jean-Edmond Toublanc ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Receptor Gene ◽  
Androgen Receptor Gene ◽  
Androgen Insensitivity Syndrome ◽  
Androgen Insensitivity ◽  
Exon 1

Analysis of a Mutant Androgen Receptor Offers a Treatment Modality in a Patient with Partial Androgen Insensitivity Syndrome

1998 ◽  
Vol 33 (2) ◽  
pp. 222-226 ◽  
Author(s):  
Christian Radmayr ◽  
Zoran Culig ◽  
Alfred Hobisch ◽  
Stefan Corvin ◽  
Georg Bartsch ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Treatment Modality ◽  
Androgen Insensitivity Syndrome ◽  
Androgen Insensitivity ◽  
Partial Androgen Insensitivity Syndrome

scholarly journals Partial androgen insensitivity syndrome presenting as pubertal gynecomastia: clinical and hormonal findings and a novel mutation in the androgen receptor gene

2018 ◽  
Vol 2018 ◽  
Author(s):  
Priya Vaidyanathan ◽  
Paul Kaplowitz
Keyword(s):  
Androgen Receptor ◽  
Novel Mutation ◽  
Receptor Gene ◽  
Androgen Receptor Gene ◽  
Androgen Insensitivity Syndrome ◽  
List Type ◽  
Androgen Insensitivity ◽  
Estrogen Production ◽  
Partial Androgen Insensitivity Syndrome ◽  
Pubertal Gynecomastia

Summary Pubertal gynecomastia is common, can be seen in 65% of the adolescent boys and is considered physiological. It is thought to be due to transient imbalance between the ratio of testosterone and estradiol in the early stages of puberty. It resolves in 1–2 years and requires no treatment. However, more persistent and severe pubertal gynecomastia is less common and can be associated with pathological disorders. These can be due to diminished androgen production, increased estrogen production or androgen resistance. We report a case of persistent pubertal gynecomastia due to partial androgen insensitivity syndrome (PAIS), classical hormone findings and a novel mutation in the androgen receptor (AR) gene. Learning points: Laboratory testing of follicle-stimulating hormone (FSH), leutinizing hormone (LH) and testosterone for pubertal gynecomastia is most helpful in the setting of undervirization. The hormonal finding of very high testosterone, elevated LH and estradiol and relatively normal FSH are classical findings of PAIS. Gynecomastia due to PAIS will not resolve and surgery for breast reduction should be recommended.

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