Novel mutation in the ligand-binding domain of the androgen receptor gene （1790p） associated with complete androgen insensitivity syndrome

Mutations in the X-linked androgen receptor （AR） gene cause androgen insensitivity syndrome （AIS）, resulting in an impaired embryonic sex differentiation in 46,XY genetic men. Complete androgen insensitivity （CAIS） produces a female external phenotype, whereas cases with partial androgen insensitivity （PALS） have various ambiguities of the genitalia. Mild androgen insensitivity （MAIS） is characterized by undermasculinization and gynecomastia. Here we describe a 2-month-old 46,XY female patient, with all of the characteristics of CAIS. Defects in testosterone （T） and dihydrotestosterone （DHT） synthesis were excluded. Sequencing of the AR gene showed the presence in exon 6 of a T to C transition in the second base of codon 790, nucleotide position 2369, causing a novel missense Leu790Pro mutation in the ligand-binding domain of the AR protein. The identification of a novel AR mutation in a girl with CAIS provides significant information due to the importance of missense mutations in the ligand-binding domain of the AR, which are able to induce functional abnormalities in the androgen binding capability, stabilization of active conformation, or interaction with coactivators.

Complete androgen insensitivity syndrome caused by the c.2678C>T mutation in the androgen receptor gene:A case report

BACKGROUND Androgen insensitivity syndrome is an X-linked recessive genetic disease caused by mutations in the androgen receptor gene(AR).However,the underlying molecular mechanisms for the majority of AR variants remain unclear.In this study,we identified a point variant in three patients with complete androgen insensitivity syndrome(CAIS),summarized the correlation analysis,and performed a literature review.CASE SUMMARY The proband was raised as a girl.In infancy,she was first referred to hospital with a right inguinal hernia.Ultrasonography revealed the absence of a uterus and ovaries,and a testis-like structure located at the inguinal canal.Further diagnostic workup detected a 46,XY karyotype,and fluorescence in situ hybridization analysis showed the presence of the SRY gene.Histological analysis revealed the excised tissue to be testicular.Twelve years later,she was admitted to our hospital with a lack of breast development.Her pubic hair and breasts were Tanner stage I.She had normal female external genitalia.Blood hormone tests showed normal testosterone levels,low estradiol levels,and high gonadotropin levels.Her two siblings underwent similar examinations,and all three had a rare hemizygous missense mutation in AR:c.2678C>T.In vitro functional analyses revealed decreased nuclear translocation in AR-c.2678C>T mutation cells.CONCLUSION This case of CAIS was caused by an AR variant(c.2678C>T).Functional studies showed impaired nuclear translocation ability of the mutant protein.

Study of bone mineral density in Chinese patients with complete androgen insensitivity syndrome

Objective:To explore the characteristics of bone mineral density(BMD)and treatment inChinese patients with complete androgen insensitivity syndrome(CAIS).Methods:Fourteen cases of CAIS were studied retrospectively through analyzing and compa-ring BMD of pre-and post-gonadectomy with healthy Chinese men and women.BMD at the lum-bar spine and the femur were measured by dual energy X-ray absorptiometry(DXA).Results:There were 10 cases of CAIS having pre-gonadectomy DXA,in which 6 cases hadvery significantly reduced lumbar 2-4 BMD[(0.92±0.08)g/cm^2]comparing with both healthymen and women(P<0.01),5 cases had significantly reduced femur neck BMD[(0.89±0.12)g/cm^2]comparing with healthy men(P<0.05).There were 7 cases having 12 post-gonadectomyDXA,in which all lumbar 2-4 BMD[(0.954-0.06)g/cm^2]were reduced very significantly com-paring with both healthy men and women(P<0.01),femur neck BMD[(0.91±0.08)g/cm^2]were also reduced significantly comparing with healthy men(P<0.01)and women(P<0.05).Conclusion:There were different degrees of osteopenia in patients of CAIS,especially inlumbar vertebra.This suggests that both estrogen and androgen play important roles in the ac-quirement and maintenance of peak bone mass.

Phenotypic and molecular characteristics of androgen insensitivity syndrome patients

Androgen insensitivity syndrome （AIS）, an X-linked recessive genetic disorder of sex development, is caused by mutations in the androgen receptor （AR） gene, and is characterized by partial or complete inability of specific tissues to respond to androgens in individuals with the 46,XY karyotype. This study aimed to investigate AR gene mutations and to characterize genotype-phenotype correlations. Ten patients from unrelated families, aged 2-31 years, were recruited in the study. Based on karyotype, altered hormone profile, and clinical manifestations, nine patients were preliminarily diagnosed with complete AIS and one with partial AIS. Genetic analysis of AR gene revealed the existence of 10 different mutations, of which five were novel （c.2112 C〉G[p.STO4R], c.2290T〉A[p.Y764N], c.2626C〉T[p.Q876X], c.933dupC[p.K313Qfs＊28], and c.1067delC[p.A356Efs＊123]）; the other five were previously reported （c.1789G〉A[p.A597T], c.2566C〉T[p.R856C], c.2668G〉A[p.V890M], c.2679C〉T[p.P893L], and c.1605C〉G[p.Y535X]）. Regarding the distribution of these mutations, 60.0% were clustered in the ligand-binding domain of AR gene. Exons 1 and 8 of AR gene each accounted for 30.0% （3/10） of all mutations. Most of the truncation mutations were in exon 1 and missense mutations were mainly located in exons 4-8. Our study expands the spectrum of AR gene mutations and confirms the usefulness of AR gene sequencing to support a diagnosis of AIS and to enable prenatal or antenatal screening.

S578N mutation of the androgen receptor in an adolescent with complete androgen insensitivity syndrome

Androgen insensitivity syndrome （AIS） was first .described by the American gynecologist Morris in 1953 and was mitially described＇in 82 patients, The syndrome was designated testicular feminization syndrome , because the testes produce hormones with estrogen-like actions. Clinical AIS manifestations include the appearance of normal female external genitalia without internal female genital organs.

A novel arg616Cys mutation in the DNA-binding domain of complete androgen insensitivity syndrome in a Chinese family

Awide spectrum of Androgen insensitivity syndrome （AIS） occur due to mutations in the androgen receptor（AR）. The clinical presentation of AIS ranges from a typically male phenotype with decreased body hair and/ or oligospermia to a typically female phenotype with primary amenorrhea and without pubic and axillary hair;