Syndromic true hermaphroditism due to an R-spondin1 (<i>RSPO1</i>) homozygous mutation

Tomaselli, Sara; Megiorni, Francesca; Bernardo, Carmelilia De; Felici, Aldo; Marrocco, Giacinto; Maggiulli, Giorgio; Grammatico, Barbara; Remotti, Daniele; Saccucci, Pietro; Valentini, Ferdinando; Mazzilli, Maria Cristina; Majore, Silvia; Grammatico, Paola

doi:10.1002/humu.20665

Cited by 167 publications

(96 citation statements)

References 19 publications

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“…Histological analysis of one gonad from another XX patient carrying an RSPO1 homozygous mutation revealed the presence of both testicular and ovarian tissues (Tomaselli et al 2008), indicating that sex reversal was partial. Moreover, seminiferous tubules yield germ cell neoplasia and tumor cells were found in the stroma.…”

Section: R99mentioning

confidence: 99%

“…Disruption of the human RSPO1 gene in a recessive syndrome is characterized by female-to-male sex reversal, palmoplantar hyperkeratosis, a predisposition to squamous cell carcinoma, corneal opacity, onychodystrophy, and seminoma (Parma et al 2006, Tomaselli et al 2008. This suggests that RSPO1 functions as a tumor suppressor.…”

Section: Rspo a Family Of Genes Regulating Morphogenesis And Maintenmentioning

confidence: 99%

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R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation

Chassot¹,

Gillot²,

Chaboissier³

2014

Reproduction

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Sex differentiation is a unique developmental process. Starting from a bipotential gonad, it gives rise to the ovary and the testis, two highly specialized organs that differ morphologically and physiologically despite sharing common reproductive and endocrine functions. This highlights the specific plasticity of the gonadal precursors and the existence of complex antagonistic genetic regulation. Mammalian sex determination is controlled by paternal transmission of the Y-linked gene, sex-determining region Y (SRY). Using mouse models, it has been shown that the main role of Sry is to activate the expression of the transcription factor Sox9; either one of these two genes is necessary and sufficient to allow testicular development through Sertoli cell differentiation. Thus, defects in SRY/Sry and/or SOX9/Sox9 expression result in male-to-female sex reversal of XY individuals. Molecular mechanisms governing ovarian differentiation remained unknown for a long time, until the discovery of the roles of R-spondin1 (RSPO1) and WNT4. In XX individuals, activation of the b-catenin signaling pathway by the secreted proteins RSPO1 and WNT4 is required to allow granulosa cell differentiation and, in turn, ovarian differentiation. Thus, mutations in RSPO1 result in female-to-male sex reversal of XX patients, and mouse models have allowed the identification of genetic cascades activated by RSPO1 and WNT4 to regulate ovarian development. In this review, we will discuss the respective roles of RSPO1, WNT4, and the b-catenin signaling pathway during ovarian differentiation in mice.Reproduction (2014) 148 R97-R110

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Section: R99mentioning

confidence: 99%

Section: Rspo a Family Of Genes Regulating Morphogenesis And Maintenmentioning

confidence: 99%

R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation

Chassot¹,

Gillot²,

Chaboissier³

2014

Reproduction

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“…Mutations in human Rspo1 were identified in individuals with female-to-male sex reversal (Parma et al 2006) or XX true hermaphroditism (Tomaselli et al 2008), a disorder of gonadal development characterized by the presence of both ovarian and testicular tissue. These mutations result either in a stop codon immediately after the signal peptide or in a truncated protein lacking the first furinlike domain, and thus are linked to the inability of Rspo1 to activate Wnt signaling.…”

Section: Role Of Rspos In Embryonic Development and Diseasementioning

confidence: 99%

Secreted and Transmembrane Wnt Inhibitors and Activators

Cruciat

Niehrs

2012

Cold Spring Harbor Perspectives in Biology

539

450

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“…In addition, RSPO1 homozygous mutation accounts for syndromic true hermaphroditism (Tomaselli et al 2008); the mutation results in splicing variants lacking Ile95, and the register shift likely affects the nearby C79-C94 (disulfide 4) integrity.…”

mentioning

confidence: 99%

The structural basis of R-spondin recognition by LGR5 and RNF43

et al. 2013

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R-spondins (RSPOs) enhance Wnt signaling, affect stem cell behavior, bind to leucine-rich repeat-containing G-proteincoupled receptors 4-6, (LGR4-6) and the transmembrane E3 ubiquitin ligases RING finger 43/zinc and RING finger 3 (RNF43/ZNRF3). The structure of RSPO1 bound to both LGR5 and RNF43 ectodomains confirms their physical linkage. RSPO1 is sandwiched by LGR5 and RNF43, with its rod module of the cysteine-rich domain (CRD) contacting LGR5 and a hairpin inserted into RNF43. LGR5 does not contact RNF43 but increases the affinity of RSPO1 to RNF43, supporting LGR5 as an engagement receptor and RNF43 as an effector receptor. Disease mutations map to the RSPO1-RNF43 interface, which promises therapeutic targeting.Supplemental material is available for this article.Received April 14, 2013; revised version accepted May 17, 2013. Wnt signaling plays crucial roles in development across species. Underlying its evolutionary significance is the large repertoire and dynamic assembly of receptors, coreceptors, agonists, and antagonists involved in Wnt signaling regulation (Clevers and Nusse 2012;Niehrs 2012). The core apparatus comprises the serpentine transmembrane receptor Frizzled (Fz), the coreceptor LRP6 in the case of canonical Wnt/b-catenin pathways, and other receptors such as Syndecan and ROR for noncanonical pathways (Wnt/PCP, for instance). Recent revelation of the core WntFz complex structure resolved long-standing questions on the molecular basis of Wnt-Fz recognition (Janda et al. 2012). Beyond Wnt-Fz, much remains unknown about how other regulators assemble to modulate Wnt pathways.The secreted glycoproteins R-spondins 1-4 (RSPO1-4) were discovered as potent activators of Wnt signaling (Kamata et al. 2004;Kazanskaya et al. 2004;de Lau et al. 2012;Cruciat and Niehrs 2013). Their enigmatic nature is highlighted by their Wnt-dependent synergistic effects, their presence only in vertebrates plus selected invertebrates, and their low sequence homology with other Wnt signaling molecules (de Lau et al. 2012;Cruciat and Niehrs 2013). RSPOs consist of an N-terminal Cys-rich furin-like domain (CRD) necessary and sufficient for activities (Kazanskaya et al. 2004;Glinka et al. 2011), a thrombospondin (TSP) type I repeat domain for heparan sulfate proteoglycan binding (Ohkawara et al. 2011), and a C-terminal basic region of variable lengths. Underlying the critical role of the CRD in signaling, RSPO1 mutations in this region lead to XX sex reversal and skin abnormalities (palmoplantar keratosis) (Parma et al. 2006), and RSPO4 mutations result in developmental defect in fingernails and toenails (anonychia) (Blaydon et al. 2006). The identities of RSPO receptors had been controversial. It was originally suggested that RSPOs bind to Fz or LRP6 (Wei et al. 2007;Ohkawara et al. 2011); in another study, RSPOs were reported to antagonize the Wnt inhibitor Kremen. None of the results from these studies were confirmed, however (Binnerts et al. 2007).Most recently, several independent studies identified LGR4-6 (leucine-ri...

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Syndromic true hermaphroditism due to an R-spondin1 (RSPO1) homozygous mutation

Cited by 167 publications

References 19 publications

R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation

R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation

Secreted and Transmembrane Wnt Inhibitors and Activators

The structural basis of R-spondin recognition by LGR5 and RNF43

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