Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Kniest and Stickler dysplasia phenotypes caused by collagen type II gene (COL2A1) defect

Abstract

Kniest and Stickler dysplasia are two chondrodysplasias characterized by specific phenotypes. No basic defect has been found in patients with Kniest dysplasia, whereas Stickler dysplasia is one of four chondrodysplasias for which mutations of type II procollagen gene (COL2A1) have been identified. We studied a 2-year-old girl presenting with manifestations of Kniest dysplasia and her mother showing a Stickler phenotype. Analysing COL2A1 in both patients, we detected the same 28 basepair deletion spanning the 3′-exon/intron boundary of exon 12 in mother and daughter. We were able to prove a somatic mosaic status for this mutation in the mother which accounts for her milder Stickler-like phenotype.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Spranger, J., Langer, L.O. & Wiedemann, H.R. Bone Dysplasias (Fischer/ Saunders, Stuttgart/Philadelphia, 1974).

    Google Scholar 

  2. 2

    Lee, B., Vissing, H., Ramirez, F., Rogers, D. & Rimoin, D. Identification of the molecular defect in a family with spondyloepiphysral dysplasia. Science 244, 978–980 (1989).

    CAS  Article  Google Scholar 

  3. 3

    Vissing, H. et al. Glycine to serine substitution in the triple helical domain of pro-α1 (II) collagen results in a lethal perinatal form of short-limbed dwarfism. J. Biol. Chem. 264, 18265–18267 (1989).

    CAS  PubMed  Google Scholar 

  4. 4

    Ala-Kokko, L., Baldwin, C.T., Moskowitz, R.W. & Prockop, D.J. Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with mild chondrodysplasia. Proc. natn. Acad. Sci. U.S.A. 87, 6565–6568 (1990).

    CAS  Article  Google Scholar 

  5. 5

    Tiller, G.E., Rimoin, D.L., Murray, L.W. & Cohn, D.H. Tandem duplication within a type II collagen gene (COL2A1) exon in an individual with spondyloepiphyseal dysplasia. Proc. natn. Acad. Sci. U.S.A. 87, 3889–3893 (1990).

    CAS  Article  Google Scholar 

  6. 6

    Ahmad, N.N. et al. Stop codon in the procollagen II gene (COL2A1) in a family with the Stickler syndrome (arthro-ophthalmopathy). Proc. natn. Acad. Sci. U.S.A. 88, 6624–6627 (1991).

    CAS  Article  Google Scholar 

  7. 7

    Norton, W.A. et al. Characterization of a type II collagen gene (COL2A1) mutation identified in cultured chondrocytes from human hypochondrogenesis. Proc. natn. Acad. Sci. U.S.A. 89, 4583–4587 (1992).

    Article  Google Scholar 

  8. 8

    Poole, A.R. et al. Kniest dysplasia is characterized by an apparent abnormal processing of the C-propeptide of type II cartilage collagen resulting in imperfect fibril assembly. J. clin. Invest. 81, 579–589 (1988).

    CAS  Article  Google Scholar 

  9. 9

    Ala-Kokko, L. & Prockop, D.J. Completion of the intron-exon structure of the gene for human type II procollagen (COL2A1): Variations in the nucleotide sequences of the alleles from three chromosomes. Genomics 8, 454–460 (1990).

    CAS  Article  Google Scholar 

  10. 10

    Orita, M., Suzuki, Y., Sekiya, T. & Hayashi, K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5, 874–879 (1989).

    CAS  Article  Google Scholar 

  11. 11

    Breathnach, A.S. & Smith, J. Fine structure of the early hair germ and dermal papilla in the human foetus. J. Anat. 102, 511–526 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Johnson, C.A., Densen, P., Hurford, R.K., Colten, H.R. & Wetsel, R.A. Type I human complement C2 deficiency. J. biol. Chem. 267, 9347–9353 (1992).

    CAS  PubMed  Google Scholar 

  13. 13

    Talerico, M. & Bertget, S.M. Effect of 5′ splice site mutations on splicing of the preceding intron. Molec. cell. Biol. 10, 6299–6305 (1990).

    CAS  Article  Google Scholar 

  14. 14

    Sakuraba, H., Eng, C.M., Desnick, R.J. & Bishop, D.F. Invariant exon skipping in the human α-galactosidase A pre-mRNA: Ag to t substitution in a 5′-splice site causing Fabry disease. Genomics 12, 643–650 (1992).

    CAS  Article  Google Scholar 

  15. 15

    Kuivaniemi, H., Sabol, C., Tromp, G., Sippola-Thiele, M. & Prockop, D.J. A 19-base pair deletion in the pro-α2(I) gene of type I procollagen that causes in-frame RNA splicing from exon 10 to exon 12 in a proband with atypical osteogenesis imperfecta and in his asymptomatic mother. J. biol. Chem. 263, 11407–11413 (1988).

    CAS  PubMed  Google Scholar 

  16. 16

    Barsh, G.S., Roush, C.L., Bonadio, J., Byers, P.M. & Gelinas, R.E. Intron-mediated recombination may cause a deletion in an α1 type I collagen chain in a lethal form of osteogenesis imperfecta. Proc. natn. Acad. Sci. U.S.A. 82, 2870–2874 (1985).

    CAS  Article  Google Scholar 

  17. 17

    Chu, M.-L., Gargiulo, V., Williams, C.J. & Ramirez, F. Multiexon deletion in an osteogenesis imperfecta variant with increased type III collagen mRNA. J. biol. Chem. 260, 691–694 (1985).

    CAS  PubMed  Google Scholar 

  18. 18

    Superti-Furga, A., Gugler, E., Gitzelmann, R. & Steinmann, B. Ehlers-Danlos syndrome type IV: A multi-exon deletion in one of the two COL3A1 alleles affecting structure, stability and processing of type III procollagen. J. biol. Chem. 263, 6226–6232 (1988).

    CAS  PubMed  Google Scholar 

  19. 19

    Wallis, G.A., Starman, B.J., Zinn, A.B. & Byers, P.H. Variable expression of osteogenesis imperfecta in a nuclear family is explained by somatic mosaicism for a lethal point mutation in the α1(I) gene (COL1A1) of type I collagen in a parent. Am. J. hum. Genet. 46, 1034–1040 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Prockop, D.J. & Kivirikko, K.I. Heritable diseases of collagen. New Engl. J. Med. 311, 376–386 (1984).

    CAS  Article  Google Scholar 

  21. 21

    Bateman, J.F., Moeller, I., Hannagan, M., Chan, D. & Cole, W.G. Lethal perinatal osteogenesis imperfecta due to a type I collagen _2(I) Gly to Arg substitution detected by chemical cleavage of an mRNArcDNA sequence mismatch. Hum. Mut. 1, 55–62 (1992).

    CAS  Article  Google Scholar 

  22. 22

    Bonadio, J. et al. Transgenic mouse model of the mild dominant form of osteogenesis imperfecta. Proc. natn. Acad. Sci. U.S.A. 87, 7145–7149 (1990).

    CAS  Article  Google Scholar 

  23. 23

    Sanger, F., Nickeln, A.R. & Coulsen, A.R. DNA sequencing with chain-terminating inhibitors. Proc. natn. Acad. Sci. U.S.A. 74, 5463–5467 (1977).

    CAS  Article  Google Scholar 

  24. 24

    Chen, E.Y. & Seeburg, P.H. Supercoil sequencing, a fast and simple method for sequencing plasmid DNA. DNA 4, 165–170 (1985).

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Winterpacht, A., Hilbert, M., Schwarze, U. et al. Kniest and Stickler dysplasia phenotypes caused by collagen type II gene (COL2A1) defect. Nat Genet 3, 323–326 (1993). https://doi.org/10.1038/ng0493-323

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing