Journal of Bone and Mineral Metabolism

, Volume 27, Issue 1, pp 9–15 | Cite as

FGFR3-related dwarfism and cell signaling

  • Daisuke Harada
  • Yoshitaka Yamanaka
  • Koso Ueda
  • Hiroyuki Tanaka
  • Yoshiki Seino
Review Article

Keywords

Fibroblast growth factor receptor 3 Cell signaling Dwarfism Clinical therapy 

Introduction

Skeletal development consists of the following steps: skeletal patterning, mesenchymal differentiation, bone growth, and homeostasis. In the early phase of embryogenesis, immature mesenchymal cells gather in the proper position, and the anteroposterior and dorsoventral axes are determined. This “skeletal patterning” is followed by “differentiation” of immature mesenchymal cells to chondrocytes or osteoblasts. In the appendicular skeleton, endochondral ossification takes part in elongation, and chondrocytes create the growth plate, a chondrocytic layer, and proliferate with high frequency in the longitudinal direction. Bone growth continues until the growth plate is closed at the time of pubertal maturation. In mature bones, a homeostasis process called bone remodeling occurs. Bone remodeling always renews old bone tissue by forming both osteoblasts and resorbing osteoclasts.

Many essential genetic mechanisms for these bone-growing steps have been described. Disorders of each bone formation step cause characteristic skeletal dysplasias. For example, polydactyly and split-hand are caused by patterning failure, dwarfism is caused by extraordinary differentiation and proliferation of chondrocytes in the growth plate, and osteoporosis and osteopetrosis are caused by abnormality of bone remodeling. Many functional genes are identified through genetic disorders of the skeleton and knockout mice. Skeletal disorders have been classified based on the responsible genes [1], clinical features [2], and molecular pathology and embryology [3]. According to the reviews, a total of 271 clinically different disorders and 75 responsible genes have been described. The most frequent genetic skeletal dysplasia is achondroplasia (ACH) (OMIM; #100800), caused by point mutations in the fibroblast growth factor receptor 3 (FGFR3; OMIM *134934) gene [4, 5]. Some other skeletal dysplasias are also caused by mutations located in the FGFR3, such as hypochondroplasia (HCH) (OMIM; #146000), thanatophoric dysplasia type I (TDI) (OMIM; #187600) and type II (TDII) (OMIM; #187601), and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) (description in OMIM *134934.0015) [6, 7, 8, 9, 10, 11]. The location of each mutation is unique. The phenotypes of those FGFR3-related skeletal dysplasias are similar to that of ACH, but the severity is quite different. Mutations of the FGFR3 gene have been reported to be responsible for craniofacial disorders and multiple myeloma, which are not a focus in this review. Many reports state all mutant FGFR3s are constitutively activated. Excessive phosphorylation of FGFR3 triggers intracellular signaling within the chondrocytes of the growth plate to terminate its proliferation [12].

In this review, we describe the correlation between mutations in the FGFR3 gene and clinical symptoms focusing on the molecular mechanism of mutated FGFR3, and we classify FGFR3-related skeletal dysplasias based on clinical severity and the essential molecular mechanism of mutated FGFR3. Furthermore, we describe the known signaling pathways and try to suggest therapeutic possibilities.

Fibroblast growth factor receptor 3 (FGFR3) and its mutations

FGFR3 is a family of four receptor tyrosine kinases for fibroblast growth factors (FGFs) and has been identified as a critical negative regulator of endochondral bone growth [12, 13, 14, 15, 16]. FGFR has three immunoglobulin-like domains (IgI, IgII, and IgIII) in its extracellular region, a transmembrane (TM) domain on the cell membrane, and two tyrosine kinase (TK1, TK2) domains in its intracellular region (Fig. 1). The IgII domain is the binding site to which the specific ligands, FGFs, bind together with heparin and promote dimerization of two FGFR3s. The TK1 domain phosphorylates the TK2 domain of the other receptor, and this triggers intracellular signaling [17, 18]. During embryogenesis, FGFR3 is expressed in differentiating hair cells of the cochlear duct and in the cartilage of developing bone [19]. In adult tissues, expression of FGFR3 is reported in brain, skin, lung, kidney, testis, spinal cord, liver, pancreas, and embryonic stem cells [20].
Fig. 1

Mutations for fibroblast growth factor receptor 3 (FGFR3)-related dwarfism. Mutations for achondroplasia (ACH) are positioned only around the transmembrane (TM) region. Mutations for thanatophoric dysplasia type II (TDII) and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) are reported as only K650 alternation, K650E and K650M, respectively. Mutations for TDI and hypochondroplasia (HCH) occur at varied positions. TDI mutations are localized in Ig, TM, and stop codon, and HCH mutations are localized in TK1 and K650 in TK2, and, additionally, the N328I N-glycosylation site. Ig immunoglobulin-like domain; TM transmembrane domain; TK1/2 tyrosine kinase domain 1/2

Each mutation of FGFR3 (see Fig. 1) for FGFR3-related skeletal dysplasias is a gain-of-function type so that FGFR3 mutants, although the degree is different, stimulate excessive intracellular signaling [21, 22]. Activation of FGFR3 leads to permanent phosphorylation of the receptor itself, so that chondrocytes in the growth plate differentiate excessively and terminate through the intracellular signaling pathways.

The point mutations for ACH are G375C and G380R, both in the TM domain of FGFR3 (see Fig. 1). This mechanism of uniformity, tight genotype–phenotype correlation, is genetically remarkable. It is also known that the TM domain is the position of the CpG island that easily mutated by methylation [23]. Various mutations for HCH are reported in FGFR3, such as N540K (the most frequent mutation), and I538V in the TK1 domain and K650N in the TK2 domain. Recently, N328I in an extracellular region was found at the N-glycosylation site N–X–T motif [24, 25, 26, 27]. Some HCH patients, however, do not have any mutation of the coding region of FGFR3, implying other causes. Many mutations of FGFR3 for TDI are reported, divided into two groups: changing to cysteine residue in the extracellular domain (R240C, A249C, G370C, Y373C), and stop codon mutations (X807C, X807R, X807G) [28, 29, 30, 31]. On the other hand, the mutation for TDII has been known only in K650E in the TK2 domain [29, 32]. The difference of the mutation pattern indicates that TDI and TDII are quite different diseases. The mutation for SADDAN is found at K650 of FGFR3, the same as TDII (K650E), but to a different amino acid, methionine (K650M) [33, 34]. It is interesting that quite different dysplasias are caused by related mutations of the same codon, K650. Actually, the amino acid range around K650 is called the activation loop, implicated as an important region for FGFR3 function, but the detailed functions have not been sufficiently described.

Clinical features of FGFR3-related dwarfisms

ACH is an autosomal dominant skeletal dysplasia characterized by rhizomelic short limbs and short stature, with the highest incidence of around 1.0 per 10,000 live births [4, 5, 35]. The adult height is 120–140 cm. Characteristic features for clinical diagnosis are a long and narrow trunk, a large head with frontal bossing, hypoplasia of the midface, depressed nasal bridge, and trident hands [36]. Some features other than abnormal shape formation are hypotonia and delayed motor milestones, but intelligence is normal, unless hydrocephalus or other central nervous system complications arise [37, 38].

HCH is characterized by mild short limbs and short stature, and mild mental retardation (9% of the patients), but no abnormality of face or trident hands [6, 7]. The adult height is 140–150 cm. However, some HCH patients do not have any mutations in FGFR3 [6, 39, 40]. Therefore, HCH is not as uniform clinically and genetically as ACH, and there might be other responsible genes.

The incidence of TD is about 1:20,000 among live births [41, 42]. Clinical aspects are characterized by severe rhizomelic short limbs and short stature, macrocephaly with depressed nasal bridge, severe platyspondylisis, and reduced thoracic cavity [43]. Most TD patients die in the perinatal period of dyspnea. TD is classified into two types by the shape of the femur. Femurs of type I TD (TDI) are curved, so-called telephone receiver like, and those of type II TD (TDII) are straight [44, 45]. The characteristic shape of the head of TDII patients is called a cloverleaf skull [44, 46].

SADDAN is used to be called the skeletal-skin-brain syndrome. Although it shows quite severe skeletal anomalies, SADDAN has a totally different clinical phenotype from TDII [47]. SADDAN patients have severe short limbs and short stature, arcuation of tibia and femur, developmental delay, and acanthosis nigricans, but do not have craniosynostosis. In spite of severe osteodysplasty, SADDAN patients are able to survive with respiratory care. Adult height is around 105 cm.

Classification of FGFR3-related dwarfism by clinical severity and by molecular features in vitro

Many facts are known about abnormal intracellular signaling and the extraordinary features of mutated FGFR3. It is also true that those diseases indicate quite different phenotypes by different mutations in the same gene, FGFR3. It has been considered that the phosphorylation levels of ACH-FGFR3 and TDII-FGFR3 are correlated with phenotypic severity [48]. Recently, it was found that TDII-FGFR3 and SADDAN-FGFR3 mutants are not successfully glycosylated and are localized in the endoplasmic reticulum (ER) [49, 50]. We tried to reveal the key genetic factor or factors for phenotype determination, focusing on the phosphorylation pattern and intracellular localization of mutant FGFR3s [51]. As a result, we found that abnormal phosphorylation elongation of the mutants is a likely checkpoint between normal and disordered (Fig. 2). This fact supported a previous study showing that the stabilization of some mutant FGFR3s dimerization is likely to enhance kinase activity [52]. Furthermore, ER localization of the receptor is more crucial than the degree of phosphorylation to develop a severe phenotype.
Fig. 2

Classification of FGFR3-related dwarfisms according to phenotype, phosphorylation pattern of the receptor, and endoplasmic reticulum (ER) localization. Continuous phosphorylation, either dependent on or independent of ligand stimulation, is the crucial factor to distinguish mutated FGFR3s from wild-type (WT)-FGFR3. Among mutants, ER localization of the receptor is the important factor of life or death for the dysplasias. Phosphorylation level of mutated FGFR3s is the final factor to decide the severity of the skeletal dysplasias

FGFR3 signaling for bone growth

Much investigation into the intracellular signaling of FGFR3 has been done, showing several pathways similar to FGFR1 or other receptor tyrosine kinases involving many signaling molecules [53, 54, 55, 56]. There are four main pathways downstream of FGFR3, such as the mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription (STAT), phospholipase C-gamma (PLCγ)/protein kinase C (PKC), and phosphatidyl inositol-3-kinase (PI3K)/v-akt murine thymoma viral oncogene (AKT) pathways (Fig. 3). Mainly, each pathway seems to work on matrix production, cell proliferation, adjustment for intracellular calcium ion concentration, and cell survival, respectively. Furthermore, the pathways are dependent on phosphorylation of unique responsible tyrosine residues [57].
Fig. 3

Intracellular signaling by activated FGFR3. Schematic representation of signaling pathways downstream of activated FGFR3. Additionally, cellular effects follow activation of the mediators. PLCγ phospholipase C-gamma; PI3K phosphatidyl inositol-4,5-diphosphate 3-kinase; IP3 inositol-1,4,5-triphosphate; MEK MAPK/ERK kinase; ECM extracellular matrix

Recent studies imply the existence of signaling crosstalk with endocrine or paracrine signaling molecules, including insulin-like growth factor 1 (IGF-1), C-type natriuretic peptide (CNP), and parathyroid hormone/parathyroid hormone-related peptide (PTH/PTHrP). IGF-I signaling is an important mediator of growth hormone effects. Because the disturbed appendicular skeleton of ACH is rescued by growth hormone (GH) treatment, for evidence of GH treatment, we proved that IGF-1 signaling prevents chondrogenic cell line ATDC5 cells from expressing activated FGFR3 by apoptosis through the PI3K pathway [58]. CNP induces activation of cyclic guanosine monophosphate (cGMP) through interaction with its receptor, natriuretic peptide receptor B (NPR-B). Both CNP and NPR-B are expressed in the proliferative and prehypertrophic zones of the growth plate, and activation of NPR-B triggers matrix synthesis in chondrocytes, repressing the MAPK pathway downstream of FGFR3 activation [59]. Activation of FGFR3 decrease the expression of bone-forming proteins such as Indian hedgehog (Ihh), Patched (Ptc), and bone morphometric protein 4 (BMP4) [60]. Ihh affects chondrocytes to produce PTHrP. Indeed, expression of PTHrP is decreased in ATDC5 expressing activated FGFR3 [61].

Therapeutic approach

As therapy for FGFR3-related dwarfisms, including ACH and HCH, treatment with GH has been tried [62, 63, 64]. We also reported that GH treatment for skeletal dysplasias produces a positive effect for a short time [65]. However, GH treatment for ACH does not have as great an effect for GH deficiency, and the effect does not persist very long. Furthermore, excessive GH medication closes the growth plate early, and no clear long-term benefit has been established [56].

Surgical limb lengthening has been also widely tried to increase the height of affected patients [66, 67, 68]. This method elongates achondroplastic or hypochondroplastic limbs as much as 15–30 cm, but there are many problems, such as the need for repeated surgeries, superficial wound infection, sequelae, and complications [56].

Investigation of intracellular signaling leads to some clues for the development of novel medications. We demonstrated that one cause of FGFR3-related skeletal dysplasia is apoptosis, responsible for decreased expression of parathyroid hormone-related peptide (PTHrP) [61]. Administration of PTH decreases apoptosis of ATDC5 expressing ACH-FGFR3 or TDII-FGFR3. PTHrP positively affects chondrocyte proliferation in the growth plate through the PTH/PTHrP receptor (PPR). Furthermore, because PPR is the common receptor of both PTH and PTHrP, we investigated possibilities of human recombinant PTH (rhPTH) [69]. Disturbed bone growth of the appendicular skeleton from ACH-FGFR3 transgenic mice was rescued by addition of rhPTH in an organ culture system. This approach is quite realistic, because rhPTH is already established as a medicine for adult osteoporosis.

C-type natriuretic peptide (CNP) and its receptor, natriuretic peptide receptor-B (NPR-B), are identified as negative regulators and inhibit mitogenesis in rat chondrocytes [70]. Even mutations in the NPR-B gene are responsible for acromesomelic dysplasia [71]. As an in vivo study, overexpression of CNP in chondrocytes has positive effects on ACH-FGFR3 transgenic mice [59]. Because other natriuretic peptides have been used clinically for their hemodynamic effects [72], CNP or a CNP analogue could be an effective medicine in the future.

Other possible trials were introduced. One is the highly specific antibody against FGFR3 and the other is the selective FGFR3 kinase inhibitor [73, 74]. These approaches have been proven to have a blocking effect on FGFR3 activation in vitro. For development of therapeutic materials, examination of treatment in intact animals is awaited.

Conclusions

From the biological view, FGFs and their receptors comprise various effects on various organs and play a very important role in the skeletal formation. By the genetic approach, each mutation of FGFR3 is quite precisely correlated with the phenotype. It is interesting that point mutations in different positions and/or to different amino acids in the FGFR3 gene result in quite different phenotypes. Although the mechanism of the mutations is complicated, as clues the crucial features are elongated phosphorylation and ER localization of the receptor. However, there might be an unrecognized molecular mechanism for developing mutation-specific phenotypes, such as mental retardation for HCH, and a lethal phenotype for TDI and TDII, but not for SADDAN, by hypoplastic lung.

Among the many genetic rhizomelic dwarfisms, FGFR3-related dwarfisms are the most common disorders. Especially, ACH and HCH patients are able to live out their entire lifetime with many difficulties throughout their social life. We desire to cure those patients; however, there are quite a few radical therapies for congenital disorders. To develop such a therapy, we need to understand the causes and mechanisms of each disease. Therefore, needless to say, clinical follow-up, and genetic or molecular and cellular biological research, are very important.

References

  1. 1.
    Superti-Furga A, Bonafe L, Rimoin DL (2001) Molecular-pathogenetic classification of genetic disorders of the skeleton. Am J Med Genet 106(4):282–293PubMedCrossRefGoogle Scholar
  2. 2.
    Hall CM (2002) International nosology and classification of constitutional disorder of bone (2001). Am J Med Genet 113(1):65–77PubMedCrossRefGoogle Scholar
  3. 3.
    Kornak U, Mundlos S (2003) Genetic disorders of the skeleton: a developmental approach. Am J Hum Genet 73(3):447–474PubMedCrossRefGoogle Scholar
  4. 4.
    Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, Winokur ST, Wasmuth JJ (1994) Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78:335–342PubMedCrossRefGoogle Scholar
  5. 5.
    Rousseau F, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet JM, Marotearx P, Le MM, Munnich A (1994) Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature (Lond) 371:252–254CrossRefGoogle Scholar
  6. 6.
    Bellus GA, McIntosh I, Smith EA, Aylsworth AS, Kaitila I, Horton WA, Greenhaw GA, Hecht JT, Francomano CA (1995) A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet 10(3):357–359PubMedCrossRefGoogle Scholar
  7. 7.
    Bellus GA, Speiser PW, Weaver CA, Garber AT, Bryke CR, Israel J, Rosengren SS, Webster MK, Donoghue DJ, Francomano CA (2000) Distinct missense mutations of the FGFR3 Lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am J Hum Genet 67:1411–1421PubMedCrossRefGoogle Scholar
  8. 8.
    Tavormina PL, Ahiang R, Thompson LM, Zhu YZ, Wilkin DJ, Lachman RS, Wilcox WR, Rimoin DL, Cohn DH, Wasmuth JJ (1995) Thanatophoric dysplasia (type I and type II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet 9:321–328PubMedCrossRefGoogle Scholar
  9. 9.
    Tavormina PL, Rimon DL, Cohn DH, Zhu YZ, Shiang R, Wamuth JJ (1995) Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type I. Hum Mol Genet 4:2175–2177PubMedCrossRefGoogle Scholar
  10. 10.
    Rousseau F, Saugier P, LeMerrer M, Munnich A, Delezoide AL, Moroteaux P, Bonaventure J, Narcy F, Sanak M (1995) Stop codon FGFR3 mutation in thanatophoric dwarfism type I. Nat Genet 10:11–12PubMedCrossRefGoogle Scholar
  11. 11.
    Tavormina PL, Bellus GA, Webster MK, Bamshad MJ, Fraley AE, Mclntosh I, Szabo J, Jiang W, Jabs EW, Wilcox WR, Wasmuth JJ, Donoghue DJ, Thompson LM, Francomano CA (1999) A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene. Am J Hum Genet 64:722–731PubMedCrossRefGoogle Scholar
  12. 12.
    Deng C, Wynshaw-Boris A, Zhou F, Kuo A, Leder P (1996) Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84:911–921PubMedCrossRefGoogle Scholar
  13. 13.
    Weksler NB, Lunstrum GP, Reid ES, Horton WA (1999) Differential effects of fibroblast growth factor (FGF) 9 and FGF2 on proliferation, differentiation and terminal differentiation of chondrocytic cells in vitro. Biochem J 342(pt 3):677–682PubMedCrossRefGoogle Scholar
  14. 14.
    De Luca F, Baron J (1999) Control of bone growth by fibroblast growth factors. Trends Endocrinol Metab 10(2):61–65PubMedCrossRefGoogle Scholar
  15. 15.
    Legeai-Mallet L, Benoist-Lasselin C, Munnich A, Bonaventure J (2004) Overexpression of FGFR3, Stat1, Stat5 and p21Cip1 correlates with phenotypic severity and defective chondrocyte differentiation in FGFR3-related chondrodysplasias. Bone (NY) 34(1):26–36Google Scholar
  16. 16.
    Colvin JS, Bohne BA, Harding GW, McEwen DG, Ornitz DM (1996) Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet 12(4):390–397PubMedCrossRefGoogle Scholar
  17. 17.
    Pantoliano MW, Horlick RA, Springer BA, Van Dyk DE, Tobery T, Wetmore DR, Lear JD, Nahapetian AT, Bradley JD, Sisk WP (1994) Multivalent ligand–receptor binding interactions in the fibroblast growth factor system produce a cooperative growth factor and heparin mechanism for receptor dimerization. Biochemistry 33(34):10229–10248PubMedCrossRefGoogle Scholar
  18. 18.
    Shi E, Kan M, Xu J, Wang F, Hou J, McKeehan WL (1993) Control of fibroblast growth factor receptor kinase signal transduction by heterodimerization of combinatorial splice variants. Mol Cell Biol 13(7):3907–3918PubMedGoogle Scholar
  19. 19.
    Peters K, Ornitz D, Werner S, Williams L (1993) Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. Dev Biol 155(2):423–430PubMedCrossRefGoogle Scholar
  20. 20.
    Hughes SE (1997) Differential expression of the fibroblast growth factor receptor (FGFR) multigene family in normal human adult tissues. J Histochem Cytochem 45(7):1005–1019PubMedGoogle Scholar
  21. 21.
    Vajo Z, Francomano CA, Wilkin DJ (2000) The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocr Rev 21(1):23–39PubMedCrossRefGoogle Scholar
  22. 22.
    Kannan K, Givol D (2000) FGF receptor mutations: dimerization syndromes, cell growth suppression, and animal models. IUBMB Life 49(3):197–205PubMedGoogle Scholar
  23. 23.
    Rousseau F, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet JM, Maroteaux P, Le Merrer M, Munnich A (1996) Mutations of the fibroblast growth factor receptor-3 gene in achondroplasia. Horm Res 45(1–2):108–110Google Scholar
  24. 24.
    Bellus GA, McIntosh I, Smith EA, Aylsworth AS, Kaitila I, Horton WA, Greenhaw GA, Hecht JT, Francomano CA (1995) A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet 10(3):357–359PubMedCrossRefGoogle Scholar
  25. 25.
    Grigelioniene G, Hagenas L, Eklof O, Neumeyer L, Haereid PE, Anvret M (1998) A novel missense mutation Ile538Val in the fibroblast growth factor receptor 3 in hypochondroplasia. Mutations in brief no. 122. Online. Hum Mutat 11(4):333PubMedCrossRefGoogle Scholar
  26. 26.
    Bellus GA, Spector EB, Speiser PW, Weaver CA, Garber AT, Bryke CR, Israel J, Rosengren SS, Webster MK, Donoghue DJ, Francomano CA (2000) Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am J Hum Genet 67(6):1411–1421PubMedCrossRefGoogle Scholar
  27. 27.
    Winterpacht A, Hilbert K, Stelzer C, Schweikardt T, Decker H, Segerer H, Spranger J, Zabel B (2000) A novel mutation in FGFR-3 disrupts a putative N-glycosylation site and results in hypochondroplasia. Physiol Genomics 2(1):9–12PubMedGoogle Scholar
  28. 28.
    Brodie SG, Kitoh H, Lachman RS, Nolasco LM, Mekikian PB, Wilcox WR (1999) Platyspondylic lethal skeletal dysplasia, San Diego type, is caused by FGFR3 mutations. Am J Med Genet 84(5):476–480PubMedCrossRefGoogle Scholar
  29. 29.
    Tavormina PL, Shiang R, Thompson LM, Zhu YZ, Wilkin DJ, Lachman RS, Wilcox WR, Rimoin DL, Cohn DH, Wasmuth JJ (1995) Thanatophoric dysplasia (type I and type II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet 9:321–328PubMedCrossRefGoogle Scholar
  30. 30.
    Tavormina PL, Rimoin DL, Cohn DH, Zhu YZ, Shiang R, Wasmuth JJ (1995) Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type I. Hum Mol Genet 4:2175–2177PubMedCrossRefGoogle Scholar
  31. 31.
    Rousseau F, Saugier P, Le Merrer M, Munnich A, Delezoide AL, Maroteaux P, Bonaventure J, Narcy F, Sanak M (1995) Stop codon FGFR3 mutation in thanatophoric dwarfism type I. Nat Genet 10:11–12PubMedCrossRefGoogle Scholar
  32. 32.
    Webster MK, D’Avis PY, Robertson SC, Donoghue DJ (1996) Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II. Mol Cell Biol 16(8):4081–4087PubMedGoogle Scholar
  33. 33.
    Tavormina PL, Bellus GA, Webster MK, Bamshad MJ, Fraley AE, McIntosh I, Szabo J, Jiang W, Jabs EW, Wilcox WR, Wasmuth JJ, Donoghue DJ, Thompson LM, Francomano CA (1999) Novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene. Am J Hum Genet 64:722–731PubMedCrossRefGoogle Scholar
  34. 34.
    Bellus GA, Bamshad MJ, Przylepa KA, Dorst J, Lee RR, Hurko O, Jabs EW, Curry CJ, Wilcox WR, Lachman RS, Rimoin DL, Francomano CA (1999) Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3. Am J Med Genet 85(1):53–65PubMedCrossRefGoogle Scholar
  35. 35.
    McAlister WH, Crane JP, Bucy RP, Craig RB (1985) A new neonatal short limbed dwarfism. Skeletal Radiol 13(4):271–275PubMedCrossRefGoogle Scholar
  36. 36.
    Langer LO Jr, Baumann PA, Gorlin RJ (1967) Achondroplasia. Am J Roentgenol 100:12–26Google Scholar
  37. 37.
    Hecht JT, Thompson NM, Weir T, Patchell L, Horton WA (1991) Cognitive and motor skills in achondroplastic infants: neurologic and respiratory correlates. Am J Hum Genet 41:208–211Google Scholar
  38. 38.
    Cohen MM Jr, Walker GF, Phillips C (1985) Morphometric analysis of the craniofacial configuration in achondroplasia. J Craniofac Genet Dev Biol 1:139–165Google Scholar
  39. 39.
    Rousseau F, Bonaventure J, Logeai-Mallet L, Schmidt H, Wessenbach J, Maroteaux P, Munnich A, Le Merrer M (1996) Clinical and genetical heterogeneity of hypochondroplasia. J Med Genet 33:749–752PubMedCrossRefGoogle Scholar
  40. 40.
    Ramaswami U, Rumsby G, Hindmarsh PC, Brook CGD (1998) Genotype and phenotype in hypochondroplasia. J Pediatr 133:99–102PubMedCrossRefGoogle Scholar
  41. 41.
    Connor JM, Connor RAC, Sweet EM, Gibson AAM, Patrick WJA, McNay MB, Redford DHA (1985) Lethal neonatal chondrodysplasias in the West of Scotland, 1970–1983, with a description of a thanatophoric, dysplasia like, autosomal recessive disorder, Glasgow variant. Am J Med Genet 22:243–253PubMedCrossRefGoogle Scholar
  42. 42.
    Martinez-Frias ML, Ramos-Arroyo MA, Salvador J (1988) Thanatophoric dysplasia: an autosomal dominant condition? Am J Med Genet 31:815–820PubMedCrossRefGoogle Scholar
  43. 43.
    Elejalde BR, de Elejalde MM (1985) Thanatophoric dysplasia: fetal manifestations and prenatal diagnosis. Am J Med Genet 22(4):669–683PubMedCrossRefGoogle Scholar
  44. 44.
    Langer LO Jr, Yang SS, Hall JG, Sommer A, Kottamasu SR, Golabi M, Krassikoff N (1987) Thanatophoric dysplasia and cloverleaf skull. Am J Med Genet Suppl 3:167–179PubMedCrossRefGoogle Scholar
  45. 45.
    Norman AM, Rimmer S, Landy S, Donnai D (1992) Thanatophoric dysplasia of the straight-bone type (type 2). Clin Dysmorph 1:115–120PubMedGoogle Scholar
  46. 46.
    Giedion A (1968) Thanatophoric dwarfism. Helv Paediat Acta 23:175–183PubMedGoogle Scholar
  47. 47.
    Bellus GA, Bamshad MJ, Przylepa KA, Dorst J, Lee RR, Hurko L, Jabs EW, Curry CJ, Wilcox WR, Lachman RS, Rimoin DL, Francomano CA (1999) Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3. Am J Med Genet 85(1):53–65PubMedCrossRefGoogle Scholar
  48. 48.
    Naski MC, Wang Q, Xu J, Ornitz DM (1996) Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nat Genet 13:233–237PubMedCrossRefGoogle Scholar
  49. 49.
    Lievens PM, Liboi E (2003) The thanatophoric dysplasia type II mutation hampers complete maturation of fibroblast growth factor receptor 3 (FGFR3), which activates signal transducer and activator of transcription 1 (STAT1) from the endoplasmic reticulum. J Biol Chem 278(19):17344–17349PubMedCrossRefGoogle Scholar
  50. 50.
    Lievens PMJ, Mutinelli C, Daynes D, Liboi E (2004) The kinase activity of fibroblast growth factor receptor 3 with activation loop mutations affects receptor trafficking and signaling. J Biol Chem 279(41):43254–43260PubMedCrossRefGoogle Scholar
  51. 51.
    Harada D, Yamanaka Y, Ueda K, Nishimura R, Morishima T, Seino Y, Tanaka H (2007) Sustained phosphorylation of mutated FGFR3 is a crucial feature of genetic dwarfism and induces apoptosis in the ATDC5 chondrogenic cell line via PLC-gamma-activated STAT1. Bone (NY) 41(2):273–281Google Scholar
  52. 52.
    Webster MK, Donoghue DJ (1996) Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia. EMBO J 15(3):520–527PubMedGoogle Scholar
  53. 53.
    Ornitz DM, Marie PJ (2002) FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev 16(12):1446–1465PubMedCrossRefGoogle Scholar
  54. 54.
    Eswarakumar VP, Lax I, Schlessinger J (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16(2):139–149PubMedCrossRefGoogle Scholar
  55. 55.
    L’Hote CG, Knowles MA (2005) Cell responses to FGFR3 signalling: growth, differentiation and apoptosis. Exp Cell Res 304(2):417–431PubMedCrossRefGoogle Scholar
  56. 56.
    Horton WA, Hall JG, Hacht JT (2007) Achondroplasia. Lancet 370:162–172PubMedCrossRefGoogle Scholar
  57. 57.
    Hart KC, Robertson SC, Donoghue DJ (2001) Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis, stat activation, and phosphatidylinositol 3-kinase activation. Mol Biol Cell 22:931–942Google Scholar
  58. 58.
    Koike M, Yamanaka Y, Inoue M, Tanaka H, Nishimura R, Seino Y (2003) Insulin-like growth factor-1 rescues the mutated FGF receptor 3 (G380R) expressing ATDC5 cells from apoptosis through phosphatidylinositol 3-kinase and MAPK. J Bone Miner Res 18:2043–2051PubMedCrossRefGoogle Scholar
  59. 59.
    Yasoda A, Komatsu Y, Chusho H, Miyazawa T, Ozasa A, Miura M, Kurihara T, Rogi T, Tanaka S, Suda M, Tamura N, Ogawa Y, Nakao K (2004) Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med 10(1):80–86PubMedCrossRefGoogle Scholar
  60. 60.
    Naski MC, Colvin JS, Coffin JD, Ornitz DM (1998) Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development (Camb) 125:4977–4988Google Scholar
  61. 61.
    Yamanaka Y, Tanaka H, Koike M, Nishimura R, Seino Y (2003) PTHrP rescues ATDC5 cells from apoptosis induced by FGF receptor 3 mutation. J Bone Miner Res 18:1395–1403PubMedCrossRefGoogle Scholar
  62. 62.
    Tanaka H, Kubo T, Yamate T, Ono T, Kanzaki S, Seino Y (1998) Effect of growth hormone therapy in children with achondroplasia: growth pattern, hypothalamic-pituitary function, and genotype. Eur J Endocrinol 138(3):275–280PubMedCrossRefGoogle Scholar
  63. 63.
    Ramaswami U, Hindmarsh PC, Brook CG (1999) Growth hormone therapy in hypochondroplasia. Acta Paediatr Suppl 88(428):116–117PubMedCrossRefGoogle Scholar
  64. 64.
    Yamanaka Y, Seino Y, Shinohara M, Ikegami S, Koike M, Miyazawa M, Inoue M, Moriwake T, Tanaka H (2000) Growth hormone therapy in achondroplasia. Horm Res 53(suppl 3):53–56PubMedGoogle Scholar
  65. 65.
    Kanazawa H, Tanaka H, Inoue M, Yamanaka Y, Namba N, Seino Y (2003) Efficacy of growth hormone therapy for patients with skeletal dysplasia. J Bone Miner Metab 21(5):307–310PubMedCrossRefGoogle Scholar
  66. 66.
    Yasui N, Kawabata H, Kojimoto H, Ohno H, Matsuda S, Araki N, Shimomura Y, Ochi T (1997) Lengthening of the lower limbs in patients with achondroplasia and hypochondroplasia. Clin Orthop Relat Res 344:298–306PubMedCrossRefGoogle Scholar
  67. 67.
    Aldegheri R, Dall’Oca C (2001) Limb lengthening in short stature patients. J Pediatr Orthop B 10(3):238–247PubMedCrossRefGoogle Scholar
  68. 68.
    Aviezer D, Golembo M, Yayon A (2003) Fibroblast growth factor receptor-3 as a therapeutic target for achondroplasia: genetic short limbed dwarfism. Curr Drug Targets 4(5):353–365PubMedCrossRefGoogle Scholar
  69. 69.
    Ueda K, Yamanaka Y, Harada D, Yamagami E, Tanaka H, Seino Y (2007) PTH has the potential to rescue disturbed bone growth in achondroplasia. Bone (NY) 41(1):13–18Google Scholar
  70. 70.
    Hagiwara H, Sakaguchi H, Itakura M, Yoshimoto T, Furuya M, Tanaka S, Hirose S (1994) Autocrine regulation of rat chondrocyte proliferation by natriuretic peptide C and its receptor, natriuretic peptide receptor-B. J Biol Chem 269(14):10729–10733PubMedGoogle Scholar
  71. 71.
    Bartels CF, Bukulmez H, Padayatti P, Rhee DK, van Ravenswaaij-Arts C, Pauli RM, Mundlos S, Chitayat D, Shih L-Y, Al-Gazali LI, Kant S, Cole T, Morton J, Cormier-Daire V, Faivre L, Lees M, Kirk J, Mortier GR, Leroy J, Zabel B, Kim CA, Crow Y, Braverman NE, van den Akker F, Warman ML (2004) Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet 75:27–34PubMedCrossRefGoogle Scholar
  72. 72.
    Potter LR, Abbey-Hosch S, Dickey DM (2006) Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev 27:47–72PubMedCrossRefGoogle Scholar
  73. 73.
    Rauchenberger R, Borges E, Thomassen-Wolf E, Rom E, Adar R, Yaniv Y, Malka M, Chumakov I, Kotzer S, Resnitzky D, Knappik A, Reiffert S, Prassler J, Jury K, Waldherr D, Bauer S, Kretzschmar T, Yayon A, Rothe C (2003) Human combinatorial Fab library yielding specific and functional antibodies against the human fibroblast growth factor receptor 3. J Biol Chem 38:38194–38205CrossRefGoogle Scholar
  74. 74.
    Aviezer D, Golembo M, Yayon A (2003) Fibroblast growth factor receptor-3 as a therapeutic target for achondroplasia: genetic short limbed dwarfism. Curr Drug Targets 4(5):353–365PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer 2008

Authors and Affiliations

  • Daisuke Harada
    • 1
  • Yoshitaka Yamanaka
    • 1
  • Koso Ueda
    • 2
  • Hiroyuki Tanaka
    • 3
  • Yoshiki Seino
    • 4
  1. 1.Department of PediatricsOkayama University Graduated School of Medicine and DentistryOkayamaJapan
  2. 2.Department of PediatricsMatsuyama Red Cross HospitalEhimeJapan
  3. 3.Department of PediatricsOkayama Saiseikai General HospitalOkayamaJapan
  4. 4.Department of PediatricsOsaka Kosei-nenkin HospitalOsakaJapan

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