Novel Heterozygous Mutations of &lt;b&gt;&lt;i&gt;NR5A1&lt;/i&gt;&lt;/b&gt; and Their Functional Characteristics in Patients with 46,XY Disorders of Sex Development without Adrenal Insufficiency

Woo, Kyu Ha; Cheon, Buwon; Kim, Ja Hye; Cho, Jahyang; Kim, Gu-Hwan; Yoo, Han-Wook; Choi, Jin‐Ho

doi:10.1159/000431324

Cited by 15 publications

(17 citation statements)

References 31 publications

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“…This variant was not present in any of the 60,706 exomes in ExAC. A nearly identical frameshift variant, c.1151del, p.Leu384Argfs*7, was recently reported in a 46,XY female with clitoromegaly and was shown to have significantly decreased activity of the protein product SF-1 on functional assays[20]. Sequencing of Subject One’s parents revealed the same variant in the subject’s father.…”

Section: Resultsmentioning

confidence: 75%

Two Unrelated Undervirilized 46,XY Males with Inherited NR5A1 Variants Identified by Whole-Exome Sequencing

Swartz

Ciarlo²,

Guo³

et al. 2016

Horm Res Paediatr

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Background: Undervirilized 46,XY males with bifid scrotum often pose a diagnostic challenge, and the majority of cases typically do not receive a genetic diagnosis. NR5A1 mutations can be seen in 10-20% of the cases and are a relatively common cause of undervirilization. Methods: Whole-exome sequencing was utilized to study 10 undervirilized 46,XY subjects with bifid scrotum. Results: Exome sequencing identified novel NR5A1 variants, both affecting exon 7, in 2 of the 10 subjects with bifid scrotum. Subject 1 had a heterozygous frameshift variant, c.1150delC, p.Leu384fsTer1, within the ligand-binding domain inherited from his unaffected father. Subject 2 had a novel splice-site variant c.1139-2T>C, affecting the canonical splice acceptor site for exon 7 and also disrupting the ligand-binding domain. Both subjects had serum testosterone levels within the normal range as infants. Conclusions: We describe two novel NR5A1 variants, demonstrating mutations in this gene as a common cause of milder cases of 46,XY undervirilization. Whole-exome sequencing results yielded the diagnosis in 2 out of 10 cases without a previous diagnosis, supporting the value of this approach. Significant genotype-phenotype variability was also noted with Subject 1's paternal inheritance from his unaffected father.

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Section: Resultsmentioning

confidence: 75%

Two Unrelated Undervirilized 46,XY Males with Inherited NR5A1 Variants Identified by Whole-Exome Sequencing

Swartz

Ciarlo²,

Guo³

et al. 2016

Horm Res Paediatr

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“…This initial patient bearing the heterozygous p.Gly35Glu mutation presented with adrenal failure and gonadal dysgenesis with persistent Mullerian derivatives (Woo et al, 2015), a phenotype that closely resembled the phenotype observed in murine Nr5a1 knockout models (Luo et al, 1994). Gonadal dysgenesis and adrenal insufficiency were also present in the second reported NR5A1‐related 46,XY DSD, in a patient bearing the homozygous p.Arg92Gln mutation (Achermann et al, 2002).…”

Section: Discussionmentioning

confidence: 72%

“…More than 80 different NR5A1 variants, distributed across the full length of the protein, have been described and the majority are nonsynonymous mutations (Pedace et al, 2014; Tantawy et al, 2014; Woo et al, 2015; Fabbri et al, 2016). Most of these mutations are located in the DBD and are in a heterozygous state or compound heterozygous state with the p.Gly146Ala (rs1110061) variant, with the exception of two mild mutations described in homozygous state (Achermann et al, 2002; Soardi et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…The reviewed data of seventy‐two 46,XY DSD patients with NR5A1 mutations reported in the literature, for whom information on presence or absence of Müllerian derivatives was available, suggested that Müllerian derivatives are present in about 24% of the cases (Pedace et al, 2014; Tantawy et al, 2014; Woo et al, 2015; Fabbri et al, 2016). However, persistently elevated FSH levels after puberty found in all patients studied suggest an impairment of Sertoli cells function in post pubertal age (Pedace et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

Domenice¹,

Machado²,

Ferreira

et al. 2016

Birth Defects Research Pt C

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Steroidogenic factor 1 (NR5A1, SF‐1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1‐related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype‐phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian‐determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1‐related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever‐expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309–320, 2016. © 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.

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“…These findings are consistent with prior observations that identical NR5A1 mutations can be associated with broad phenotypic variations. 8,10,11 Indeed, C-terminal mutations of NR5A1 have been shown to cause 46,XY DSD of various clinical severities without any genotype–phenotype correlations (Supplementary Figure S1). 4–8 Our case provides an additional example of the intrafamilial phenotypic variation of NR5A1 abnormalities.…”

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confidence: 99%

A novel C-terminal truncating NR5A1 mutation in dizygotic twins

et al. 2017

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Nuclear receptor subfamily 5, group A, member 1 (NR5A1) is a nuclear receptor involved in gonadal and adrenal development. We identified a novel C-terminally truncating NR5A1 mutation, p.Leu423Trpfs*7, in dizygotic twins with 46,XY disorders of sex development. Our results highlight the functional importance of C-terminal region of NR5A1 and indicate that NR5A1 mutations can be associated with intrafamilial phenotypic variations, progressive testicular dysfunction, hypogonadotropic hypogonadism, and borderline adrenal dysfunction.

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Novel Heterozygous Mutations of <b><i>NR5A1</i></b> and Their Functional Characteristics in Patients with 46,XY Disorders of Sex Development without Adrenal Insufficiency

Cited by 15 publications

References 31 publications

Two Unrelated Undervirilized 46,XY Males with Inherited NR5A1 Variants Identified by Whole-Exome Sequencing

Two Unrelated Undervirilized 46,XY Males with Inherited NR5A1 Variants Identified by Whole-Exome Sequencing

Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

A novel C-terminal truncating NR5A1 mutation in dizygotic twins

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