Alternative titles; symbols
HGNC Approved Gene Symbol: FGF8
Cytogenetic location: 10q24.32 Genomic coordinates (GRCh38): 10:101,770,109-101,780,369 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q24.32 | Hypogonadotropic hypogonadism 6 with or without anosmia | 612702 | Autosomal dominant | 3 |
Fibroblast growth factors are secreted proteins that interact with FGF tyrosine kinase receptors to mediate growth and development. Lorenzi et al. (1995) isolated a cDNA encoding Fgf8, or Aigf, from mouse testis. A 1.6-kb Fgf8 transcript was detected in testis, but not in other adult tissues analyzed. During development, expression of Fgf8 was restricted to embryonic days 9 through 13, suggesting to Lorenzi et al. (1995) that Fgf8 plays a role during a discrete stage of mouse embryogenesis.
Using mouse Aigf to screen a placenta genomic phage library, Tanaka et al. (1995) cloned human AIGF. The deduced 215-amino acid human protein is identical to mouse Aigf. RT-PCR detected AIGF expression in human prostate and breast cancer cell lines.
Gemel et al. (1996) noted that the mouse Fgf8 gene has at least 4 different first exons that can be alternatively spliced to generate at least 8 potential proteins, designated Fgf8a through Fgf8h, that differ at their N termini. Using mouse Fgf8g to screen a human placenta genomic DNA library, they obtained the human FGF8 genomic sequence and determined that it could generate transcripts corresponding to mouse Fgf8a, Fgf8b, Fgf8e, and Fgf8f, but not the other 4 mouse transcripts. FGF8B corresponds to the AIGF protein reported by Tanaka et al. (1995). The predicted mouse and human proteins share 98 to 100% identity.
By RT-PCR of a human prostate cancer cell line using primers based on mouse Fgf8, Ghosh et al. (1996) cloned FGF8A, FGF8B, and FGF8E. The deduced proteins contain 204, 215, and 233 amino acids, respectively. All 3 isoforms contain a predicted 23-amino acid signal sequence, and they differ only at the N termini of their mature forms; their C-terminal 180 amino acids are identical. Northern blot analysis of several adult and fetal tissues detected FGF8 expression in fetal kidney only. RT-PCR detected FGF8 expression in testis, prostate, and kidney, the only tissues examined. FGF8B was the predominant form in prostate, and both FGF8A and FGF8B were expressed in testis and kidney. FGF8B was also the predominant form expressed in normal prostate and prostate carcinoma cell lines.
Gemel et al. (1996) determined that the FGF8 gene contains 6 exons, including 4 alternative first exons, and spans about 6 kb.
Yoshiura et al. (1997) described the genomic sequence of human FGF8 and demonstrated conservation between the human and mouse sequences, including alternatively spliced exons in the mouse.
By isotopic in situ hybridization, Mattei et al. (1995) found that the Fgf8 gene maps to mouse chromosome 19 in region C3-D. On the basis of conserved regions of synteny between mouse chromosome 19 and human chromosomes (Copeland et al., 1993), they predicted that FGF8 maps to human chromosome 10q. Using a panel of human/rodent somatic cell hybrids, Lorenzi et al. (1995) demonstrated that the FGF8 gene is indeed located on human chromosome 10. White et al. (1995) mapped FGF8 to 10q25-q26 using Southern blots of somatic cell hybrid DNAs containing portions of chromosome 10. By fluorescence in situ hybridization and by genetic linkage analysis, Yoshiura et al. (1997) mapped the FGF8 gene to 10q24. Using somatic cell hybrid analysis and fluorescence in situ hybridization, Payson et al. (1996) mapped the FGF8 gene to 10q24.
Tanaka et al. (1995) showed that AIGF stimulated growth of human prostate carcinoma cells and mouse fibroblasts and mammary carcinoma cells in a dose-dependent manner.
Ghosh et al. (1996) transfected human FGF8B in mouse fibroblasts and found that it induced an elongated spindle shape morphology and permitted higher cell density at confluence. Furthermore, FGF8B-transfected cells were strongly tumorigenic when injected into nude mice. FGF8A and FGF8E were moderately transforming in transfected cells, and these cells were moderately tumorigenic.
FGF8, alternatively referred to as AIGF, was originally isolated from the conditioned medium of an androgen-dependent carcinoma cell line. The temporal and spatial patterns of FGF8 gene expression suggest that FGF8 is involved in gastrulation, regionalization of the brain, and organogenesis of the limb and face as an embryonic epithelial factor. The adult expression of FGF8 is restricted to gonads, including testes and ovaries. Payson et al. (1996) showed that FGF8 gene expression in a human breast cancer cell line is inducible by androgen. They stated that their findings will facilitate understanding of the molecular mechanism underlying hormone-responsive breast and prostate cancers.
FGF8 stimulates the androgen-dependent growth of mouse mammary carcinoma cells. Studies of mouse development also indicate that FGF8 may play an important role in growth and patterning of limbs, face, and central nervous system (Yoshiura et al., 1997).
Zammit et al. (2002) found that FGF8 is expressed in increased levels in breast cancer and in lactating human breast; it was also detected in human milk. A survey of other normal tissues showed that FGF8 is expressed in the proliferative cells of the skin and epithelial cells in colon, ovary, fallopian tube, and uterus.
Yu et al. (2009) showed that Fgf8 morphogen gradients in living zebrafish embryos are established and maintained by 2 essential factors: fast, free diffusion of single molecules away from the source through extracellular space, and a sink function of the receiving cells, regulated by receptor-mediated endocytosis. Evidence was provided by directly examining single molecules of Fgf8 in living tissue by fluorescence correlation spectroscopy, quantifying their local mobility and concentration with high precision. By changing the degree of uptake of Fgf8 into its target cells, Yu et al. (2009) were able to alter the shape of the Fgf8 gradient. Yu et al. (2009) concluded that their results demonstrated that a freely diffusing morphogen can set up concentration gradients in a complex multicellular tissue by a simple source-sink mechanism.
Role in Early Development
A molecular pathway leading to left-right asymmetry in the chick embryo has been described in which FGF8 is a right determinant and Sonic hedgehog (Shh; 600725) is a left determinant. Meyers and Martin (1999) presented evidence that in the mouse, FGF8 and Sonic hedgehog genes are also required for left-right axis determination, but with different functions from those reported in the chick. In the mouse, FGF8 is a left determinant, and Sonic hedgehog is required to prevent left determinants from being expressed on the right.
The precise specification of left-right asymmetry is an essential process for patterning internal organs in vertebrates. In mouse embryonic development, the symmetry-breaking process in left-right determination is initiated by a leftward extraembryonic fluid flow on the surface of the ventral node. Tanaka et al. (2005) showed that FGF signaling triggers secretion of membrane-sheathed objects 0.3 to 5 microns in diameter, termed 'nodal vesicular parcels' (NVPs), which carry Sonic hedgehog and retinoic acid. These NVPs are transported leftward by the fluid flow and eventually fragment close to the left wall of the ventral node. The silencing effects of an FGF receptor (FGFR2; 176943) inhibitor on NVP secretion and on a downstream rise in calcium were sufficiently reversed by exogenous Sonic hedgehog peptide or retinoic acid, suggesting that FGF-triggered surface accumulation of cargo morphogens may be essential for launching NVPs. Tanaka et al. (2005) proposed that NVP flow is a mode of extracellular transport that forms a left-right gradient of morphogens. Using time-lapse imaging, Tanaka et al. (2005) found that these NVPs were transported leftward once every 5 to 15 seconds.
Fgf8 and Fgf4 (164980) are coexpressed in the primitive streak of the gastrulating mouse embryo. Sun et al. (1999) found that Fgf8 -/- embryos failed to express Fgf4 in the streak. Other observations indicated that Fgf8 is essential for gastrulation and showed that signaling via FGF8 and/or FGF4 is required for cell migration away from the primitive streak.
Streit et al. (2000) showed that FGF8-coated beads induce expression of the chick Erni gene (605105) to initiate neural induction before gastrulation.
Vertebrate segmentation requires a molecular oscillator, the segmentation clock, acting in presomitic mesoderm (PSM) cells to set the pace at which segmental boundaries are laid down. Dubrulle et al. (2001) reported that FGF8, which is expressed in the posterior PSM, generates a moving wavefront at which level both segment boundary position and axial identity become determined. Furthermore, by manipulating boundary position in the chick embryo, they showed that Hox gene (see 142950) expression is maintained in the appropriately numbered somite rather than at an absolute axial position. These results implicated FGF8 in ensuring tight coordination of the segmentation process and spatiotemporal HOX gene activation.
Jung et al. (1999) studied the initiation of mammalian liver development from endoderm by fibroblast growth factors. Close proximity of cardiac mesoderm, which expresses FGF1 (131220), FGF2 (134920), and FGF8, causes the foregut endoderm to develop into the liver. Treatment of isolated foregut endoderm from mouse embryos with FGF1 or FGF2, but not FGF8, was sufficient to replace cardiac mesoderm as an inducer of the liver gene expression program, the latter being the first step of hepatogenesis. The hepatogenic response was restricted to endoderm tissue, which selectively coexpresses FGF receptors 1 (136350) and 4 (134935). Further studies with FGFs and their specific inhibitors showed that FGF8 contributes to the morphogenic outgrowth of hepatic endoderm. Thus, different FGF signals appear to initiate distinct phases of liver development during mammalian organogenesis.
Dubrulle and Pourquie (2004) demonstrated that transcription of Fgf8 mRNA is restricted to the growing posterior tip of the embryo in mouse. Fgf8 mRNA was progressively degraded in the newly formed tissues, resulting in the formation of an mRNA gradient in the posterior part of the embryo. This Fgf8 mRNA gradient was translated into a gradient of Fgf8 protein, which correlated with graded phosphorylation of the kinase AKT (164730), a downstream effector of FGF signaling. Such a mechanism provides an efficient means to monitor the timing of FGF signaling, coupling the differentiation of embryonic tissues to the posterior elongation of the embryo. In addition, Dubrulle and Pourquie (2004) concluded that this mechanism provides a novel model for morphogen gradient formation.
Ladher et al. (2005) demonstrated that Fgf8 is required for otic induction in chicken and mouse embryos.
Neugebauer et al. (2009) provided several lines of evidence showing that fibroblast growth factor signaling regulates cilia length and function in diverse epithelia during zebrafish and Xenopus development. Morpholino knockdown of Fgfr1 (136350) in zebrafish cell-autonomously reduced cilia length in Kupffer vesicle and perturbed directional fluid flow required for left-right patterning of the embryo. Expression of a dominant-negative Fgfr1, treatment with a pharmacological inhibitor of FGF signaling, or genetic and morpholino reduction of redundant FGF ligands Fgf8 and Fgf24 reproduced this cilia length phenotype. Knockdown of Fgfr1 also resulted in shorter tethering of cilia in the otic vesicle and shorter motile cilia in the pronephric ducts. In Xenopus, expression of a dominant-negative fgfr1 resulted in shorter monocilia in the gastrocoel roof plate that control left-right patterning and in shorter multicilia in external mucociliary epithelium. Neugebauer et al. (2009) concluded that their results indicated a fundamental and highly conserved role for FGF signaling in the regulation of cilia length in multiple tissues. Abrogation of Fgfr1 signaling downregulated expression of 2 ciliogenic transcription factors, foxj1 (602291) and rfx2 (142765), and of the intraflagellar transport gene ift88 (600595), indicating that FGF signaling mediates cilia length through an Fgf8/Fgf24-Fgfr1-intraflagellar transport pathway. Neugebauer et al. (2009) proposed that a subset of developmental defects and diseases ascribed to FGF signaling are due in part to loss of cilia function.
Using fluorescence correlation spectroscopy and image analysis, Nowak et al. (2011) showed that the ubiquitin ligase Cbl (165360) regulated Fgf8 signaling during zebrafish embryonic development through intracellular interpretation of the extracellular gradient. Fgf8-positive endosomes showed increased colocalization with Rab7 (602298), a marker of late endosomes, and Lamp1 (153330), a marker of lysosomes, during zebrafish development, indicating trafficking toward degradative endosomal compartments. Significant proportions of Fgf8-positive endosomes also colocalized with Rab11 (605570), a marker of recycling endosomes, caveolin-1 (CAV1; 601047), a marker of caveolae, and a plasma membrane marker. Expression of a dominant-negative Cbl mutant resulted in reduced colocalization of Fgf8 endosomes with markers of degradative endosomal compartments, without altering the presence of Fgf8 in early and recycling endosomes. Similarly, expression of dominant-negative Cbl significantly reduced association of Fgfr1, the main receptor for Fgf8 during gastrulation, with Rab7 and increased its colocalization with Cav1. Further studies showed that dominant-negative Cbl caused a direct increase in Fgfr signaling complexes in target cells. Nowak et al. (2011) concluded that endocytic sorting regulates morphogen gradient interpretation.
Role in Limb Development
For a review of the role of this gene in limb development, see Johnson and Tabin (1997).
Using the Cre/loxP system, Sun et al. (2000) found that maintenance of Fgf9 (600921) and Fgf17 (603725) expression is dependent on Shh (600725), whereas Fgf8 expression is not. Sun et al. (2000) developed a model in which no individual Fgf expressed in the apical ectodermal ridge is solely necessary to maintain Shh expression, but instead the combined activity of 2 or more apical ectodermal ridge (AER) Fgfs function in a positive feedback loop with Shh to control limb development.
Lewandoski et al. (2000) reported that inactivating Fgf8 in early limb ectoderm caused a substantial reduction in limb-bud size, delay in Shh expression, misregulation of Fgf4 expression, and hypoplasia or aplasia of specific skeletal elements. The data indicated that Fgf8 is the only known AER-Fgf individually necessary for normal limb development.
The expression pattern and activity of fibroblast growth factor-8 in experimental assays indicated that it has important roles in limb development, but early embryonic lethality resulting from mutation of Fgf8 in the germline of mice prevented direct assessment of these roles. Moon and Capecchi (2000) found it possible to bypass embryonic lethality by conditional disruption of Fgf8 in the forelimb of developing mice and found a requirement for Fgf8 in the formation of the stylopod, anterior zeugopod, and autopod. Lack of Fgf8 in the apical ectodermal ridge (AER) altered expression of other Fgf genes, Shh, and Bmp2 (112261).
To determine the role of fibroblast growth factor signaling from the apical ectodermal ridge, Sun et al. (2002) inactivated Fgf4 and Fgf8 in apical ectodermal ridge cells or their precursors at different stages of mouse limb development. Sun et al. (2002) showed that Fgf4 and Fgf8 regulate cell number in the nascent limb bud and are required for survival of cells located far from the apical ectodermal ridge. On the basis of the skeletal phenotypes observed, Sun et al. (2002) concluded that these functions are essential to ensure that sufficient progenitor cells are available to form the normal complement of skeletal elements, and perhaps other limb tissues. In the absence of both Fgf4 and Fgf8 activities, limb development fails. None of 23 newborn double knockout mice examined had hindlimbs. In contrast, forelimbs contained elements of all 3 limb segments but were shorter and thinner than normal. Sun et al. (2002) found that in double homozygotes, forelimb proximal elements were invariably missing or severely hypoplastic when distal elements were present. They suggested that these observations argue against the progress zone model, which had been the prevailing model of limb proximal-distal patterning. Sun et al. (2002) hypothesized that limb skeletal patterning is achieved as a function of basic cellular processes including cell division, cell survival, and stereotypic behaviors of chondrocyte progenitors such as aggregate formation.
In a series of experiments involving removal of the apical ectodermal ridge from chick limb buds, Dudley et al. (2002) demonstrated that the various limb bud segments are specified early in limb development as distinct domains, with subsequent development involving expansion of progenitor populations before differentiation. Dudley et al. (2002) also found that the distal limb mesenchyme becomes progressively determined, that is, irreversibly fixed, to a progressively limited range of potential proximodistal fates. Their observations, coupled with those of Sun et al. (2002), refuted the progress zone model of vertebrate limb development.
Classical models of craniofacial development argue that the neural crest is prepatterned or preprogrammed to make specific head structures before its migration from the neural tube. In contrast, recent studies in several vertebrates, including mouse, chick, and zebrafish, have provided evidence for plasticity in patterning neural crest populations. Using tissue transposition and molecular analyses in avian embryos, Trainor et al. (2002) reconciled these findings by demonstrating that classical manipulation experiments, which form the basis of the prepatterning model, involved transplantation of a local signaling center, the isthmic organizer. FGF8 signaling from the isthmus alters HOXA2 (142960) expression and consequently branchial arch patterning, demonstrating that neural crest cells are patterned by environmental signals.
Mariani et al. (2008) demonstrated that mouse limbs lacking Fgf4 (164920), Fgf9 (600921), and Fgf17 (603725) have normal skeletal pattern, indicating that Fgf8 is sufficient among apical ectodermal ridge fibroblast growth factors (AER-FGFs) to sustain normal limb formation. Inactivation of Fgf8 alone causes a mild skeletal phenotype; however, when Mariani et al. (2008) also removed different combinations of the other AER-FGF genes, they obtained unexpected skeletal phenotypes of increasing severity, reflecting the contribution that each FGF can make to the total AER-FGF signal. Analysis of the compound mutant limb buds revealed that, in addition to sustaining cell survival, AER-FGFs regulate proximal-distal patterning gene expression during early limb bud development, providing genetic evidence that AER-FGFs function to specify a distal domain and challenging the longstanding hypothesis that AER-FGF signaling is permissive rather than instructive for limb patterning. Mariani et al. (2008) also developed a 2-signal model for proximal-distal patterning to explain early specification.
Limb bud outgrowth is driven by signals in a positive feedback loop involving Fgf genes, Sonic hedgehog (600725), and Gremlin-1 (GREM1; 603054). Precise termination of these signals is essential to restrict limb bud size. That the sequence in mouse limb buds is different from that in chick limb buds drove Verheyden and Sun (2008) to explore alternative mechanisms. By analyzing compound mouse mutants defective in genes comprising the positive loop, Verheyden and Sun (2008) provided genetic evidence that Fgf signaling can repress Grem1 expression, revealing a novel Fgf/Grem1 inhibitory loop. The repression occurs in both mouse and chick limb buds and is dependent on high Fgf activity. These data supported a mechanism where the positive Fgf/Shh loop drives outgrowth and an increase in FGF signaling, which triggers the Fgf/Grem1 inhibitory loop. The inhibitory loop then operates to terminate outgrowth signals in the order observed in either mouse or chick limb buds. Verheyden and Sun (2008) concluded that their study unveils the concept of a self-promoting and self-terminating circuit that may be used to attain proper tissue size in a broad spectrum of developmental and regenerative settings. Verheyden and Sun (2008) demonstrated that Fgf8 repression of Fgf4 expression is dependent on Grem1 but not Sonic hedgehog.
Cooper et al. (2011) observed that mesenchymal cells cultured in the combination of the 3 signaling molecules retinoic acid, Fgf8, and Wnt3a (606359) to which early limb cells are normally exposed maintain the capacity to form both proximal and distal structures despite the passage of time and continued proliferation. This strongly argues against a mechanism linking proximodistal specification to a cell cycle-based internal clock. Cooper et al. (2011) concluded that the trigger for initiating the process of specification of the zeugopod and autopod is the cessation due to displacement of retinoic acid exposure. Similar conclusions were independently reached by Rosello-Diez et al. (2011). Using heterotopic transplantation of intact and recombinant chick limb buds, Rosello-Diez et al. (2011) identified signals in the embryo trunk that proximalize distal limb cells to generate a complete proximodistal axis. In these transplants, retinoic acid induces proximalization, which is counteracted by fibroblast growth factors from the distal limb bud; these related actions suggested that the first limb bud proximodistal regionalization results from the balance between proximal and distal signals.
Nacu et al. (2016) clarified the molecular basis of the requirement for both anterior and posterior tissue during limb regeneration and supernumerary limb formation in axolotls. Nacu et al. (2016) showed that the 2 tissues provide complementary cross-inductive signals that are required for limb outgrowth. A blastema composed solely of anterior tissue normally regresses rather than forming a limb, but activation of hedgehog (HH) signaling was sufficient to drive regeneration of an anterior blastema to completion owing to its ability to maintain fibroblast growth factor (FGF) expression, the key signaling activity responsible for blastema outgrowth. In blastemas composed solely of posterior tissue, HH signaling was not sufficient to drive regeneration; however, ectopic expression of FGF8 together with endogenous HH signaling was sufficient. In axolotls, FGF8 is expressed only in the anterior mesenchyme and maintenance of its expression depends on SHH (600725) signaling from posterior tissue. Nacu et al. (2016) concluded that their data identified key anteriorly and posteriorly localized signals that promote limb regeneration.
Role in Brain Development
Fukuchi-Shimogori and Grove (2001) provided evidence that FGF8 regulates development of the area map of neurogenesis from a source in the anterior telencephalon. Using electroporation-mediated gene transfer in mouse embryos, they showed that augmenting the endogenous anterior FGF8 signal shifts area boundaries posteriorly, reducing the signal shifts them anteriorly, and introducing a posterior source of FGF8 elicits partial area duplications, revealed by ectopic somatosensory barrel fields. Fukuchi-Shimogori and Grove (2001) concluded that their findings support a role for FGF signaling in specifying positional identity in the neocortex.
Using in utero microelectroporation to manipulate gene expression and function in mouse cortical primordium, Fukuchi-Shimogori and Grove (2003) found that the transcription factor Emx2 (600035) regulates Fgf8 in the development of neocortical area patterning.
Storm et al. (2003) investigated the effects of varying the level of Fgf8 expression in the mouse forebrain. They detected 2 distinct responses, one that was proportionate with Fgf8 expression and another that was not. The latter response, which led to effects on cell survival, displayed a paradoxical relationship to Fgf8 dosage. Either eliminating or increasing Fgf8 expression increased apoptosis, whereas reducing Fgf8 expression had the opposite effect. To explain these counterintuitive observations, the authors suggested that an FGF8-dependent cell-survival pathway is negatively regulated by intracellular inhibitors produced in proportion to FGF8 concentration.
Gunhaga et al. (2003) examined the signals that induce the initial early dorsal character of telencephalic cells. Studies in vitro and in chick embryos showed that Wnt3A (606359) inhibited the generation of ventral telencephalic cells and was required to induce early dorsal characterization at the neural plate stage. Later, at the early neural tube stage, FGF8 signaling was required to characterize the dorsal telencephalic cells definitively, as defined by EMX1 (600034) expression. The authors emphasized that the sequential signaling of Wnt3A and FGF8 was required for dorsal characterization of the cells.
Role in Eye Development
Martinez-Morales et al. (2005) demonstrated that Fgf3 and Fgf8 cooperate in initiating neuronal differentiation in the zebrafish retina. In both chicken and zebrafish, Fgf8 triggered retinal progenitor cells to undergo terminal mitosis and differentiate into retinal ganglion cells.
Role in Tooth Development
Dlx1 (600029) and Dlx2 (126255) are involved in patterning of murine dentition, since loss of these transcription factors results in early developmental failure in upper molar teeth. Thomas et al. (2000) found that Fgf8, which was expressed in the epithelium overlying the mesenchyme in the mouse first branchial arch, regulated the mesenchymal expression of Dlx2. Fgf8 also inhibited expression of Dlx2 in the epithelium by a signaling pathway that required the mesenchyme. Bmp4 (112262), which was coexpressed with Ldx2 in distal oral epithelium, regulated Dlx2 expression by planar signaling. Thomas et al. (2000) concluded that Bmp4 and Fgf8 maintain strict epithelial and mesenchymal expression domains of Dlx2 in the first branchial arch of developing mice.
Olsen et al. (2006) solved the crystal structure of FGF8B in complex with the 'c' splice isoform of FGFR2 (176943) and, using surface plasmon resonance, characterized the receptor binding specificities of FGF8A and FGF8B. They found that, compared with FGF8A, FGF8B makes an additional contact between phe32 (F32) of FGF8B and the hydrophobic groove within Ig domain 3 of the receptor that is also present in the c isoforms of FGFR1 (136350) and FGFR3 (134934) and in FGFR4 (134935). Mutation of F32 to alanine (F32A) reduced the affinity of FGF8B toward all these receptors to levels characteristic of FGF8A. Analysis of the mid-hindbrain patterning of the FGF8B F32A mutant in chicken embryos and mouse midbrain explants showed that this mutation functionally converted FGF8B to FGF8A.
Hypogonadotropic Hypogonadism 6 with or without Anosmia
Using a candidate gene approach, Falardeau et al. (2008) screened the FGF8 gene in 461 unrelated probands with idiopathic hypogonadotropic hypogonadism (IHH), including 193 normosmic patients, 237 anosmic patients, and 21 patients with adult-onset idiopathic hypogonadotropic hypogonadism (see HH6, 612702). They identified 6 mutations in the FGF8 gene, in 2 familial cases of Kallmann syndrome (600483.0002 and 600483.0005, respectively), 1 familial case of IHH (600483.0004), 2 sporadic cases of IHH (600483.0001 and 600483.0003, respectively) and 1 case of adult-onset IHH (600483.0006). Probands harboring an FGF8 mutation were screened for other loci underlying IHH, and 2 probands with normosmic IHH (see 600483.0003 and 600483.0004, respectively) were found to carry additional mutations in the FGFR1 gene (see 136350.0023-136350.0025, respectively).
By sequencing the FGF8 gene in 2 unrelated probands from Brazil with hypogonadotropic hypogonadism-6, one with and one without anosmia, Trarbach et al. (2010) identified different heterozygous nonsense mutations (R127X, 600483.0007 and R129X, 600483.0008). Both patients had a family history of the disorder. Both mutations mapped to the core domain of the protein, affected all 4 FGF8 isoforms, and led to deletion of a large portion of the protein, predicted to result in nonfunctional FGF8 ligands. The mutations were not found in 150 Brazilian control individuals.
Hypoplastic Femurs and Pelvis
Socha et al. (2021) reported 2 families with hypoplastic femurs and pelvis (HYPOFP; 619545) and overlapping duplications at chromosome 10q24.32 that segregated with disease. Breakpoint sequencing showed tandem orientation in both duplications, which in family 1 involved 533,943 kb (chr10q24.32(103,012,761_103,546,704)x3; GRCh37), and in family 2 involved 542,061 kb (chr10q24.32(103,001,852_103,543,913)x3; GRCh37). The duplications involved 6 genes, including BTRC (603482), POLL (606343), DPCD (616467), FBXW4 (608071), FGF8, and NPM3 (606456). The authors noted that the duplications almost completely overlapped with split-hand/foot malformation (SHFM3; 246560)-associated 10q24.32 duplications, with the only gene unique to the femoral hypoplasia phenotype being FGF8. Analysis of local chromosome architecture in patient fibroblasts showed strong ectopic interaction between FGF8 and an approximately 230-kb region within the neighboring topologically associating domain of BTRC. Expression analysis in patient fibroblasts showed a 2.9-fold increase in expression of FGF8 and a 2.3-fold increase in expression of BTRC. Analysis of transgenic mouse models suggested that the phenotype is mostly likely due to position effects causing altered FGF8 expression rather than gene dosage effects. The authors noted that other genes within the duplicated fragments might also contribute to the phenotype.
Associations Pending Confirmation
Riley et al. (2007) analyzed 12 genes involved in the fibroblast growth factor signaling pathway in nonsyndromic cleft lip or palate families and identified 7 likely disease-causing mutations in which structural analysis predicted functional impairment in the FGFR1, FGFR2, FGFR3 (134934), and FGF8 genes. One patient with apparent nonsyndromic cleft lip and palate had a de novo asp73-to-his (D73H) substitution in the FGF8 gene, predicted to reduce binding affinity of FGF8 towards its cognate receptors. Riley et al. (2007) suggested that the FGF signaling pathway may contribute to as much as 3 to 5% of nonsyndromic cleft lip or palate.
Exclusion Studies
Since FGF8 maps to the same chromosomal region as FGFR2 (176943), is a ligand for FGFR2, and has an expression pattern consistent with limb and craniofacial anomalies, Yoshiura et al. (1997) screened 2 kindreds with Pfeiffer syndrome (101600) previously linked to markers from 10q24-q25 and a large number of individuals with craniosynostosis and limb anomalies for mutations in the coding sequence of FGF8. No mutations were found.
Meyers et al. (1998) generated a mouse line carrying a hypomorphic Fgf8 allele that could be converted to a null allele or reverted to wildtype by Cre- and Flp-mediated recombination. They found that homozygosity for the Fgf8-null allele resulted in defective gastrulation. Embryos carrying different combinations of hypomorphic, null, and wildtype alleles showed a range of phenotypes, including deletion and/or malformation of major brain structures, abnormal development of the heart, posterior compartment, or craniofacial structures, and generally retarded development.
Watanabe et al. (2010) generated compound Fgf8 and Fgf10 (602115) mutant mice in the cardiac and pharyngeal mesoderm. They found that pharyngeal arch artery (PAA) development was perturbed by Fgf8 deletion. The frequency and severity of PAA and outflow tract (OFT) defects increased with decreasing expression of Fgf8 and Fgf10. Watanabe et al. (2010) concluded that there is functional overlap of mesodermal FGF8 and FGF10 during second heart field/OFT and PAA development, and that FGF10 has a role in formation of the arterial pole of the heart. The findings indicated that the sensitivity of these processes is influenced by incremental reductions in FGF levels.
Naiche et al. (2011) showed that deletion of both Fgf4 and Fgf8 in PSM of mouse embryos resulted in loss of expression of most PSM genes, including cycling genes, Wnt pathway genes, and markers of undifferentiated PSM. In contrast, markers of nascent somite cell fate expanded throughout the PSM. Restoration of Wnt signaling only partially restored PSM markers, and premature PSM differentiation continued. Naiche et al. (2011) concluded that FGF signaling operates independently of Wnt signaling to maintain the wavefront signal that controls somatogenesis and that FGF4 and FGF8 are the sole signaling mediators of this wavefront activity.
Boulet and Capecchi (2012) reported that loss of expression of both Fgf4 and Fgf8 in mice during late gastrulation resulted in thoracic vertebrae and ribs with abnormal morphology, malformed or absent lumbar and sacral vertebrae, and no tail vertebrae. Expression of Wnt3a in tail and transcription factor T (601397) in nascent mesoderm was severely reduced. Expression of genes in the Notch (see 190198) signaling pathway involved in segmentation were also severely affected. After production of 15 to 20 somites, somite formation ceased. The defects appeared to result from a failure to produce sufficient paraxial mesoderm. Boulet and Capecchi (2012) proposed that FGF4 and FGF8 are required to maintain a population of progenitor cells in the epiblast that generates mesoderm and contributes to the stem-cell population that is incorporated in the tailbud and required for axial elongation of the mouse embryo after gastrulation.
In a 32-year-old woman of mixed European descent with normosmic idiopathic hypogonadotropic hypogonadism (HH6; 612702), Falardeau et al. (2008) identified heterozygosity for a 40C-A transversion in exon 1B of the FGF8 gene, resulting in a his14-to-asn (H14N) substitution at a highly conserved residue within the hydrophobic signal peptide present in all 4 isoforms of the protein. Additional features in the patient included high-arched palate and osteoporotic fractures. The mutation was not found in 180 ethnically matched controls, and the patient's daughter, who did not carry the mutation, initiated pubertal development at age 11 years.
In a 28-year-old man of mixed European descent who had been diagnosed at age 16 with hypogonadism and who was found to have a decreased sense of smell, consistent with Kallmann syndrome (HH6; 612702), Falardeau et al. (2008) identified heterozygosity for a 77C-T transition in exon 1C of the FGF8 gene, resulting in a pro26-to-leu (P26L) substitution at a highly conserved residue present in the FGF8e and FGF8f isoforms of the protein. Structural and in vitro biochemical analysis of the mutation demonstrated a loss of function. Brain MRI in the proband revealed partial empty sella and bilateral hypoplastic olfactory bulbs and tracts. His father, who carried the mutation, had a history of decreasing olfaction; the mutation was not found in his asymptomatic mother or in 180 ethnically matched controls.
In a 19-year-old man who was evaluated at age 15.5 years for delayed puberty and found to have a hypogonadal serum testosterone level with undetectable serum gonadotropins (HH6; 612702), Falardeau et al. (2008) identified homozygosity for a 118T-C transition in exon 1C of the FGF8 gene, resulting in a phe40-to-leu (F40L) substitution at a highly conserved residue present in the FGF8e and FGF8f isoforms of the protein. Structural and in vitro biochemical analysis of the mutation demonstrated a loss of function; the mutation was not found in 180 ethnically matched controls. The patient, who had a normal brain MRI, was also found to be compound heterozygous for mutations in the FGFR1 gene, Q784H (136350.0023) and D768Y (136350.0024).
In a 10-year-old boy of mixed European descent who was born with microphallus and found to have undetectable serum testosterone and gonadotropins and normal olfaction (HH6; 612702), Falardeau et al. (2008) identified heterozygosity for a de novo 298A-G transition in exon 1D of the FGF8 gene, resulting in a lys100-to-glu (K100E) substitution at a highly conserved residue present in all 4 isoforms of the protein. Structural and in vitro biochemical analysis of the mutation demonstrated a loss of function. The mutation was not found in either parent or in 180 ethnically matched controls. Both the patient and his father, who had normal olfaction, bilateral hearing loss, and a history of delayed puberty, were also found to be heterozygous for a mutation in the FGFR1 gene (R250Q; 136350.0025).
In a 19-year-old woman of mixed European descent who was born with cleft lip and palate and was evaluated at age 14 years for primary amenorrhea and lack of breast development and found to have anosmia and undetectable serum gonadotropins (HH6; 612702), Falardeau et al. (2008) identified heterozygosity for a 379C-G transversion in exon 2 of the FGF8 gene, resulting in an arg127-to-gly (R127G) substitution at a highly conserved residue present in all 4 isoforms of the protein. Structural and in vitro biochemical analysis of the mutation demonstrated a loss of function. Additional features in the patient included short stature, hypertelorism, flattened bridge of the nose, hyperlaxity of the digits, camptodactyly, and mild scoliosis; further examination revealed color blindness and bilateral hearing loss, and imaging studies showed normal olfactory bulbs and nerves, normal renal ultrasound, and very low bone density. The proband's mother, who also carried the mutation, had normosmic hypogonadotropic hypogonadism. The proband's dizygotic twin sibs had markedly different phenotypes: one harbored the R127G mutation and had severe Kallmann syndrome, with microphallus, undescended testes, absent puberty, and cleft lip/palate, whereas the other did not carry the mutation and underwent normal puberty but had short stature. The father, who was wildtype for FGF8, had a normal sense of smell but a history of delayed puberty, and the paternal grandmother also had a history of delayed puberty. The mutation was not found in 180 ethnically matched controls.
This variant, formerly titled HYPOGONADOTROPIC HYPOGONADISM 6 WITHOUT ANOSMIA (612702), has been reclassified based on the findings of Arauz et al. (2010).
In a 40-year-old man of mixed European descent who presented for evaluation of infertility and decreased libido and was found to have undetectable serum gonadotropins with hypogonadal testosterone levels, Falardeau et al. (2008) identified heterozygosity for a 686C-T transition in exon 3 of the FGF8 gene, resulting in a thr229-to-met (T229M) substitution at a highly conserved residue in the C-terminal tail. Structural and in vitro biochemical analysis of the mutation demonstrated a loss of function, and the mutation was not found in 180 ethnically matched controls. The patient had normal brain MRI, renal ultrasound, and bone density; he was subsequently diagnosed with Graves disease (see 275000), type 2 diabetes (see 125853), and hypertension (see 145500). There was no family history of reproductive or olfactory defects.
Arauz et al. (2010) identified a heterozygous T229M substitution in 1 of 360 unrelated patients with holoprosencephaly (236100). The patient had semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus, and severe neurologic impairment. The mutation was also found in her dizygotic twin sister, who had above-average intelligence, a single central incisor, and hypotelorism; she had subtle midline anomalies with olfactory bulb dysplasia apparent in brain MRI at age 1 year, but no evidence of midline abnormalities on follow-up imaging at age 8 years. The mother, who also carried the mutation, had mild hypotelorism and above-average intelligence. None had signs of hypogonadotropic hypogonadism or any endocrine disturbance. Based on the highly variable phenotype in this family, Arauz et al. (2010) concluded that there must be additional genetic and/or environmental factors in the pathogenesis of HPE. However, defects in FGF8 may play a rare role in midline defects.
In an 18-year-old Brazilian woman with familial hypogonadotropic hypogonadism 6 and moderate microsmia (HH6; 612702), Trarbach et al. (2010) sequenced the FGF8 gene and identified a heterozygous c.763C-T transition (c.763C-T, NM_033163) in the FGF8 gene, resulting in an arg127-to-ter (R127X) substitution in the highly conserved FGF beta-trefoil core domain. Four sibs of the patient with HH6 without anosmia were also heterozygous for the mutation, which was not found in 150 unaffected Brazilian control individuals.
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