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. 1995 Feb;56(2):368–373.

Achondroplasia is defined by recurrent G380R mutations of FGFR3.

G A Bellus 1, T W Hefferon 1, R I Ortiz de Luna 1, J T Hecht 1, W A Horton 1, M Machado 1, I Kaitila 1, I McIntosh 1, C A Francomano 1
PMCID: PMC1801129  PMID: 7847369

Abstract

Genomic DNA from 154 unrelated individuals with achondroplasia was evaluated for mutations in the fibroblast growth factor receptor 3 (FGFR3) transmembrane domain. All but one, an atypical case, were found to have a glycine-to-arginine substitution at codon 380. Of these, 150 had a G-to-A transition at nt 1138, and 3 had a G-to-C transversion at this same position. On the basis of estimates of the prevalence of achondroplasia, the mutation rate at the FGFR3 1138 guanosine nucleotide is two to three orders of magnitude higher than that previously reported for tranversions and transitions in CpG dinucleotides. To date, this represents the most mutable single nucleotide reported in the human genome. The homogeneity of mutations in achondroplasia is unprecedented for an autosomal dominant disorder and may explain the relative lack of heterogeneity in the achondroplasia phenotype.

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Selected References

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  1. Amor M., Parker K. L., Globerman H., New M. I., White P. C. Mutation in the CYP21B gene (Ile-172----Asn) causes steroid 21-hydroxylase deficiency. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1600–1604. doi: 10.1073/pnas.85.5.1600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Andersen P. E., Jr, Hauge M. Congenital generalised bone dysplasias: a clinical, radiological, and epidemiological survey. J Med Genet. 1989 Jan;26(1):37–44. doi: 10.1136/jmg.26.1.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Braun L., Schneider P. M., Giles C. M., Bertrams J., Rittner C. Null alleles of human complement C4. Evidence for pseudogenes at the C4A locus and for gene conversion at the C4B locus. J Exp Med. 1990 Jan 1;171(1):129–140. doi: 10.1084/jem.171.1.129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bullock P., Champoux J. J., Botchan M. Association of crossover points with topoisomerase I cleavage sites: a model for nonhomologous recombination. Science. 1985 Nov 22;230(4728):954–958. doi: 10.1126/science.2997924. [DOI] [PubMed] [Google Scholar]
  5. Chellaiah A. T., McEwen D. G., Werner S., Xu J., Ornitz D. M. Fibroblast growth factor receptor (FGFR) 3. Alternative splicing in immunoglobulin-like domain III creates a receptor highly specific for acidic FGF/FGF-1. J Biol Chem. 1994 Apr 15;269(15):11620–11627. [PubMed] [Google Scholar]
  6. Collier S., Tassabehji M., Sinnott P., Strachan T. A de novo pathological point mutation at the 21-hydroxylase locus: implications for gene conversion in the human genome. Nat Genet. 1993 Mar;3(3):260–265. doi: 10.1038/ng0393-260. [DOI] [PubMed] [Google Scholar]
  7. Cooper D. N., Youssoufian H. The CpG dinucleotide and human genetic disease. Hum Genet. 1988 Feb;78(2):151–155. doi: 10.1007/BF00278187. [DOI] [PubMed] [Google Scholar]
  8. Francomano C. A., Ortiz de Luna R. I., Hefferon T. W., Bellus G. A., Turner C. E., Taylor E., Meyers D. A., Blanton S. H., Murray J. C., McIntosh I. Localization of the achondroplasia gene to the distal 2.5 Mb of human chromosome 4p. Hum Mol Genet. 1994 May;3(5):787–792. doi: 10.1093/hmg/3.5.787. [DOI] [PubMed] [Google Scholar]
  9. Gardner R. J. A new estimate of the achondroplasia mutation rate. Clin Genet. 1977 Jan;11(1):31–38. doi: 10.1111/j.1399-0004.1977.tb01274.x. [DOI] [PubMed] [Google Scholar]
  10. Green P. M., Montandon A. J., Bentley D. R., Ljung R., Nilsson I. M., Giannelli F. The incidence and distribution of CpG----TpG transitions in the coagulation factor IX gene. A fresh look at CpG mutational hotspots. Nucleic Acids Res. 1990 Jun 11;18(11):3227–3231. doi: 10.1093/nar/18.11.3227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Grundy C. B., Schulman S., Krawczak M., Kobosko J., Kakkar V. V., Cooper D. N. Protein C deficiency and thromboembolism: recurrent mutation at Arg 306 in the protein C gene. Hum Genet. 1992 Mar;88(5):586–588. doi: 10.1007/BF00219350. [DOI] [PubMed] [Google Scholar]
  12. Hall B. D., Spranger J. Hypochondroplasia: clinical and radiological aspects in 39 cases. Radiology. 1979 Oct;133(1):95–100. doi: 10.1148/133.1.95. [DOI] [PubMed] [Google Scholar]
  13. Hecht J. T., Francomano C. A., Horton W. A., Annegers J. F. Mortality in achondroplasia. Am J Hum Genet. 1987 Sep;41(3):454–464. [PMC free article] [PubMed] [Google Scholar]
  14. Hecht J. T., Horton W. A., Butler I. J., Goldie W. D., Miner M. E., Shannon R., Pauli R. M. Foramen magnum stenosis in homozygous achondroplasia. Eur J Pediatr. 1986 Dec;145(6):545–547. doi: 10.1007/BF02429060. [DOI] [PubMed] [Google Scholar]
  15. Jabs E. W., Li X., Scott A. F., Meyers G., Chen W., Eccles M., Mao J. I., Charnas L. R., Jackson C. E., Jaye M. Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2. Nat Genet. 1994 Nov;8(3):275–279. doi: 10.1038/ng1194-275. [DOI] [PubMed] [Google Scholar]
  16. Johnson D. E., Williams L. T. Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res. 1993;60:1–41. doi: 10.1016/s0065-230x(08)60821-0. [DOI] [PubMed] [Google Scholar]
  17. Kazazian H. H., Jr, Waber P. G., Boehm C. D., Lee J. I., Antonarakis S. E., Fairbanks V. F. Hemoglobin E in Europeans: further evidence for multiple origins of the beta E-globin gene. Am J Hum Genet. 1984 Jan;36(1):212–217. [PMC free article] [PubMed] [Google Scholar]
  18. Keegan K., Johnson D. E., Williams L. T., Hayman M. J. Isolation of an additional member of the fibroblast growth factor receptor family, FGFR-3. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1095–1099. doi: 10.1073/pnas.88.4.1095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Koeberl D. D., Bottema C. D., Ketterling R. P., Bridge P. J., Lillicrap D. P., Sommer S. S. Mutations causing hemophilia B: direct estimate of the underlying rates of spontaneous germ-line transitions, transversions, and deletions in a human gene. Am J Hum Genet. 1990 Aug;47(2):202–217. [PMC free article] [PubMed] [Google Scholar]
  20. Kulozik A. E., Wainscoat J. S., Serjeant G. R., Kar B. C., Al-Awamy B., Essan G. J., Falusi A. G., Haque S. K., Hilali A. M., Kate S. Geographical survey of beta S-globin gene haplotypes: evidence for an independent Asian origin of the sickle-cell mutation. Am J Hum Genet. 1986 Aug;39(2):239–244. [PMC free article] [PubMed] [Google Scholar]
  21. Kunkel L. M., Smith K. D., Boyer S. H., Borgaonkar D. S., Wachtel S. S., Miller O. J., Breg W. R., Jones H. W., Jr, Rary J. M. Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc Natl Acad Sci U S A. 1977 Mar;74(3):1245–1249. doi: 10.1073/pnas.74.3.1245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Langer L. O., Jr, Baumann P. A., Gorlin R. J. Achondroplasia. Am J Roentgenol Radium Ther Nucl Med. 1967 May;100(1):12–26. doi: 10.2214/ajr.100.1.12. [DOI] [PubMed] [Google Scholar]
  23. Le Merrer M., Rousseau F., Legeai-Mallet L., Landais J. C., Pelet A., Bonaventure J., Sanak M., Weissenbach J., Stoll C., Munnich A. A gene for achondroplasia-hypochondroplasia maps to chromosome 4p. Nat Genet. 1994 Mar;6(3):318–321. doi: 10.1038/ng0394-318. [DOI] [PubMed] [Google Scholar]
  24. Loux N., Benlian P., Pastier D., Boileau C., Cambou J. P., Monnier L., Percheron C., Junien C. Recurrent mutation at aa 792 in the LDL receptor gene in a French patient. Hum Genet. 1991 Jul;87(3):373–375. doi: 10.1007/BF00200923. [DOI] [PubMed] [Google Scholar]
  25. Matsuno Y., Yamashiro Y., Yamamoto K., Hattori Y., Yamamoto K., Ohba Y., Miyaji T. A possible example of gene conversion with a common beta-thalassemia mutation and Chi sequence present in the beta-globin gene. Hum Genet. 1992 Jan;88(3):357–358. doi: 10.1007/BF00197277. [DOI] [PubMed] [Google Scholar]
  26. McKusick V. A., Kelly T. E., Dorst J. P. Observations suggesting allelism of the achondroplasia and hypochondroplasia genes. J Med Genet. 1973 Mar;10(1):11–16. doi: 10.1136/jmg.10.1.11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Muenke M., Schell U., Hehr A., Robin N. H., Losken H. W., Schinzel A., Pulleyn L. J., Rutland P., Reardon W., Malcolm S. A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nat Genet. 1994 Nov;8(3):269–274. doi: 10.1038/ng1194-269. [DOI] [PubMed] [Google Scholar]
  28. Murdoch J. L., Walker B. A., Hall J. G., Abbey H., Smith K. K., McKusick V. A. Achondroplasia--a genetic and statistical survey. Ann Hum Genet. 1970 Jan;33(3):227–244. doi: 10.1111/j.1469-1809.1970.tb01648.x. [DOI] [PubMed] [Google Scholar]
  29. Nelson F. W., Hecht J. T., Horton W. A., Butler I. J., Goldie W. D., Miner M. Neurological basis of respiratory complications in achondroplasia. Ann Neurol. 1988 Jul;24(1):89–93. doi: 10.1002/ana.410240117. [DOI] [PubMed] [Google Scholar]
  30. Oberklaid F., Danks D. M., Jensen F., Stace L., Rosshandler S. Achondroplasia and hypochondroplasia. Comments on frequency, mutation rate, and radiological features in skull and spine. J Med Genet. 1979 Apr;16(2):140–146. doi: 10.1136/jmg.16.2.140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Okano Y., Wang T., Eisensmith R. C., Güttler F., Woo S. L. Recurrent mutation in the human phenylalanine hydroxylase gene. Am J Hum Genet. 1990 May;46(5):919–924. [PMC free article] [PubMed] [Google Scholar]
  32. Partanen J., Vainikka S., Alitalo K. Structural and functional specificity of FGF receptors. Philos Trans R Soc Lond B Biol Sci. 1993 Jun 29;340(1293):297–303. doi: 10.1098/rstb.1993.0071. [DOI] [PubMed] [Google Scholar]
  33. Pattinson J. K., Millar D. S., McVey J. H., Grundy C. B., Wieland K., Mibashan R. S., Martinowitz U., Tan-Un K., Vidaud M., Goossens M. The molecular genetic analysis of hemophilia A: a directed search strategy for the detection of point mutations in the human factor VIII gene. Blood. 1990 Dec 1;76(11):2242–2248. [PubMed] [Google Scholar]
  34. Pauli R. M., Conroy M. M., Langer L. O., Jr, McLone D. G., Naidich T., Franciosi R., Ratner I. M., Copps S. C. Homozygous achondroplasia with survival beyond infancy. Am J Med Genet. 1983 Dec;16(4):459–473. doi: 10.1002/ajmg.1320160404. [DOI] [PubMed] [Google Scholar]
  35. Peters K., Ornitz D., Werner S., Williams L. Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. Dev Biol. 1993 Feb;155(2):423–430. doi: 10.1006/dbio.1993.1040. [DOI] [PubMed] [Google Scholar]
  36. Reardon W., Winter R. M., Rutland P., Pulleyn L. J., Jones B. M., Malcolm S. Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet. 1994 Sep;8(1):98–103. doi: 10.1038/ng0994-98. [DOI] [PubMed] [Google Scholar]
  37. Reiss J., Cooper D. N., Bal J., Slomski R., Cutting G. R., Krawczak M. Discrimination between recurrent mutation and identity by descent: application to point mutations in exon 11 of the cystic fibrosis (CFTR) gene. Hum Genet. 1991 Aug;87(4):457–461. doi: 10.1007/BF00197168. [DOI] [PubMed] [Google Scholar]
  38. Rousseau F., Bonaventure J., Legeai-Mallet L., Pelet A., Rozet J. M., Maroteaux P., Le Merrer M., Munnich A. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature. 1994 Sep 15;371(6494):252–254. doi: 10.1038/371252a0. [DOI] [PubMed] [Google Scholar]
  39. Shen J. C., Rideout W. M., 3rd, Jones P. A. High frequency mutagenesis by a DNA methyltransferase. Cell. 1992 Dec 24;71(7):1073–1080. doi: 10.1016/s0092-8674(05)80057-1. [DOI] [PubMed] [Google Scholar]
  40. Shiang R., Thompson L. M., Zhu Y. Z., Church D. M., Fielder T. J., Bocian M., Winokur S. T., Wasmuth J. J. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell. 1994 Jul 29;78(2):335–342. doi: 10.1016/0092-8674(94)90302-6. [DOI] [PubMed] [Google Scholar]
  41. Sorge J., Gross E., West C., Beutler E. High level transcription of the glucocerebrosidase pseudogene in normal subjects and patients with Gaucher disease. J Clin Invest. 1990 Oct;86(4):1137–1141. doi: 10.1172/JCI114818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Steinberg R. A., Gorman K. B. Linked spontaneous CG----TA mutations at CpG sites in the gene for protein kinase regulatory subunit. Mol Cell Biol. 1992 Feb;12(2):767–772. doi: 10.1128/mcb.12.2.767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Stoll C., Dott B., Roth M. P., Alembik Y. Birth prevalence rates of skeletal dysplasias. Clin Genet. 1989 Feb;35(2):88–92. doi: 10.1111/j.1399-0004.1989.tb02912.x. [DOI] [PubMed] [Google Scholar]
  44. Thompson L. M., Plummer S., Schalling M., Altherr M. R., Gusella J. F., Housman D. E., Wasmuth J. J. A gene encoding a fibroblast growth factor receptor isolated from the Huntington disease gene region of human chromosome 4. Genomics. 1991 Dec;11(4):1133–1142. doi: 10.1016/0888-7543(91)90041-c. [DOI] [PubMed] [Google Scholar]
  45. Urabe K., Kimura A., Harada F., Iwanaga T., Sasazuki T. Gene conversion in steroid 21-hydroxylase genes. Am J Hum Genet. 1990 Jun;46(6):1178–1186. [PMC free article] [PubMed] [Google Scholar]
  46. Urioste M., Martinez-Frias M. L., Bermejo E., Villa A., Jimenez N., Romero D., Nieto C. Chromosome 4p16 and osteochondroplasias. Nat Genet. 1994 Apr;6(4):334–334. doi: 10.1038/ng0494-334. [DOI] [PubMed] [Google Scholar]
  47. Velinov M., Slaugenhaupt S. A., Stoilov I., Scott C. I., Jr, Gusella J. F., Tsipouras P. The gene for achondroplasia maps to the telomeric region of chromosome 4p. Nat Genet. 1994 Mar;6(3):314–317. doi: 10.1038/ng0394-314. [DOI] [PubMed] [Google Scholar]
  48. Wynne-Davies R., Walsh W. K., Gormley J. Achondroplasia and hypochondroplasia. Clinical variation and spinal stenosis. J Bone Joint Surg Br. 1981;63B(4):508–515. doi: 10.1302/0301-620X.63B4.7298674. [DOI] [PubMed] [Google Scholar]
  49. Youssoufian H., Antonarakis S. E., Bell W., Griffin A. M., Kazazian H. H., Jr Nonsense and missense mutations in hemophilia A: estimate of the relative mutation rate at CG dinucleotides. Am J Hum Genet. 1988 May;42(5):718–725. [PMC free article] [PubMed] [Google Scholar]

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