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Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.

ABSTRACT: 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.S704R], 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.

SUBMITTER: Yuan SM

PROVIDER: S-EPMC6116692 | biostudies-literature | 2018 Sep-Oct

REPOSITORIES: biostudies-literature

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Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.

Yuan Shi-Min SM Zhang Ya-Nan YN Du Juan J Li Wen W Tu Chao-Feng CF Meng Lan-Lan LL Lin Ge G Lu Guang-Xiu GX Tan Yue-Qiu YQ

Asian journal of andrology 20180901 5

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 karyotyp ...[more]

PMID: 29785970

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Project description:BACKGROUND:Abnormal androgen receptor (AR) genes can cause androgen insensitivity syndrome (AIS), and AIS can be classified into complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS) and mild AIS. We investigated the characteristics of clinical manifestations, serum sex hormone levels and AR gene mutations of 39 AIS patients, which provided deeper insight into this disease. METHODS:We prospectively evaluated 39 patients with 46, XY disorders of sex development (46, XY DSD) who were diagnosed with AIS at the Department of Endocrinology of Shanghai Children's Hospital from 2014 to 2019. We analysed clinical data from the patients including hormone levels and AR gene sequences. Furthermore, we screened the AR gene sequences of the 39 AIS patients to identify probable mutations. RESULTS:The 39 AIS patients came from 37 different families; 19 of the patients presented CAIS, and 20 of them presented PAIS. The CAIS patients exhibited a higher cryptorchidism rate than the PAIS (100 and 55%, P?=?0.001). There were no significant difference between the CAIS and PAIS groups regarding the levels of inhibin B (INHB), sex hormone-binding globulin (SHBG), basal luteinizing hormone (LH), testosterone (T), or basal dihydrotestosterone (DHT), the T:DHT ratio, DHT levels after human chorionic gonadotropin (HCG) stimulation or T levels after HCG stimulation. However, the hormone levels of AMH (P?=?0.010), peak LH (P?=?0.033), basal FSH (P?=?0.009) and peak FSH (P?=?0.033) showed significant differences between the CAIS group and the PAIS group. Twenty-one reported pathogenic and 9 novel AR mutations were identified. Spontaneous AR mutations were found in 5 AIS patients, and 21 patients inherited mutations from their mothers, who carried heterozygous mutations. CONCLUSIONS:Forty-six XY DSD patients with cryptorchidism and female phenotypes were highly suspected of having AIS. We demonstrated that CAIS patients could not be distinguished by their hormone levels alone. Compared with PAIS patients, CAIS patients exhibited higher basal FSH, peak FSH, and peak LH hormone levels but lower AMH expression. We identified 21 reported pathogenic AR mutations and 9 novel AR mutations that led to different types of AIS. Missense mutations were the major cause of AIS and mostly occurred in exon 7 of the AR gene. These findings provided deeper insight into the diagnosis and classification of AIS and will even contributed to its clinical assessment.

Project description:BackgroundAndrogen insensitivity syndrome (AIS) is caused by abnormal androgen receptor (AR) genes that show variable genotypes and phenotypes. However, the correlation between genotype and phenotype is unclear.MethodsWe retrospectively evaluated 64 patients with AIS at Shanghai Children's Hospital from 2015 to 2022. We analysed the clinical data of the patients, including hormone levels, AR gene variants, and functional domains.ResultsVariants occurred in the 3 major functional domains in 56 patients, including 23 patients with complete androgen insensitivity syndrome (CAIS) and 33 with partial androgen insensitivity syndrome (PAIS). The incidence of nonscrotal fusion (P = 0.019) and proximal urethral opening (P = 0.0002) in the ligand-binding domain (LBD) group was higher than that in the non-LBD group. The phallus length in the LBD group was significantly shorter than that in the non-LBD group (P = 0.009). The external masculinization score (EMS) in the LBD group was significantly lower than that in the non-LBD group (P = 0.013). The levels of inhibin-B (INHB; P = 0.0007), basal luteinizing hormone (LH; P = 0.033), LH peak (P = 0.002), and testosterone (T) after human chorionic gonadotropin (HCG) stimulation (P = 0.001) in the LBD group were higher than those in the non-LBD group. There were 53 variants in 64 patients, including 42 reported and 11 novel AR variants, including p.Met247Arg, p.Asp266Glyfs*39, p.Arg362Serfs*140, p.Ala385Val, p.Glu541Asp, p.Pro613Leu, p.Pro695Leu, p.Asn757Asp, c.1616 + 1dup, c.1886-1G > A and exon 5-7 deletion.ConclusionsThe EMS of patients with AIS in the LBD group was significantly lower than that in the non-LBD group. The phallus length was shorter, and the incidences of proximal urethral opening and nonscrotal fusion were higher, suggesting that the phenotypes in the LBD group were more severe. The levels of INHB, basal LH, peak LH, and T after HCG stimulation in the LBD group were higher than those in the non-LBD group, suggesting that androgen resistance in the LBD group was more severe. We identified 53 variants in 64 patients: 42 reported and 11 novel AR variants. These findings provide new and deeper insight into AIS diagnosis and genetic assessment of AIS.

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Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.

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Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.

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