Somatic mutations in the androgen receptor gene as the cause of androgen insensitivity syndrome

2019 ◽  
Vol 65 (4) ◽  
pp. 268-272
Author(s):  
Natalia Yu. Kalinchenko ◽  
Anna A. Kolodkina ◽  
Vasiliy M. Petrov ◽  
Evgeniy V. Vasiliev ◽  
Anatoly N. Tiulpakov
Keyword(s):  
Somatic Mutations ◽  
Receptor Gene ◽  
Molecular Genetic ◽  
Somatic Mosaicism ◽  
Point Mutations ◽  
Disorders Of Sex Development ◽  
Androgen Insensitivity Syndrome ◽  
Normal Female ◽  
Genetic Characteristics ◽  
Androgen Insensitivity

Androgen insensitivity syndrome is an X-linked disorder characterized by either complete or partial insensitivity of target tissues to androgens. This disease is caused by mutations in the AR gene located on the Х chromosome. Currently, there are no distinct clinical, biochemical, or hormonal markers that would allow one to differentiate androgen insensitivity syndrome from a number of other forms of 46,XY disorders of sex development. Therefore, final verification of this condition is based on the results of molecular genetic tests. Although more than 1,000 point mutations in the AR gene have been reported, somatic mutations in this gene have been described rather rarely. However, this very type of mutations makes the course of this disease difficult to predict, since various cells in the human body contain both normal and mutant receptors. Somatic mosaicism can cause spontaneous masculization during puberty in individuals born with a completely normal female phenotype. In this case report, we describe the phenotypic and molecular genetic characteristics of eight patients with various forms of androgen insensitivity syndrome caused by somatic mutations in the AR gene.

scholarly journals Mosaicism due to a Somatic Mutation of the Androgen Receptor Gene Determines Phenotype in Androgen Insensitivity Syndrome1

1997 ◽  
Vol 82 (11) ◽  
pp. 3584-3589
Author(s):  
Paul-Martin Holterhus ◽  
Hennie T. Brüggenwirth ◽  
Olaf Hiort ◽  
Annette Kleinkauf-Houcken ◽  
Klaus Kruse ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Stop Codon ◽  
Receptor Gene ◽  
Molecular Genetic ◽  
Somatic Mosaicism ◽  
Premature Stop Codon ◽  
Tanner Stage ◽  
Careful Examination ◽  
Wild Type ◽  
Androgen Insensitivity

Premature stop codons of the human androgen receptor (AR) gene are usually associated with a complete androgen insensitivity syndrome. We, however, identified an adult patient with a 46,XY karyotype carrying a premature stop codon in exon 1 of the AR gene presenting with signs of partial virilization: pubic hair Tanner stage 4 and clitoral enlargement. No other family members were affected. A point mutation at codon position 172 of the AR gene was detected that replaced the original TTA (Leu) with a premature stop codon TGA (opal). Careful examination of the sequencing gel, however, also identified a wild-type allele, indicating a mosaicism. In addition, elimination of the unique AflII recognition site induced by the mutation was incomplete, thus confirming the coexistence of mutant and wild-type AR alleles in the patient. Normal R1881 binding and a normal 110/112-kDa AR doublet in Western immunoblots consolidated the molecular genetic data by demonstrating the expression of the wild-type AR in the patient’s genital skin fibroblasts. Transfection analysis revealed that only relatively high plasmid concentrations carrying the mutated AR complementary DNA lead to expression of a shortened AR due to downstream reinitiation at methionine 189. Thus, reinitiation does not play a role in the presentation of the phenotype; rather, the partial virilization is caused by the expression of the wild-type AR due to a somatic mosaic. We conclude that somatic mosaicism of the AR gene can represent a substantial factor for the individual phenotype by shifting it to a higher degree of virilization than expected from the genotype of the mutant allele alone.

Partial androgen insensitivity syndrome due to somatic mosaicism of the androgen receptor

2018 ◽  
Vol 31 (2) ◽  
pp. 223-228 ◽  
Author(s):  
Rafael Loch Batista ◽  
Andresa De Santi Rodrigues ◽  
Aline Zamboni Machado ◽  
Mirian Yumie Nishi ◽  
Flávia Siqueira Cunha ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Gender Identity ◽  
Gender Role ◽  
Somatic Mosaicism ◽  
Disorders Of Sex Development ◽  
Androgen Insensitivity Syndrome ◽  
Gender Assignment ◽  
Allelic Variants ◽  
Androgen Insensitivity ◽  
And Gender

Abstract Background: Androgen insensitivity syndrome (AIS) is the most frequent etiology of 46,XY disorders of sex development (DSDs), and it is an X-linked disorder caused by mutations in the androgen receptor (AR) gene. AIS patients present a broad phenotypic spectrum and individuals with a partial phenotype present with different degrees of undervirilized external genitalia. There are more than 500 different AR gene allelic variants reported to be linked to AIS, but the presence of somatic mosaicisms has been rarely identified. In the presence of a wild-type AR gene, a significant degree of spontaneous virilization at puberty can be observed, and it could influence the gender assignment, genetic counseling and the clinical and psychological management of these patients and the psychosexual outcomes of these patients are not known. Case presentation: In this study, we report two patients with AR allelic variants in heterozygous (c.382G>T and c.1769-1G>C) causing a partial AIS (PAIS) phenotype. The first patient was raised as female and she had undergone a gonadectomy at puberty. In both patients there was congruency between gender of rearing and gender identity and gender role. Conclusions: Somatic mosaicism is rare in AIS and nonsense AR variant allelic can cause partial AIS phenotype in this situation. Despite the risk of virilization and prenatal androgen exposure, the gender identity and gender role was concordant with sex of rearing in both cases. A better testosterone response can be expected in male individuals and this should be considered in the clinical management.

scholarly journals Complete Androgen Insensitivity Syndrome: From Bench to Bed

2021 ◽  
Vol 22 (3) ◽  
pp. 1264
Author(s):  
Nina Tyutyusheva ◽  
Ilaria Mancini ◽  
Giampiero Igli Baroncelli ◽  
Sofia D’Elios ◽  
Diego Peroni ◽  
...  
Keyword(s):  
Receptor Gene ◽  
Hormone Replacement ◽  
Basic Research ◽  
Well Being ◽  
Androgen Receptor Gene ◽  
Androgen Insensitivity Syndrome ◽  
Primary Amenorrhea ◽  
Complete Androgen Insensitivity Syndrome ◽  
Androgen Insensitivity

Complete androgen insensitivity syndrome (CAIS) is due to complete resistance to the action of androgens, determining a female phenotype in persons with a 46,XY karyotype and functioning testes. CAIS is caused by inactivating mutations in the androgen receptor gene (AR). It is organized in eight exons located on the X chromosome. Hundreds of genetic variants in the AR gene have been reported in CAIS. They are distributed throughout the gene with a preponderance located in the ligand-binding domain. CAIS mainly presents as primary amenorrhea in an adolescent female or as a bilateral inguinal/labial hernia containing testes in prepubertal children. Some issues regarding the management of females with CAIS remain poorly standardized (such as the follow-up of intact testes, the timing of gonadal removal and optimal hormone replacement therapy). Basic research will lead to the consideration of new issues to improve long-term well-being (such as bone health, immune and metabolic aspects and cardiovascular risk). An expert multidisciplinary approach is mandatory to increase the long-term quality of life of women with CAIS.

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
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