Clinical, cytogenetic and molecular analysis of androgen insensitivity syndromes from south Indian cohort and detection and in-silico characterization of androgen receptor gene mutations

Abilash, V G; Radha, S.; Marimuthu, K. M.; Thangaraj, Kumarasamy; Arun, S; Nishu, Susmita Das; Priya, A Mohana; Meena, Jitendra K.; Anuradha, Deenadayalu

doi:10.1016/j.cca.2015.12.012

Cited by 7 publications

(4 citation statements)

References 34 publications

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“…More than 1,100 different pathogenic variants including deletions, duplications, insertions, and point variants have been documented in the AR gene (www.androgendb.mcgill.ca), with the majority being missense pathogenic variants. There are very few studies from India on clinical, biochemical, and molecular aspects of AIS, the majority being case reports [Abilash et al, 2016;Saranya et al, 2016;Akella, 2017], and no hotspot pathogenic variant has been identified [Nagaraja et al, 2010].…”

Section: Introductionmentioning

confidence: 99%

Clinical, Biochemical, and Molecular Characterization of Indian Children with Clinically Suspected Androgen Insensitivity Syndrome

Kumar

Sharma

Faruq

et al. 2021

Sex Dev

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This study describes the clinical, biochemical, and molecular characteristics of Indian children with 46,XY DSD and suspected androgen insensitivity syndrome (AIS). Fifty children (median age 3.0 years, range 0–16.5 years) with 46,XY DSD and a suspected diagnosis of AIS were enrolled. Sanger sequencing was performed to identify pathogenic variants in the androgen receptor (AR) gene and to study genotype-phenotype correlations. All 5 (100%) patients with CAIS and 14/45 (31%) patients with PAIS had pathogenic/likely pathogenic variants in the AR gene (overall, 14 different variants in 19 patients; 38.8%). There was no significant difference in clinical (cryptorchidism, hypospadias, or external masculinizing score) or biochemical parameters (gonadotropins and testosterone) between patients with or without pathogenic variants. However, patients with AIS were more likely to have a positive family history, be assigned female gender at birth, and present with gynaecomastia at puberty. Three novel pathogenic/likely pathogenic variants, including one splice donor site variant c.2318+1G>A, one frameshift variant p.H790Lfs*40, and one missense variant p.G821E, were identified in 3 patients with CAIS. The missense variant p.G821E was predicted as deleterious, damaging, disease-causing, and likely functionally inactive by in silico analysis and protein modelling study. Two previously not reported pathogenic/likely pathogenic variants, including p.R386H and p.G396R, were identified in patients with PAIS. This study contributes in expanding the spectrum of pathogenic variants in the AR gene in patients with AIS. Only 31% patients with a provisional diagnosis of PAIS had pathogenic variants in the AR gene, suggesting other possible mechanisms or candidate genes may be responsible for such a phenotypic presentation.

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Section: Introductionmentioning

confidence: 99%

Clinical, Biochemical, and Molecular Characterization of Indian Children with Clinically Suspected Androgen Insensitivity Syndrome

Kumar

Sharma

Faruq

et al. 2021

Sex Dev

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“…However, there are no definite genotype correlations observed between the different phenotypes. [11121314151617181920]…”

Section: Discussionmentioning

confidence: 99%

Mutational analysis of androgen receptor gene in two families with androgen insensitivity

Akella

2017

Indian J Endocr Metab

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Background:Androgen insensitivity syndrome (AIS) is a rare X-linked disorder due to mutations in the androgen receptor (AR) gene causing end-organ resistance to the androgenic hormone.Subjects and Methods:Genetic studies were carried out in two families by karyotype and targeted exome sequencing of the AR gene.Results:Two novel missense mutations were identified, p.L822P and p.P392S, in two families with complete androgen insensitivity (CAIS) and partial androgen insensitivity (PAIS), respectively. Both had 46, XY karyotype. The mother was a heterozygous carrier in PAIS and negative in CAIS. These two were novel mutations, reported for the first time, in the AR gene. In silico analysis predicted that both mutations were damaging. We reviewed the various reported Indian mutations in the AR gene.Conclusion:AR gene mutations cause a wide spectrum of disorders from CAIS to male infertility or primary amenorrhea. Early diagnosis is essential for gender assignment and further management, family counseling, and prenatal diagnosis.

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“…Oligogenic inheritance of DSD variants was observed for four individuals with a GATA4 or ZFPM2 variant. Both probands with the GATA4 p.P394T variant had an additional DSD gene variant; case 3 ZFPM2:NM_012082:c.1003C > G (p.L335V) (benign classification) and case 4 had a well-described pathogenic variant in the ligand binding domain of the androgen receptor (AR:NM_000044.4:exon7:c.2599G > A (p.V867M)) (Abilash et al, 2016;Li et al, 2017;Lubahn et al, 1989) in association with androgen resistance syndrome (AIS; MIM# 300068), consistent with the patients phenotype (Table S1). Two individuals with a ZFPM2 variant also had additional variants in diagnostic DSD such as AR and NR5A1 which also correlate with the described 46,XY phenotype (case 15: AR:NM_000044.4:exon5:c.2191G > A (p.V731M) and case 16: NR5A1:NM_004959.4:c.251G > A (p.R84H) (Köhler et al, 2008;Robevska et al, 2017).…”

Section: Dsd Genesmentioning

confidence: 99%

“…Oligogenic inheritance of DSD variants was observed for four individuals with a GATA4 or ZFPM2 variant. Both probands with the GATA4 p.P394T variant had an additional DSD gene variant; case 3 ZFPM2:NM_012082:c.1003C > G (p.L335V) (benign classification) and case 4 had a well-described pathogenic variant in the ligand binding domain of the androgen receptor (AR:NM_000044.4:exon7:c.2599G > A (p.V867M))(Abilash et al, 2016;Li et al, 2017;Lubahn et al, 1989) inF I G U R E 1 Protein schematic of GATA4 and ZFPM2/FOG2 showing coding variants identified in 46,XY individuals. (a) The human GATA4 protein (NP_002043) is 440 amino acids with the following functional elements: two highly conserved N-terminal and C-terminal zinc finger domains (N-Zn and C-Zn, grey filled boxes); three transactivation domains (TAD1-3); and a nuclear localization signal (NLS, black box).…”

mentioning

confidence: 99%

Analysis of variants in GATA4 and FOG2/ZFPM2 demonstrates benign contribution to 46,XY disorders of sex development

Bergen

Robevska

Eggers

et al. 2020

Molec Gen & Gen Med

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Background GATA‐binding protein 4 (GATA4) and Friend of GATA 2 protein (FOG2, also known as ZFPM2) form a heterodimer complex that has been shown to influence transcription of genes in a number of developmental systems. Recent evidence has also shown these genes play a role in gonadal sexual differentiation in humans. Previously we identified four variants in GATA4 and an unexpectedly large number of variants in ZFPM2 in a cohort of individuals with 46,XY Differences/Disorders of Sex Development (DSD) (Eggers et al, Genome Biology, 2016; 17: 243). Method Here, we review variant curation and test the functional activity of GATA4 and ZFPM2 variants. We assess variant transcriptional activity on gonadal specific promoters (Sox9 and AMH) and variant protein–protein interactions. Results Our findings support that the majority of GATA4 and ZFPM2 variants we identified are benign in their contribution to 46,XY DSD. Indeed, only one variant, in the conserved N‐terminal zinc finger of GATA4, was considered pathogenic, with functional analysis confirming differences in its ability to regulate Sox9 and AMH and in protein interaction with ZFPM2. Conclusions Our study helps define the genetic factors contributing to 46,XY DSD and suggests that the majority of variants we identified in GATA4 and ZFPM2/FOG2 are not causative.

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Clinical, cytogenetic and molecular analysis of androgen insensitivity syndromes from south Indian cohort and detection and in-silico characterization of androgen receptor gene mutations

Cited by 7 publications

References 34 publications

Clinical, Biochemical, and Molecular Characterization of Indian Children with Clinically Suspected Androgen Insensitivity Syndrome

Clinical, Biochemical, and Molecular Characterization of Indian Children with Clinically Suspected Androgen Insensitivity Syndrome

Mutational analysis of androgen receptor gene in two families with androgen insensitivity

Analysis of variants in GATA4 and FOG2/ZFPM2 demonstrates benign contribution to 46,XY disorders of sex development

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