This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vajo, Z. Articles by Wilkin, D. J. Search for Related Content PubMed PubMed Citation Articles by Vajo, Z. Articles by Wilkin, D. J.

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 Nigricans¹

Department of Endocrinology and Medicine (Z.V.), Veterans Affairs Medical Center, Phoenix, Arizona 85012; and Medical Genetics Branch (Z.V., C.A.F.), National Human Genome Research Institute and Craniofacial and Skeletal Diseases Branch (D.J.W.), National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, 20892

Achondroplasia, the most common form of short-limbed dwarfism in humans, occurs between 1 in 15,000 and 40,000 live births. More than 90% of cases are sporadic and there is, on average, an increased paternal age at the time of conception of affected individuals. More then 97% of persons with achondroplasia have a Gly380Arg mutation in the transmembrane domain of the fibroblast growth factor receptor (FGFR) 3 gene. Mutations in the FGFR3 gene also result in hypochondroplasia, the lethal thanatophoric dysplasias, the recently described SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) dysplasia, and two craniosynostosis disorders: Muenke coronal craniosynostosis and Crouzon syndrome with acanthosis nigricans. Recent evidence suggests that the phenotypic differences may be due to specific alleles with varying degrees of ligand-independent activation, allowing the receptor to be constitutively active.

Since the Gly380Arg achondroplasia mutation was recognized, similar observations regarding the conserved nature of FGFR mutations and resulting phenotype have been made regarding other skeletal phenotypes, including hypochondroplasia, thanatophoric dysplasia, and Muenke coronal craniosynostosis. These specific genotype-phenotype correlations in the FGFR disorders seem to be unprecedented in the study of human disease. The explanation for this high degree of mutability at specific bases remains an intriguing question.

This article has been cited by other articles:

				T. Kake, H. Kitamura, Y. Adachi, T. Yoshioka, T. Watanabe, H. Matsushita, T. Fujii, E. Kondo, T. Tachibe, Y. Kawase, et al. Chronically elevated plasma C-type natriuretic peptide level stimulates skeletal growth in transgenic mice Am J Physiol Endocrinol Metab, December 1, 2009; 297(6): E1339 - E1348. [Abstract] [Full Text] [PDF]

				K. S. Alatzoglou, P. C. Hindmarsh, C. Brain, J. Torpiano, and M. T. Dattani Acanthosis Nigricans and Insulin Sensitivity in Patients with Achondroplasia and Hypochodroplasia due to FGFR3 Mutations J. Clin. Endocrinol. Metab., October 1, 2009; 94(10): 3959 - 3963. [Abstract] [Full Text] [PDF]

				R. Khatri and E. Schipani About the importance of being desulfated Genes & Dev., October 15, 2008; 22(20): 2750 - 2754. [Abstract] [Full Text] [PDF]

				L. Castro-Feijoo, L. Loidi, A. Vidal, S. Parajes, E. Roson, A. Alvarez, P. Cabanas, J. Barreiro, A. Alonso, F. Dominguez, et al. Hypochondroplasia and acanthosis nigricans: a new syndrome due to the p.Lys650Thr mutation in the fibroblast growth factor receptor 3 gene? Eur. J. Endocrinol., September 1, 2008; 159(3): 243 - 249. [Abstract] [Full Text] [PDF]

				M. Dighe, C. Fligner, E. Cheng, B. Warren, and T. Dubinsky Fetal Skeletal Dysplasia: An Approach to Diagnosis with Illustrative Cases1 RadioGraphics, July 1, 2008; 28(4): 1061 - 1077. [Abstract] [Full Text] [PDF]

				C. Hafner, E. Lopez-Knowles, N. M. Luis, A. Toll, E. Baselga, A. Fernandez-Casado, S. Hernandez, A. Ribe, T. Mentzel, R. Stoehr, et al. Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern PNAS, August 14, 2007; 104(33): 13450 - 13454. [Abstract] [Full Text] [PDF]

				R. G Rosenfeld Pharmacogenomics and pharmacoproteomics in the evaluation and management of short stature Eur. J. Endocrinol., August 1, 2007; 157(suppl_1): S27 - S31. [Abstract] [Full Text] [PDF]

				S. Hernandez, E. Lopez-Knowles, J. Lloreta, M. Kogevinas, A. Amoros, A. Tardon, A. Carrato, C. Serra, N. Malats, and F. X. Real Prospective Study of FGFR3 Mutations As a Prognostic Factor in Nonmuscle Invasive Urothelial Bladder Carcinomas J. Clin. Oncol., August 1, 2006; 24(22): 3664 - 3671. [Abstract] [Full Text] [PDF]

				S H Khan, J A Britto, R D Evans, and K K Nischal Expression of FGFR-2 and FGFR-3 in the normal human fetal orbit Br J Ophthalmol, December 1, 2005; 89(12): 1643 - 1645. [Abstract] [Full Text] [PDF]

				C. H. Evans and R. N. Rosier Molecular Biology in Orthopaedics: The Advent of Molecular Orthopaedics J. Bone Joint Surg. Am., November 1, 2005; 87(11): 2550 - 2564. [Abstract] [Full Text] [PDF]

				B. Kuhnert and E. Nieschlag Reproductive functions of the ageing male Hum. Reprod. Update, July 1, 2004; 10(4): 327 - 339. [Abstract] [Full Text] [PDF]

				C Steiner, N Ehtesham, K D Taylor, E Sebald, R Cantor, L M King, X Guo, T Hang, M S Hu, J-R Cui, et al. A locus for spondylocarpotarsal synostosis syndrome at chromosome 3p14 J. Med. Genet., April 1, 2004; 41(4): 266 - 269. [Abstract] [Full Text] [PDF]

				J.-C. Carel, N. Lahlou, M. Roger, and J. L. Chaussain Precocious puberty and statural growth Hum. Reprod. Update, March 1, 2004; 10(2): 135 - 147. [Abstract] [Full Text] [PDF]

				B. C. J. van der Eerden, M. Karperien, and J. M. Wit Systemic and Local Regulation of the Growth Plate Endocr. Rev., December 1, 2003; 24(6): 782 - 801. [Abstract] [Full Text] [PDF]

				G. Binder, M. B. Ranke, and D. D. Martin Auxology Is a Valuable Instrument for the Clinical Diagnosis of SHOX Haploinsufficiency in School-Age Children with Unexplained Short Stature J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4891 - 4896. [Abstract] [Full Text] [PDF]

				B. W.G. van Rhijn, A. N. Vis, T. H. van der Kwast, W. J. Kirkels, F. Radvanyi, E. C.M. Ooms, D. K. Chopin, E. R. Boeve, A. C. Jobsis, and E. C. Zwarthoff Molecular Grading of Urothelial Cell Carcinoma With Fibroblast Growth Factor Receptor 3 and MIB-1 is Superior to Pathologic Grade for the Prediction of Clinical Outcome J. Clin. Oncol., May 15, 2003; 21(10): 1912 - 1921. [Abstract] [Full Text] [PDF]

				G M S Mancini, O P van Diggelen, W J Kleijer, M Di Rocco, V Farina, M Yuksel-Apak, H Kayserili, and D J J Halley Studies on the pathogenesis of Costello syndrome J. Med. Genet., April 1, 2003; 40(4): e37 - 37. [Full Text] [PDF]

				R. T. Ballock and R. J. O'Keefe The Biology of the Growth Plate J. Bone Joint Surg. Am., March 31, 2003; 85(4): 715 - 726. [Full Text] [PDF]

				D. M. Ornitz and P. J. Marie FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease Genes & Dev., June 15, 2002; 16(12): 1446 - 1465. [Full Text] [PDF]

				P. Liu, A. Gucwa, M. L. Stover, E. Buck, A. Lichtler, and D. Rowe Analysis of inhibitory action of modified U1 snRNAs on target gene expression: discrimination of two RNA targets differing by a 1 bp mismatch Nucleic Acids Res., June 1, 2002; 30(11): 2329 - 2339. [Abstract] [Full Text] [PDF]

				A. Amsterdam, K. Kannan, D. Givol, Y. Yoshida, K. Tajima, and A. Dantes Apoptosis of Granulosa Cells and Female Infertility in Achondroplastic Mice Expressing Mutant Fibroblast Growth Factor Receptor 3G374R Mol. Endocrinol., September 1, 2001; 15(9): 1610 - 1623. [Abstract] [Full Text] [PDF]