Impaired Fibroblast Growth Factor Receptor 1 Signaling as a Cause of Normosmic Idiopathic Hypogonadotropic Hypogonadism

Raivio, Taneli; Sidis, Yisrael; Plummer, Lacey; Chen, Huaibin; Ma, Jinghong; Mukherjee, Abir; Jacobson-Dickman, Elka; Quinton, Richard; Vliet, Guy Van; Lavoie, Hélène B.; Hughes, Virginia; Dwyer, Andrew A.; Hayes, Frances J.; Xu, Shuyun; Sparks, Susan; Kaiser, Ursula B.; Mohammadi, Moosa; Pitteloud, Nelly

doi:10.1210/jc.2009-0179

Cited by 89 publications

(125 citation statements)

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“…4). FGFR1 R250 is involved in binding FGF8 (32), and was independently associated with another case of GnRH deficiency (33). Because FGFR1 requires HS 6-O-sulfation for interaction with FGF8 (32), the HS6ST1 R296W and FGFR1 R250Q mutations may synergize to compromise FGF signaling, consistent with prior reports of digenicity (17,24,34,35).…”

Section: Ihh Associated With Hs6st1 Mutations Displays Clinical Hetersupporting

confidence: 78%

Heparan sulfate 6-O-sulfotransferase 1 , a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism

Tornberg¹,

Sykiotis

Keefe

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Neuronal development is the result of a multitude of neural migrations, which require extensive cell-cell communication. These processes are modulated by extracellular matrix components, such as heparan sulfate (HS) polysaccharides. HS is molecularly complex as a result of nonrandom modifications of the sugar moieties, including sulfations in specific positions. We report here mutations in HS 6-O-sulfotransferase 1 (HS6ST1) in families with idiopathic hypogonadotropic hypogonadism (IHH). IHH manifests as incomplete or absent puberty and infertility as a result of defects in gonadotropin-releasing hormone neuron development or function. IHH-associated HS6ST1 mutations display reduced activity in vitro and in vivo, suggesting that HS6ST1 and the complex modifications of extracellular sugars are critical for normal development in humans. Genetic experiments in Caenorhabditis elegans reveal that HS cell-specifically regulates neural branching in vivo in concert with other IHH-associated genes, including kal-1, the FGF receptor, and FGF. These findings are consistent with a model in which KAL1 can act as a modulatory coligand with FGF to activate the FGF receptor in an HS-dependent manner.heparan sulfotransferase | Kallmann syndrome T he coordinated assembly of the nervous system in metazoans requires the migration of the large majority of neurons from their place of origin to their final destination in the brain (1). These processes require the complex interplay of many factors, including secreted and transmembrane proteins that mediate communication between cells. The activity of such factors is greatly influenced by the extracellular environment (2). For example, heparan sulfates (HSs), a class of molecularly diverse extracellular glycosaminoglycans, have been shown to be crucial for neural development in mice (3). From work in model organisms, it has become clear that much of the function of HS during neural development is embedded within complex modification patterns of the HS sugar residues (reviewed in refs. 4 and 5). HS modification patterns serve specific and instructive functions during neural development and are believed to regulate ligand-receptor interactions (6-8). These patterns arise as the consequence of nonuniform modifications of the sugar moieties, including sulfations, deacetylations, and epimerizations that are introduced by specific HS-modifying enzymes (9) (Fig. 1A). It is unknown whether the function of HS modifications impinges on normal human development and disease susceptibility.Idiopathic hypogonadotropic hypogonadism (IHH) is a clinically and genetically heterogeneous condition that is characterized by lack of sexual maturation and infertility in the absence of other organic etiologies (10). Patients with IHH either have a normal sense of smell [normosmic IHH (nIHH)] or have an impaired sense of smell (anosmia

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Section: Ihh Associated With Hs6st1 Mutations Displays Clinical Hetersupporting

confidence: 78%

Heparan sulfate 6-O-sulfotransferase 1 , a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism

Tornberg¹,

Sykiotis

Keefe

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Neither FGF was able to induce luciferase activity in cells transfected with an expression vector lacking an Fgfr cDNA (empty vector), whereas, as expected, FGF8, but not FGF10, induced luciferase activity significantly above background levels in cells transfected with a wild-type FGFR1c expression vector. FGFR1c was also activated by FGF2 to the same extent seen by Raivio et al (2009) (data not shown). These control conditions confirmed that there is no endogenous FGFR expression in L6 cells (Olwin and Hauschka 1989;Roghani et al 1996) and that there is endogenous FGF expression and/or perdurant FGF from the serum used to culture the L6 cells.…”

Section: Fgf10 Activates Fgfr3b P244r and Fgfr3c P244r But Not Their mentioning

confidence: 52%

“…Both the wild-type and mutated cDNAs were transferred into the pcDNA1 expression vector used by Chellaiah et al (1994) to express other Fgfr3 constructs. A human FGFR1c expression vector (Raivio et al 2009) was used as a control. The FGFresponsive OCFRE-luc vector was described previously (Newberry et al 1996).…”

Section: Transient Transfection Of L6 Myoblasts To Assay Fgfr Activitymentioning

confidence: 99%

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Genetic rescue of Muenke syndrome model hearing loss reveals prolonged FGF-dependent plasticity in cochlear supporting cell fates

Mansour

Urness

2013

Genes Dev.

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The stereotyped arrangement of cochlear sensory and supporting cells is critical for auditory function. Our previous studies showed that Muenke syndrome model mice (Fgfr3 P244R/+ ) have hearing loss associated with a supporting cell fate transformation of two Deiters' cells to two pillar cells. We investigated the developmental origins of this transformation and found that two prospective Deiters' cells switch to an outer pillar cell-like fate sequentially between embryonic day 17.5 (E17.5) and postnatal day 3 (P3). Unexpectedly, the Fgfr3 P244R/+ hearing loss and supporting cell fate transformation are not rescued by genetically reducing fibroblast growth factor 8 (FGF8), the FGF receptor 3c (FGFR3c) ligand required for pillar cell differentiation. Rather, reducing FGF10, which normally activates FGFR2b or FGFR1b, is sufficient for rescue of cochlear form and function. Accordingly, we found that the P244R mutation changes the specificity of FGFR3b and FGFR3c such that both acquire responsiveness to FGF10. Moreover, Fgf10 heterozygosity does not block the Fgfr3 P244R/+ supporting cell fate transformation but instead allows a gradual reversion of fate-switched cells toward the normal phenotype between P5 and at least P14. This study indicates that Deiters' and pillar cells can reversibly switch fates in an FGFdependent manner over a prolonged period of time. This property might be exploited for the regulation of sensory cell regeneration from support cells.

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“…Part of this phenomenon can be explained by the interaction of mutations in two or more genes/proteins (oligogenicity) as has been reported in several studies (19,25,28). Further, some patients with reversible CHH harbor mutations in genes implicated in CHH, (29) including cases of oligogenicity (30). Such reversal cases highlight the importance of environmental (i.e.…”

Section: Pathophysiology and Genetics Of Chhmentioning

confidence: 86%

MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism

Dwyer

Raivio

Pitteloud

2016

European Journal of Endocrinology

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Congenital hypogonadotropic hypogonadism (CHH) is characterized by lack of puberty and infertility. Traditionally, it has been considered a life-long condition yet cases of reversibility have been described wherein patients spontaneously recover function of the reproductive axis following treatment. Reversibility occurs in both male and female CHH cases and appears to be more common (~10-15%) than previously thought. These reversal patients span a range of GnRH deficiency from mild to severe and many reversal patients harbor mutations in genes underlying CHH. However, to date there are no clear factors for predicting reversible CHH. Importantly, recovery of reproductive axis function may not be permanent. Thus, CHH is not always life-long and the incidence of reversal warrants periodic treatment withdrawal with close monitoring and follow-up. Reversible CHH highlights the importance of environmental (epigenetic) factors such as sex steroid treatment on the reproductive axis in modifying the phenotype. This review provides an overview and an update on what is known about this phenomenon.

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Impaired Fibroblast Growth Factor Receptor 1 Signaling as a Cause of Normosmic Idiopathic Hypogonadotropic Hypogonadism

Abstract: Loss-of-function mutations in FGFR1 underlie 7% of nIHH with different degrees of impairment in vitro. These mutations act in concert with other gene defects in several cases, consistent with oligogenicity.

Cited by 89 publications

References 46 publications

Heparan sulfate 6-O-sulfotransferase 1 , a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism

Heparan sulfate 6-O-sulfotransferase 1 , a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism

Genetic rescue of Muenke syndrome model hearing loss reveals prolonged FGF-dependent plasticity in cochlear supporting cell fates

MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism

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