The Molecular Basis of 5α-Reductase Type 2 Deficiency

Batista, Rafael Loch; Mendonca, Berenice B.

doi:10.1159/000525119

Cited by 9 publications

(3 citation statements)

References 101 publications

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“…Endocrine analysis (blood and urine) and a human chorionic gonadotropin (hCG) test at 4 weeks of age did not show signs of disturbed testosterone synthesis and did indicate the presence of male gonadal tissue (Table 1 ). The T/DHT ratio was normal, indicating normal conversion of T into DHT by 5-alpha reductase activity 15 . Genitography and ultrasound 1 day after birth as well as laparoscopy at age 1.5 years did not show signs of Mullerian structures or a rudimentary vagina.…”

Section: Resultsmentioning

confidence: 96%

LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome

Pozojevic,

Sivaprasad,

Laß

et al. 2024

Sci Rep

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Androgen insensitivity syndrome (AIS) is a difference of sex development (DSD) characterized by different degrees of undervirilization in individuals with a 46,XY karyotype despite normal to high gonadal testosterone production. Classically, AIS is explained by hemizygous mutations in the X-chromosomal androgen receptor (AR) gene. Nevertheless, the majority of individuals with clinically diagnosed AIS do not carry an AR gene mutation. Here, we present a patient with a 46,XY karyotype, born with undervirilized genitalia, age-appropriate testosterone levels and no uterus, characteristic for AIS. Diagnostic whole exome sequencing (WES) showed a maternally inherited LINE1 (L1) retrotransposon insertion in the 5′ untranslated region (5′UTR) of the AR gene. Long-read nanopore sequencing confirmed this as an insertion of a truncated L1 element of ≈ 2.7 kb and showed an increased DNA methylation at the L1 insertion site in patient-derived genital skin fibroblasts (GSFs) compared to healthy controls. The insertion coincided with reduced AR transcript and protein levels in patient-derived GSFs confirming the clinical diagnosis AIS. Our results underline the relevance of retrotransposons in human disease, and expand the growing list of human diseases associated with them.

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Section: Resultsmentioning

confidence: 96%

LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome

Pozojevic,

Sivaprasad,

Laß

et al. 2024

Sci Rep

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“…[1] Reported variant types include missense, nonsense, splice site, frameshift, and large deletions, with over 200 variants in ClinVar and 186 in HGMD. [8,9] Here, the couple had the common p.G203S variant, causing a glycine to serine change at residue 203 in the transmembrane domain, and the rare p.D193S variant, changing aspartic acid to serine at residue 193. The p.G203S variant reduces enzyme activity by ~60% and correlates with moderate to severe phenotypes, [7,8] while the p.D193S variant has not been functionally characterized.…”

Section: Discussionmentioning

confidence: 99%

Preimplantation genetic testing and prenatal diagnosis in a family with pseudovaginal perineoscrotal hypospadias: A case report

Chen,

Zhang,

Shi

et al. 2023

Medicine

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Rationale: Pseudovaginal perineoscrotal hypospadias (PPSH) is a rare autosomal recessive disorder of sex development caused by biallelic mutations in SRD5A2. PPSH is characterized by a vaginal-like blind ending perineal opening, penoscrotal hypospadias, and impaired masculinization. Patient concerns: We reported preimplantation genetic testing and prenatal diagnosis in a family with PPSH. Diagnosis: Whole-exome sequencing of the family identified 2 SRD5A2 pathogenic variants (c.578A>G and c.607G>A). Haplotype analysis showed that the variants were inherited from the previous generation of this family. Interventions: During subsequent in vitro fertilization, preimplantation genetic testing was performed on 9 embryos. One unaffected embryo was transferred, resulting in a singleton pregnancy. Outcomes: The prenatal diagnosis at 20 weeks’ gestation confirmed the fetus was unaffected. A healthy female infant weighing 3100 g and measuring 50 cm was delivered vaginally at 39+5 weeks of gestation. Lessons subsections: This case highlights the use of preimplantation genetic testing and prenatal diagnosis to prevent the transmission of PPSH in families at risk. Our approach provides an effective strategy for identification and management of families with autosomal recessive disorders like PPSH.

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“…5-α-reductase plays an important role in the development of distinctive sexual features in children, adolescents and young males. At the earliest stages of human life, 5-α-reductase catalyses the conversion of testosterone into DHT [25]. It has to be noted that there is backdoor pathway in which DHT is obtained in the reaction of androstanediol reduction by the aldo-keto reductase family 1 member C2 enzyme (AKR1C2).…”

Section: The Role Of Testosterone and 5-α-reductase Dht Ar In Agamentioning

confidence: 99%

The role of 5-α-reductase inhibition in supressing progression of male androgenetic alopecia − a postulate for further studies on possible application of saw palmetto extracts

Piwecki,

Urban,

Pełszyńska

2023

Ann. Acad. Med. Siles.

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W pracy przedstawiono mechanizm łysienia androgenowego u mężczyzn (male androgenetic alopecia – MAGA) z uwzględnieniem roli enzymu 5-α-reduktazy, która odpowiada za konwersję testosteronu, najważniejszego hormonu męskiego, do jego aktywnej formy – dihydrotestosteronu (DHT). Opisane zostały konsekwencje pobudzenia przez DHT receptorów androgenowych (androgen receptors – ARs), zlokalizowanych w chromosomie X komórek linii brodawkowej (dermal papilla cells – DPCs). Powoduje to transkrypcję genów uruchamianą przez androgeny, zostaje zaburzone odżywianie mieszka włosowego, ale przede wszystkim przyspieszeniu ulega moment zakończenia anagenu i przejścia do fazy katagenu. Przedstawiono również, w jaki sposób enzym ten może być poddawany działaniu molekuł pełniących funkcję jego inhibitorów. Ponadto zaprezentowano uzasadnienie dla prowadzenia bardziej dogłębnych badań poświęconych mechanizmom działania, w których ekstrakty palmy sabałowej (Serenoa repens) wywołują efekt inhibicji 5-α-reduktazy. Dodatkowo w pracy został zawarty postulat na rzecz rozpoznawania i pomiaru substancji aktywnych znajdujących się w ekstraktach palmy sabałowej, w tym dwóch najbardziej obiecujących związków fitosterolowych – stigmasterolu i β-sitosterolu – ze względu na udowodnioną już aktywność inhibitorową w stosunku do 5-α-reduktazy w ekstraktach z surowców pochodzących z innych gatunków roślin. W ramach postulatu na rzecz pogłębienia badań zwrócono uwagę na konieczność oceny wpływu stosowania ekstraktów z palmy sabałowej na cykl życia włosów, cykl życia mieszka włosowego, różne czynniki wzrostu i angiogenezę, a także aktywność układu immunologicznego czy stres oksydacyjny. Inne obszary obserwacji działania ekstraktów z palmy sabałowej mogłyby obejmować ich zastosowanie w terapiach w połączeniu z innymi ekstraktami roślinnymi lub środkami terapii, np. z osoczem bogatopłytkowym czy osoczem bogatym w fibrynę.

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The Molecular Basis of 5α-Reductase Type 2 Deficiency

Cited by 9 publications

References 101 publications

LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome

LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome

Preimplantation genetic testing and prenatal diagnosis in a family with pseudovaginal perineoscrotal hypospadias: A case report

The role of 5-α-reductase inhibition in supressing progression of male androgenetic alopecia − a postulate for further studies on possible application of saw palmetto extracts

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