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.
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Spranger, J., Langer, L.O. & Wiedemann, H.R. Bone Dysplasias (Fischer/ Saunders, Stuttgart/Philadelphia, 1974).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Talerico, M. & Bertget, S.M. Effect of 5′ splice site mutations on splicing of the preceding intron. Molec. cell. Biol. 10, 6299–6305 (1990).
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).
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).
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).
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).
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).
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).
Prockop, D.J. & Kivirikko, K.I. Heritable diseases of collagen. New Engl. J. Med. 311, 376–386 (1984).
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).
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).
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).
Chen, E.Y. & Seeburg, P.H. Supercoil sequencing, a fast and simple method for sequencing plasmid DNA. DNA 4, 165–170 (1985).
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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
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