SOX3 Overdosage Permits Normal Sex Development in Females with Random X Inactivation

Igarashi, Maki; Mikami, Hitoshi; Katsumi, Momori; Miyado, Mami; Izumi, Yasukatsu; Ogata, Tsutomu; Fukami, Maki

doi:10.1159/000377653

Cited by 7 publications

(5 citation statements)

References 20 publications

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“…Although SOX3 does not seem to be required for normal testicular differentiation, its overexpression in the developing XX mouse gonad provokes testicular development, by synergizing with SF1 to upregulate SOX9 expression . It should, however, be noticed that a SOX3 duplication may not be sufficient to induce testicular differentiation when the regulatory sequences are lacking in the duplicated DNA fragment …”

mentioning

confidence: 98%

46,XX ovotesticular DSD associated with a SOX3 gene duplication in a SRY‐negative boy

Grinspon

Nevado

Alvarez

et al. 2016

Clinical Endocrinology

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confidence: 98%

46,XX ovotesticular DSD associated with a SOX3 gene duplication in a SRY‐negative boy

Grinspon

Nevado

Alvarez

et al. 2016

Clinical Endocrinology

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“…Most cases are maternally inherited. However, the mothers usually exhibit a normal phenotype, which may be due to skewed inactivation of the affected X chromosome (Arya et al, 2019; Hol et al, 2000); low penetrance of DSD caused by SOX3 overdosage has also been suggested (Igarashi et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

SOX3 duplication in a boy with 46,XX ovotesticular disorder of sex development and his 46,XX sister with atypical genitalia: Probable germline mosaicism

Oliveira

Barros

Santos

et al. 2022

American J of Med Genetics Pt A

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Ovotesticular disorders of sex development (OT‐DSD) are characterized by ovarian follicles and seminiferous tubules in the same individual, with a wide range of atypical genitalia. We report on two sibs with atypical genitalia and SRY‐negative 46,XX DSD, OT‐DSD was confirmed only in the boy, while the girl had bilateral ovaries. Chromosome microarray analysis (CMA) showed a 737‐kb duplication at Xq27.1 including the entire SOX3 gene in both sibs, which was confirmed by quantitative real time PCR. Also, X chromosome inactivation assay showed random inactivation in both sibs. Whole exome sequencing revealed no pathogenic or likely pathogenic variant. CMA of the parents showed normal results for both, suggesting that germline mosaicism could be the reason of recurrence of this duplication in the siblings. Our results support a pathogenic role of SOX3 overexpression in 46,XX subjects leading to variable DSD phenotypes.

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“…In XX mice lacking the SRY gene, it was found that the expression of the SOX3 gene with the acquired function was related to partial differentiation of testis. Overexpression of SOX3, synergistically expression with SF1, upregulated SOX9 stimulated gonad development into testis in XX mice [9,40]. SRY gene was derived from a new mutation in the regulatory region of the SOX3 gene and expressed in the early gonad.…”

Section: Discussionmentioning

confidence: 99%

Identification of an SRY-Negative 46,XX Infertility Male with a Heterozygous Deletion Downstream of SOX3 Gene

Qin

Wang

2021

Preprint

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Background: A male individual with a non-chimeric karyotype of 46,XX is very rare. We explored the genetic aetiology of an infertility male with 46,XX and SRY negative.Methods: The peripheral blood sample was collected from the patient and subjected to a range of genetic testing, including conventional chromosomal karyotyping, short tandem repeat (STR) analysis for chromosome 13, 18, 21, X, Y contained SRY gene, azoospermia factor (AZF) deletion analysis including SRY gene, fluorescence in situ hybridization (FISH) with specific probes for CSP X/CSP Y/SRY, chromosomal microarray analysis (CMA) for genomic copy number variations (CNVs), and whole-genome analysis(WGA) for SNV&InDel variants, and the X chromosome inactivation (XCI) analysis for AR gene.Results: The patient was found to have a 46,XX karyotype. Neither AZFa+b+c nor SRY band was detected in the electrophoresis result. FISH results of both interphase cells with CSPX/CSPY probe and metaphase cells with CSPX/CSPY/SRY probe showed two green fluorescence signals at the centromeres of X chromosomes, but no Y chromosome and SRY fluorescence signal. QF-PCR results showed that the patient had only the AMELX fluorescence peak of the X chromosome but no AMELY and SRY fluorescence peak. All results of the Karyotype, FISH, and STR did not suggest limited Y chimerism. CMA showed he had a heterozygous deletion of about 867 kb in Xq27.1 (hg19: chrX: 138,612,879-139,480,163 bp), located at 104 kb downstream of SOX3 gene, including F9, CXorf66, MCF2 and ATP11C; Meanwhile, whole-genome sequencing also found no SNV&InDel mutation associated with abnormal sex development. 75% X chromosome inactivation was detected.Conclusions: Although the pathogenicity of 46,XX male patients with SRY negative remains unclear, SOX3 expression of the acquired function may be associated with partial testis differentiation. Therefore, copy number variation of SOX3 gene and regulatory region should be performed routinely for these patients.

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SOX3 Overdosage Permits Normal Sex Development in Females with Random X Inactivation

Cited by 7 publications

References 20 publications

46,XX ovotesticular DSD associated with a SOX3 gene duplication in a SRY‐negative boy

46,XX ovotesticular DSD associated with a SOX3 gene duplication in a SRY‐negative boy

SOX3 duplication in a boy with 46,XX ovotesticular disorder of sex development and his 46,XX sister with atypical genitalia: Probable germline mosaicism

Identification of an SRY-Negative 46,XX Infertility Male with a Heterozygous Deletion Downstream of SOX3 Gene

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