In silico and functional studies reveal novel loss-of-function variants of SRD5A2, but no variants explaining excess 5α-reductase activity

Katharopoulos, Efstathios; Sauter, Kay Sara; Pandey, Amit V.; Flück, Christa E.

doi:10.1016/j.jsbmb.2019.01.017

Cited by 5 publications

(7 citation statements)

References 85 publications

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“…A 3D protein model for SRD5A2 protein was recently constructed. 58 That model suggests that the SRD5A2 protein is comprised of six α-helices and two smaller loops corresponding to transmembrane domains. According to this model, the residues Y98, N102, Y107, L167, R171, H231, and Y235 are in direct contact with NADPH in the binding cavity.…”

Section: Functional Studies On Allelic Variants Of the Srd5a2 Genementioning

confidence: 99%

“…The exon 4 is made up of 28 conserved amino acids (28 out 49 = 57%). 58 Among the variants in homozygous located at exon 4 in the literature, 66 out of 68 (97%) are in conserved amino acids. Functional analysis of some variants in the exon 4 showed either no residual activity (p.Gly196Ser, p.Glu197Asp, p. Ala2017Asp, p.Pro212Arg, p.Leu224Pro, p.Ala228Val, and p.His230Pro) or alter the affinity of the enzyme for NADPH (p.Asn193Ser and p.Gly196Ser).…”

Section: Genotype-phenotype Relationship In Individuals With 5α-reducmentioning

confidence: 99%

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Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide

Batista¹,

Mendonca²

2020

TACG

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The conversion of testosterone into dihydrotestosterone is catalyzed by the 5αreductase type 2 enzyme which plays a crucial role in the external genitalia virilization. It is encoded by the SRD5A2 gene. Allelic variants in this gene cause a 46,XY DSD with no genotype-phenotype relationship. It was firstly reported in the early 70s from isolated clusters. Since then, several cases have been reported. Putting together, it will expand the knowledge on the molecular bases of androgen milieu. Methods: We searched for SRD5A2 allelic variants (AV) in the literature (PubMed, Embase, MEDLINE) and websites (ensembl, HGMD, ClinVar). Only cases with AV in both alleles, either in homozygous or compound heterozygous were included. The included cases were analyzed according to ethnicity, exon, domain, aminoacid (aa) conservation, age at diagnosis, sex assignment, gender reassignment, external genitalia virilization and functional studies. External genitalia virilization was scored using Sinnecker scale. Conservation analysis was carried out using the CONSURF platform. For categorical variables, we used X2 test and Cramer's V. Continuous variables were analyzed by t test or ANOVA. Concordance was estimated by Kappa. Results: We identified 434 cases of 5ARD2 deficiencies from 44 countries. Most came from Turkey (23%), China (17%), Italy (9%), and Brazil (7%). Sixty-nine percent were assigned as female. There were 70% of homozygous allelic variants and 30% compound heterozygous. Most were missense variants (76%). However, small indels (11%), splicing (5%) and large deletions (4%) were all reported. They were distributed along with all exons with exon 1 (33%) and exon 4 (25%) predominance. Allelic variants in the exon 4 (NADPH-binding domain) resulted in lower virilization (p<0.0001). The codons 55, 65, 196, 235 and 246 are hotspots making up 25% of all allelic variants. Most of them (76%) were located at conserved aa. However, allelic variants at non-conserved aa were more frequently indels (28% vs 6%; p<0.01). The overall rate of gender change from female to male ranged from 16% to 70%. The lowest rate of gender change from female to male occurred in Turkey and the highest in Brazil. External genitalia virilization was similar between those who changed and those who kept their assigned gender. The gender change rate was significantly different across the countries (V=0.44; p<0.001) even with similar virilization scores. Conclusion: 5ARD2 deficiency has a worldwide distribution. Allelic variants at the NADPHligand region cause lower virilization. Genitalia virilization influenced sex assignment but not gender change which was influenced by cultural aspects across the countries. Molecular diagnosis influenced on sex assignment, favoring male sex assignment in newborns with 5α-reductase type 2 deficiency.

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Section: Functional Studies On Allelic Variants Of the Srd5a2 Genementioning

confidence: 99%

Section: Genotype-phenotype Relationship In Individuals With 5α-reducmentioning

confidence: 99%

Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide

Batista¹,

Mendonca²

2020

TACG

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“…An alternative pathway for androgen biosynthesis could explain it since androstenediol can generate DHT through the androgen backdoor pathway [Reisch et al, 2019]. A 3D protein model for SRD5A2 was recently constructed [Katharopoulos et al, 2019]. This model suggests that the SRD5A2 residues Y98, N102, Y107, L167, R171, H231, and Y235 are in direct contact with NADPH at the binding cavity.…”

Section: Functional Studies On Srd5a2 Allelic Variantsmentioning

confidence: 99%

The Molecular Basis of 5α-Reductase Type 2 Deficiency

Batista

Mendonca

2022

Sex Dev

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The 5α-reductase type 2 enzyme catalyzes the conversion of testosterone into dihydrotestosterone, playing a crucial role in male development. This enzyme is encoded by the SRD5A2 gene, which maps to chromosome 2 (2p23), consists of 5 exons and 4 introns, and encodes a 254 amino acid protein. Disruptions in this gene are the molecular etiology of a subgroup of differences of sex development (DSD) in 46,XY patients. Affected individuals present a large range of external genitalia undervirilization, ranging from almost typically female external genitalia to predominantly typically male external genitalia with minimal undervirilization, including isolated micropenis. This is an updated review of the implication of the SRD5A2 gene in 5α-reductase type 2 enzyme deficiency. For that, we identified 451 cases from 48 countries of this particular 46,XY DSD from the literature with reported variants in the SRD5A2 gene. Herein, we present the SRD5A2 mutational profile, the SRD5A2 polymorphisms, and the functional studies related to SRD5A2 variants to detail the molecular etiology of this condition.

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“…The study demonstrated that tocopherols occupy the SRD5A2 binding pocket similarly to finasteride but display distinct binding patterns. SRD5A2 contains seven transmembrane α-helices with NADPH buried in cytosolic loops [7]. The post-MD binding pose showed that all ligands enter the port and mainly interact with residues in TM2 and TM4.…”

Section: Post-molecular Dynamics Simulation Binding Mode Analysismentioning

confidence: 99%

“…SRD5A comprises five members, SRD5A1, SRD5A2, SRD5A3, and the little characterised glycoprotein synaptic 2 (GSPN2) and GSPN2-like [5]. SRD5As are dihydronicotinamide adenine dinucleotide phosphate (NADPH)-dependent [6] and play a significant role in steroidogenesis by catalysing 4-ene-3-keto steroids into more active 5α-reduced derivatives, including the reduction of testosterone (T) to dihydrotestosterone (DHT) [7]. SRD5A1, SRD5A2, and SRD5A3 are encoded by separate genes: SRD5A1, SRD5A2, and SRD5A3, respectively.…”

Section: Introductionmentioning

confidence: 99%

Effects on Steroid 5-Alpha Reductase Gene Expression of Thai Rice Bran Extracts and Molecular Dynamics Study on SRD5A2

Khantham

Yooin

Sringarm

et al. 2021

Biology

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Steroid 5-alpha reductases (SRD5As) are responsible for the conversion of testosterone to dihydrotestosterone, a potent androgen, which is the aetiologic factor of androgenetic alopecia. This study aimed to compare the SRD5A gene expression suppression activity exerted by Thai rice bran extracts and their components and investigate the interactional mechanism between bioactive compounds and SRD5A2 using molecular dynamics (MD) simulation. Bran of Oryza sativa cv. Tubtim Chumphae (TRB), Yamuechaebia Morchor (YRB), Riceberry (RRB), and Malinil Surin (MRB), all rice milling by-products, was solvent-extracted. The ethanolic extract of TRB had the highest sum of overall bioactive compounds (γ-oryzanol; α-, β-, and γ-tocopherol; phenolics; and flavonoids). Among all extracts, TRB greatly downregulated the expression of SRD5A1, SRD5A2, and SRD5A3; there were no significant differences between TRB and finasteride regarding SRD5A suppression. The linear relationship and principal component analysis supported that the α-tocopherol content was correlated with the SRD5A suppression exerted by TRB. Furthermore, MD simulation demonstrated that α-tocopherol had the highest binding affinity towards SRD5A2 by interacting with residues Phe118 and Trp201. Our findings indicate that α-tocopherol effectively downregulates the expression of SRD5A genes and inhibits SRD5A2 activity, actions that are comparable to standard finasteride. TRB, a source of α-tocopherol, could be developed as an anti-hair loss product.

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In silico and functional studies reveal novel loss-of-function variants of SRD5A2, but no variants explaining excess 5α-reductase activity

Cited by 5 publications

References 85 publications

<p>Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide</p>

<p>Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide</p>

The Molecular Basis of 5α-Reductase Type 2 Deficiency

Effects on Steroid 5-Alpha Reductase Gene Expression of Thai Rice Bran Extracts and Molecular Dynamics Study on SRD5A2

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