Aetiological bases of 46,XY disorders of sex development in the Hong Kong Chinese population

Chan, Antony C. S.; But, WM; Lee, C Y; Lam, YY; Ng, Ka Lun; Loung, P Y; Lam, Aimen; Cheng, Christina W.; Shek, Chi Chung; Wong, Wai‐Shan; Wong, K.F.; Wong, MY; Tse, W. Y.

doi:10.12809/hkmj144402

Cited by 13 publications

(12 citation statements)

References 16 publications

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“…Previous functional analyses suggest that NR5A1 p.Arg92Trp cannot activate testicular development via male pathway genes including Sox9 , Amh , and Cyp11a1 (Bashamboo et al., ). Instead these variants lose male‐pathway regulatory ability, this is consistent with the fact that these variants have also been described in 46,XY DSD (Bashamboo et al., ; Chan et al., ) where activation of testis differentiation is lost and ovarian development takes over. Consistent with these results, we found that neither the p.Arg92Trp variant nor the novel p.Ala260Val variant had increased SOX9 activation, thus in vitro there is no evidence for NR5A1 variants abnormally activating the testis pathway.…”

Section: Discussionsupporting

confidence: 83%

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NR5A1gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients

et al. 2018

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Several recent reports have described a missense variant in the gene NR5A1 (c.274C>T; p.Arg92Trp) in a significant number of 46,XX ovotesticular or testicular disorders of sex development (DSDs) cases. The affected residue falls within the DNA‐binding domain of the NR5A1 protein, however the exact mechanism by which it causes testicular development in 46,XX individuals remains unclear. We have screened a cohort of 26 patients with 46,XX (ovo)testicular DSD and identified three unrelated individuals with this NR5A1 variant (p.Arg92Trp), as well as one patient with a novel NR5A1 variant (c.779C>T; p.Ala260Val). We examined the functional effect of these changes, finding that while protein levels and localization were unaffected, variant NR5A1 proteins repress the WNT signaling pathway and have less ability to upregulate the anti‐testis gene NR0B1 . These findings highlight how NR5A1 variants impact ovarian differentiation across multiple pathways, resulting in a switch from ovarian to testis development in genetic females.

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Section: Discussionsupporting

confidence: 83%

“…The NR5A1 p.Ala260Val variant was extremely rare in the population (gnomAD frequency: 4.13e‐6) and predicted to be damaging in two of the four in silico algorithms used. It has been previously implicated in 46,XY DSD (Chan et al., ). These two NR5A1 variants were found in heterozygous form and flagged for functional validation.…”

Section: Resultsmentioning

confidence: 97%

NR5A1gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients

et al. 2018

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“…This mutation yields impaired 5 α‐reductase activity as a consequence of reduced NADPH binding capacity (Mendonca et al, ). The p.Asn193Ser mutation was first reported in an Iranian 5‐alpha‐reductase deficiency type 2 patient and has also been previously reported in Spanish (Fernández‐Cancio et al, ), Polish (Boudon et al, ; Fénichel et al, ), Chinese (Chan et al, ; Cheng et al, ; Fernández‐Cancio et al, ), African, Brazilian (Maimoun et al, ) and Mexican‐Mestizo (Vilchis et al, ) families. To date, around 130 different mutations have been described in the SRD5A2 gene causing 5‐alpha‐reductase type 2 deficiency.…”

Section: Discussionmentioning

confidence: 68%

Molecular investigation of mutations in androgen receptor and 5‐alpha‐reductase‐2 genes in 46,XY Disorders of Sex Development with normal testicular development

et al. 2019

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In this study, we aimed to determine androgen receptor (AR) and SRD5A2 gene mutations in 45 patients characterised by 46,XY Disorders of Sex Differentiation (DSD) signs with normal testicular development referred to the Children's Medical Center from February 2015 to September 2017. Karyotype and sex hormone analyses were performed. Cytogenetic investigation showed that seven patients were 46,XX DSD, six patients were chromosomal DSD and 32 patients were 46,XY DSD. Eight exons of the AR gene and five exons of the SRD5A2 gene were amplified. Two cases were affected with androgen insensitivity syndrome (AIS) (missense mutation on exon 7, position c.3637 G>A: p.R841H and position c.3610 G>A: p.R832Q), one case was affected with 5‐alpha‐reductase deficiency type 2 (missense mutation at c.578A>G: p.N193S on exon 4), and 22 cases (88%) did not demonstrate AIS or 5α‐RD2 gene abnormality. Due to the great impact of these disorders on human lifestyle, evaluation of genes involved can improve genetic counselling and therapeutic management. We focused on the AR and SRD5A2 genes in patients with 46,XY DSDs with normal testicular development referred to the Children's Medical Center from all over the country to eventually culminate in a reliable prenatal diagnosis protocol at this major referral centre giving service to a great number of families with consanguineous marriages.

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“…With any clinical picture consisting of genital anomalies at birth, renal symptomatology (facial edema, proteinuria and high blood pressure) during childhood and the diagnosis of renal failure during adolescence, rare genetic nephropathies, such as Frasier syndrome and Dennis Drash syndrome, must be considered. (7,20,23,24). In low-income settings such as ours, where genetic technology is not always available, the diagnosis of Frasier syndrome should be considered in any child with developmental abnormalities of the external genitalia presenting with isolated proteinuria and/or signs of impaired renal function during childhood or adolescence.…”

Section: Discussionmentioning

confidence: 99%

Suspicion of Frasier's syndrome in the nephrology unit of the Internal Medicine department of the HUEH: Case study and review of the literature.

Paul

Louis

Desravines

et al. 2021

Preprint

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ObjectiveFrasier syndrome is a rare genetic nephropathy characterized by the presence of progressive glomerulopathy with proteinuria associated with male pseudo hermaphroditism. This case study described a picture of a young boy where the clinical suspicion context reminded the Frasier Syndrome. To our knowledge, this case is the first described in Haiti.Case studyThis is a 19 years old young phenotypically male, born with a genital anomaly, was seen on referral at the nephrology/dialysis unit of the internal medicine department of HUEH for evaluation and follow-up. Insidious progression of symptoms had occurred over 3 years. Over three months of outpatient follow-up, he had four sets of renal labs drawn, and all showed impaired renal function. At the ultrasound a bilateral cryptorchidism is described in the inguinal, and presence of functional ovaries with follicles of variable size scattered in the parenchyma. So, in the light of these anamnestic, clinical and paraclinical findings we concluded to the diagnosis of end-stage renal failure by progressive glomerulopathy in a context of Frasier's syndrome.ConclusionWith any clinical picture consisting of genital anomalies at birth, renal symptomatology during childhood and the diagnosis of renal failure during adolescence, rare genetic nephropathies, such as Frasier syndrome must be considered.

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Aetiological bases of 46,XY disorders of sex development in the Hong Kong Chinese population

Cited by 13 publications

References 16 publications

NR5A1gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients

NR5A1gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients

Molecular investigation of mutations in androgen receptor and 5‐alpha‐reductase‐2 genes in 46,XY Disorders of Sex Development with normal testicular development

Suspicion of Frasier's syndrome in the nephrology unit of the Internal Medicine department of the HUEH: Case study and review of the literature.

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