Skip to main content
SpringerLink
Log in

Pseudoachondroplasia and Multiple Epiphyseal Dysplasia: Molecular Genetics, Disease Mechanisms and Therapeutic Targets

  • Chapter
  • First Online:
Cartilage

  • 1213 Accesses

Abstract

Genetic skeletal diseases (GSDs) are a diverse and complex group of over 450 rare diseases that affect the development and homoeostasis of the skeleton. Although individually rare, as a group of related genetic skeletal diseases, they have an overall prevalence of at least 1 per 4000 children, which extrapolates to a minimum of 225,000 people in the European Union, and this extensive burden in pain and disability leads to poor quality of life and high healthcare costs.

Dominant-negative (qualitative) defects in numerous cartilage structural proteins result in a broad range of GSDs, and this chapter will focus on a disease spectrum resulting from mutations in the glycoproteins, cartilage oligomeric matrix protein (COMP), type IX collagen and matrilin-3, which together cause a continuum of phenotypes that are amongst the most common of the autosomal dominant GSDs.

Pseudoachondroplasia (PSACH) and autosomal dominant multiple epiphyseal dysplasia (MED) define a disease spectrum typified by varying degrees of short-limbed dwarfism, joint pain with stiffness and early-onset osteoarthritis (OA). The generation and deep phenotyping of a range of genetic cell and mouse models of the PSACH and MED disease spectrum has allowed the disease mechanisms to be characterised in detail. Furthermore, the generation of novel phenocopies to model specific disease mechanisms has confirmed the importance of endoplasmic reticulum stress, reduced chondrocyte proliferation and increased dysregulated apoptosis as key indicators of growth plate dysplasia and eventually reduced bone growth. Lastly, new insight into disease-related musculoskeletal complications such as myopathy, ligamentous laxity and tendinopathy has been gained through the analysis of mouse models of the PSACH and MED disease spectrum.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Barrie H, Carter C, Sutcliffe J (1958) Multiple epiphyseal dysplasia. Br Med J 2:133–137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bateman JF, Wilson R, Freddi S, Lamande SR, Savarirayan R (2005) Mutations of COL10A1 in Schmid metaphyseal chondrodysplasia. Hum Mutat 25(6):525–534

    Article  CAS  PubMed  Google Scholar 

  • Bonnemann CG, Cox GF, Shapiro F, Wu JJ, Feener CA, Thompson TG, Anthony DC, Eyre DR, Darras BT, Kunkel LM (2000) A mutation in the alpha 3 chain of type IX collagen causes autosomal dominant multiple epiphyseal dysplasia with mild myopathy. Proc Natl Acad Sci U S A 97(3):1212–1217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borochowitz ZU, Scheffer D, Adir V, Dagoneau N, Munnich A, Cormier-Daire V (2004) Spondylo-epi-metaphyseal dysplasia (SEMD) matrilin 3 type: homozygote matrilin 3 mutation in a novel form of SEMD. J Med Genet 41(5):366–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Briggs MD, Chapman KL (2002) Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations. Hum Mutat 19(5):465–478

    Article  CAS  PubMed  Google Scholar 

  • Briggs MD, Hoffman SM, King LM, Olsen AS, Mohrenweiser H, Leroy JG, Mortier GR, Rimoin DL, Lachman RS, Gaines ES et al (1995) Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nat Genet 10(3):330–336

    Article  CAS  PubMed  Google Scholar 

  • Briggs MD, Brock J, Ramsden SC, Bell PA (2014) Genotype to phenotype correlations in cartilage oligomeric matrix protein associated chondrodysplasias. Eur J Hum Genet 22(11):1278–1282. doi:10.1038/ejhg.2014.30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Briggs MD, Bell PA, Pirog KA (2015a) The utility of mouse models to provide information regarding the pathomolecular mechanisms in human genetic skeletal diseases: the emerging role of endoplasmic reticulum stress (review). Int J Mol Med. doi:10.3892/ijmm.2015.2158

    PubMed  PubMed Central  Google Scholar 

  • Briggs MD, Bell PA, Wright MJ, Pirog KA (2015b) New therapeutic targets in rare genetic skeletal diseases. Expert Opin Orphan Drugs 3(10):1137–1154. doi:10.1517/21678707.2015.1083853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buckwalter JA, Mower D, Ungar R, Schaeffer J, Ginsberg B (1986) Morphometric analysis of chondrocyte hypertrophy. J Bone Joint Surg Am 68(2):243–255

    Article  CAS  PubMed  Google Scholar 

  • Budde B, Blumbach K, Ylostalo J, Zaucke F, Ehlen HW, Wagener R, Ala-Kokko L, Paulsson M, Bruckner P, Grassel S (2005) Altered integration of matrilin-3 into cartilage extracellular matrix in the absence of collagen IX. Mol Cell Biol 25(23):10465–10478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chapman KL, Mortier GR, Chapman K, Loughlin J, Grant ME, Briggs MD (2001) Mutations in the region encoding the von Willebrand factor A domain of matrilin-3 are associated with multiple epiphyseal dysplasia. Nat Genet 28(4):393–396

    Article  CAS  PubMed  Google Scholar 

  • Chen TL, Stevens JW, Cole WG, Hecht JT, Vertel BM (2004) Cell-type specific trafficking of expressed mutant COMP in a cell culture model for PSACH. Matrix Biol 23(7):433–444

    Article  CAS  PubMed  Google Scholar 

  • Chen FH, Thomas AO, Hecht JT, Goldring MB, Lawler J (2005) Cartilage oligomeric matrix protein/thrombospondin 5 supports chondrocyte attachment through interaction with integrins. J Biol Chem 280(38):32655–32661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cotterill SL, Jackson GC, Leighton MP, Wagener R, Makitie O, Cole WG, Briggs MD (2005) Multiple epiphyseal dysplasia mutations in MATN3 cause misfolding of the A-domain and prevent secretion of mutant matrilin-3. Hum Mutat 26(6):557–565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cowell HR, Hunziker EB, Rosenberg L (1987) The role of hypertrophic chondrocytes in endochondral ossification and in the development of secondary centers of ossification. J Bone Joint Surg Am 69(2):159–161

    Article  CAS  PubMed  Google Scholar 

  • Czarny-Ratajczak M, Lohiniva J, Rogala P, Kozlowski K, Perala M, Carter L, Spector TD, Kolodziej L, Seppanen U, Glazar R, Krolewski J, Latos-Bielenska A, Ala-Kokko L (2001) A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity. Am J Hum Genet 69(5):5

    Article  Google Scholar 

  • Fairbank T (1947) Dysplasia epiphysialis multiplex. Proc R Soc Med (Ortho Sec) 39:315–317

    Google Scholar 

  • Fresquet (2007a) Novel mutations in exon 2 of MATN3 affect residues within the a-helices of the A-domain and may act through different disease mechanisms to those of the more common b-sheet mutations. Manuscript under review.

    Google Scholar 

  • Fresquet (2007b) Structural and functional characterisation of recombinant matrilin-3 A-domain and implications for human genetic disease. J Biol Chem. Manuscript accepted.

    Google Scholar 

  • Gibson BG, Briggs MD. The aggrecanopathies; an evolving phenotypic spectrum of human genetic skeletal diseases. Orphanet J Rare Dis. 2016 Jun 28;11(1):86. doi: 10.1186/s13023-016-0459-2. Review. PubMed PMID: 27353333; PubMed Central PMCID: PMC4924316.

  • Gualeni B, Rajpar MH, Kellogg A, Bell PA, Arvan P, Boot-Handford RP, Briggs MD (2013) A novel transgenic mouse model of growth plate dysplasia reveals that decreased chondrocyte proliferation due to chronic ER stress is a key factor in reduced bone growth. Dis Model Mech 6(6):1414–1425. doi:10.1242/dmm.013342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Halasz K, Kassner A, Morgelin M, Heinegard D (2007) Comp acts as a catalyst in collagen fibrillogenesis. J Biol Chem 282:31166–31173

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto Y, Tomiyama T, Yamano Y, Mori H (2003) Mutation (D472Y) in the type 3 repeat domain of cartilage oligomeric matrix protein affects its early vesicle trafficking in endoplasmic reticulum and induces apoptosis. Am J Pathol 163(1):101–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hecht JT, Nelson LD, Crowder E, Wang Y, Elder FF, Harrison WR, Francomano CA, Prange CK, Lennon GG, Deere M et al (1995) Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia. Nat Genet 10(3):325–329

    Article  CAS  PubMed  Google Scholar 

  • Hecht JT, Montufar-Solis D, Decker G, Lawler J, Daniels K, Duke PJ (1998) Retention of cartilage oligomeric matrix protein (COMP) and cell death in redifferentiated pseudoachondroplasia chondrocytes. Matrix Biol 17(8–9):625–633

    Article  CAS  PubMed  Google Scholar 

  • Hecht JT, Hayes E, Snuggs M, Decker G, Montufar-Solis D, Doege K, Mwalle F, Poole R, Stevens J, Duke PJ (2001) Calreticulin, PDI, Grp94 and BiP chaperone proteins are associated with retained COMP in pseudoachondroplasia chondrocytes. Matrix Biol 20(4):251–262

    Article  CAS  PubMed  Google Scholar 

  • Hecht JT, Makitie O, Hayes E, Haynes R, Susic M, Montufar-Solis D, Duke PJ, Cole WG (2004) Chondrocyte cell death and intracellular distribution of COMP and type IX collagen in the pseudoachondroplasia growth plate. J Orthop Res 22(4):759–767

    Article  CAS  PubMed  Google Scholar 

  • Hecht JT, Hayes E, Haynes R, Cole WG (2005) COMP mutations, chondrocyte function and cartilage matrix. Matrix Biol 23(8):525–533. doi:10.1016/j.matbio.2004.09.006, doi:S0945-053X(04)00123-4 [pii]

    Article  CAS  PubMed  Google Scholar 

  • Holden P, Meadows RS, Chapman KL, Grant ME, Kadler KE, Briggs MD (2001) Cartilage oligomeric matrix protein interacts with type IX collagen, and disruptions to these interactions identify a pathogenetic mechanism in a bone dysplasia family. J Biol Chem 276(8):6046–6055

    Article  CAS  PubMed  Google Scholar 

  • International nomenclature and classification of the osteochondrodysplasias (1997). International Working Group on Constitutional Diseases of Bone (1998) Am J Med Genet 79(5):376–382

    Google Scholar 

  • Itoh T, Shirahama S, Nakashima E, Maeda K, Haga N, Kitoh H, Kosaki R, Ohashi H, Nishimura G, Ikegawa S (2006) Comprehensive screening of multiple epiphyseal dysplasia mutations in Japanese population. Am J Med Genet A 140(12):1280–1284

    Article  PubMed  Google Scholar 

  • Jackson GC, Barker FS, Jakkula E, Czarny-Ratajczak M, Makitie O, Cole WG, Wright MJ, Smithson SF, Suri M, Rogala P, Mortier GR, Baldock C, Wallace A, Elles R, Ala-Kokko L, Briggs MD (2004) Missense mutations in the beta strands of the single A-domain of matrilin-3 result in multiple epiphyseal dysplasia. J Med Genet 41(1):52–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jackson GC, Marcus-Soekarman D, Stolte-Dijkstra I, Verrips A, Taylor JA, Briggs MD (2010) Type IX collagen gene mutations can result in multiple epiphyseal dysplasia that is associated with osteochondritis dissecans and a mild myopathy. Am J Med Genet A 152A(4):863–869. doi:10.1002/ajmg.a.33240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jackson GC, Mittaz-Crettol L, Taylor JA, Mortier GR, Spranger J, Zabel B, Le Merrer M, Cormier-Daire V, Hall CM, Offiah A, Wright MJ, Savarirayan R, Nishimura G, Ramsden SC, Elles R, Bonafe L, Superti-Furga A, Unger S, Zankl A, Briggs MD (2012) Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution. Hum Mutat 33(1):144–157. doi:10.1002/humu.21611

    Article  CAS  PubMed  Google Scholar 

  • Jakkula E, Makitie O, Czarny-Ratajczak M, Jackson GC, Damignani R, Susic M, Briggs MD, Cole WG, Ala-Kokko L (2005) Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations. Eur J Hum Genet 13(3):292–301. doi:10.1038/sj.ejhg.5201314

    Article  CAS  PubMed  Google Scholar 

  • Karsenty G (2003) The complexities of skeletal biology. Nature 423(6937):316–318

    Article  CAS  PubMed  Google Scholar 

  • Ko Y, Kobbe B, Nicolae C, Miosge N, Paulsson M, Wagener R, Aszodi A (2004) Matrilin-3 is dispensable for mouse skeletal growth and development. Mol Cell Biol 24(4):1691–1699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kung LH, Rajpar MH, Preziosi R, Briggs MD, Boot-Handford RP (2015) Increased classical endoplasmic reticulum stress is sufficient to reduce chondrocyte proliferation rate in the growth plate and decrease bone growth. PLoS One 10(2):e0117016. doi:10.1371/journal.pone.0117016

    Article  PubMed  PubMed Central  Google Scholar 

  • Leighton MP, Nundlall S, Starborg T, Meadows RS, Suleman F, Knowles L, Wagener R, Thornton DJ, Kadler KE, Boot-Handford RP, Briggs MD (2007) Decreased chondrocyte proliferation and dysregulated apoptosis in the cartilage growth plate are key features of a murine model of epiphyseal dysplasia caused by a matn3 mutation. Hum Mol Genet 16:1728–1741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mabuchi A, Haga N, Maeda K, Nakashima E, Manabe N, Hiraoka H, Kitoh H, Kosaki R, Nishimura G, Ohashi H, Ikegawa S (2004) Novel and recurrent mutations clustered in the von Willebrand factor A domain of MATN3 in multiple epiphyseal dysplasia. Hum Mutat 24(5):439–440

    Article  PubMed  Google Scholar 

  • Maeda K, Nakashima E, Horikoshi T, Mabuchi A, Ikegawa S (2005) Mutation in the von Willebrand factor-A domain is not a prerequisite for the MATN3 mutation in multiple epiphyseal dysplasia. Am J Med Genet A 136(3):285–286

    Article  PubMed  Google Scholar 

  • Mann HH, Ozbek S, Engel J, Paulsson M, Wagener R (2004) Interactions between the cartilage oligomeric matrix protein and matrilins. Implications for matrix assembly and the pathogenesis of chondrodysplasias. J Biol Chem 279(24):25294–25298

    Article  CAS  PubMed  Google Scholar 

  • Min JL, Meulenbelt I, Riyazi N, Kloppenburg M, Houwing-Duistermaat JJ, Seymour AB, van Duijn CM, Slagboom PE (2006) Association of matrilin-3 polymorphisms with spinal disc degeneration and osteoarthritis of the first carpometacarpal joint of the hand. Ann Rheum Dis 65(8):1060–1066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mostert AK, Dijkstra PF, Jansen BR, van Horn JR, de Graaf B, Heutink P, Lindhout D (2003) Familial multiple epiphyseal dysplasia due to a matrilin-3 mutation: further delineation of the phenotype including 40 years follow-up. Am J Med Genet A 120(4):490–497

    Article  Google Scholar 

  • Muragaki Y, Mariman EC, van Beersum SE, Perala M, van Mourik JB, Warman ML, Olsen BR, Hamel BC (1996) A mutation in the gene encoding the alpha 2 chain of the fibril- associated collagen IX, COL9A2, causes multiple epiphyseal dysplasia (EDM2). Nat Genet 12(1):103–105

    Article  CAS  PubMed  Google Scholar 

  • Newton G, Weremowicz S, Morton CC, Copeland NG, Gilbert DJ, Jenkins NA, Lawler J (1994) Characterization of human and mouse cartilage oligomeric matrix protein. Genomics 24(3):435–439

    Article  CAS  PubMed  Google Scholar 

  • Ortega N, Behonick DJ, Werb Z (2004) Matrix remodeling during endochondral ossification. Trends Cell Biol 14(2):86–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Otten C, Wagener R, Paulsson M, Zaucke F (2005) Matrilin-3 mutations that cause chondrodysplasias interfere with protein trafficking while a mutation associated with hand osteoarthritis does not. J Med Genet 42(10):774–779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pirog KA, Irman A, Young S, Halai P, Bell PA, Boot-Handford RP, Briggs MD (2014) Abnormal chondrocyte apoptosis in the cartilage growth plate is influenced by genetic background and deletion of CHOP in a targeted mouse model of pseudoachondroplasia. PLoS One 9(2):e85145. doi:10.1371/journal.pone.0085145

    Article  PubMed  PubMed Central  Google Scholar 

  • Pirog-Garcia KA, Meadows RS, Knowles L, Heinegard D, Thornton DJ, Kadler KE, Boot-Handford RP, Briggs MD (2007) Reduced cell proliferation and increased apoptosis are significant pathological mechanisms in a murine model of mild pseudoachondroplasia resulting from a mutation in the C-terminal domain of COMP. Hum Mol Genet 16:2072–2088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Provot S, Schipani E (2005) Molecular mechanisms of endochondral bone development. Biochem Biophys Res Commun 328(3):658–665

    Article  CAS  PubMed  Google Scholar 

  • Pullig O, Tagariello A, Schweizer A, Swoboda B, Schaller P, Winterpacht A (2007) MATN3 (matrilin-3) sequence variation (pT303M) is a risk factor for osteoarthritis of the CMC1 joint of the hand, but not for knee osteoarthritis. Ann Rheum Dis 66(2):279–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rimoin DL, Rasmussen IM, Briggs MD, Roughley PJ, Gruber HE, Warman ML, Olsen BR, Hsia YE, Yuen J, Reinker K et al (1994) A large family with features of pseudoachondroplasia and multiple epiphyseal dysplasia: exclusion of seven candidate gene loci that encode proteins of the cartilage extracellular matrix. Hum Genet 93(3):236–242

    Article  CAS  PubMed  Google Scholar 

  • Rosenberg K, Olsson H, Morgelin M, Heinegard D (1998) Cartilage oligomeric matrix protein shows high affinity zinc-dependent interaction with triple helical collagen. J Biol Chem 273(32):20397–20403

    Article  CAS  PubMed  Google Scholar 

  • Rossi A, Superti-Furga A (2001) Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat 17(3):159–171

    Article  CAS  PubMed  Google Scholar 

  • Schmitz M, Becker A, Schmitz A, Weirich C, Paulsson M, Zaucke F, Dinser R (2006) Disruption of extracellular matrix structure may cause pseudoachondroplasia phenotypes in the absence of impaired cartilage oligomeric matrix protein secretion. J Biol Chem 281(43):32587–32595

    Article  CAS  PubMed  Google Scholar 

  • Spayde EC, Joshi AP, Wilcox WR, Briggs M, Cohn DH, Olsen BR (2000) Exon skipping mutation in the COL9A2 gene in a family with multiple epiphyseal dysplasia. Matrix Biol 19(2):121–128

    Article  CAS  PubMed  Google Scholar 

  • Spitznagel L, Nitsche DP, Paulsson M, Maurer P, Zaucke F (2004) Characterization of a pseudoachondroplasia-associated mutation (His587→Arg) in the C-terminal, collagen-binding domain of cartilage oligomeric matrix protein (COMP). Biochem J 377(Pt 2):479–487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spranger J (1988) Bone dysplasia ‘families’. Pathol Immunopathol Res 7(1–2):76–80

    Article  CAS  PubMed  Google Scholar 

  • Spranger JW, Zabel B, Kennedy J, Jackson G, Briggs M (2005) A disorder resembling pseudoachondroplasia but without COMP mutation. Am J Med Genet A 132A(1):20–24

    Article  CAS  PubMed  Google Scholar 

  • Stefansson SE, Jonsson H, Ingvarsson T, Manolescu I, Jonsson HH, Olafsdottir G, Palsdottir E, Stefansdottir G, Sveinbjornsdottir G, Frigge ML, Kong A, Gulcher JR, Stefansson K (2003) Genomewide scan for hand osteoarthritis: a novel mutation in matrilin-3. Am J Hum Genet 72(6):1448–1459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suleman F, Gualeni B, Gregson HJ, Leighton MP, Pirog KA, Edwards S, Holden P, Boot-Handford RP, Briggs MD (2012) A novel form of chondrocyte stress is triggered by a COMP mutation causing pseudoachondroplasia. Hum Mutat 33(1):218–231. doi:10.1002/humu.21631

    Article  CAS  PubMed  Google Scholar 

  • Superti-Furga A, Bonafe L, Rimoin DL (2001) Molecular-pathogenetic classification of genetic disorders of the skeleton. Am J Med Genet 106(4):282–293

    Article  CAS  PubMed  Google Scholar 

  • Svensson L, Aszodi A, Heinegard D, Hunziker EB, Reinholt FP, Fassler R, Oldberg A (2002) Cartilage oligomeric matrix protein-deficient mice have normal skeletal development. Mol Cell Biol 22(12):4366–4371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thur J, Rosenberg K, Nitsche DP, Pihlajamaa T, Ala-Kokko L, Heinegard D, Paulsson M, Maurer P (2001) Mutations in cartilage oligomeric matrix protein causing pseudoachondroplasia and multiple epiphyseal dysplasia affect binding of calcium and collagen I, II, and IX. J Biol Chem 276(9):6083–6092

    Article  CAS  PubMed  Google Scholar 

  • Tompson SW, Merriman B, Funari VA, Fresquet M, Lachman RS, Rimoin DL, Nelson SF, Briggs MD, Cohn DH, Krakow D (2009) A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan. Am J Hum Genet 84(1):72–79. doi:10.1016/j.ajhg.2008.12.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wagener R, Kobbe B, Paulsson M (1997) Primary structure of matrilin-3, a new member of a family of extracellular matrix proteins related to cartilage matrix protein (matrilin-1) and von Willebrand factor. FEBS Lett 413(1):129–134

    Article  CAS  PubMed  Google Scholar 

  • Wagener R, Ehlen HW, Ko YP, Kobbe B, Mann HH, Sengle G, Paulsson M (2005) The matrilins--adaptor proteins in the extracellular matrix. FEBS Lett 579(15):3323–3329

    Article  CAS  PubMed  Google Scholar 

  • Wu JJ, Eyre DR (1998) Matrilin-3 forms disulfide-linked oligomers with matrilin-1 in bovine epiphyseal cartilage. J Biol Chem 273(28):17433–17438

    Article  CAS  PubMed  Google Scholar 

  • Zankl A, Jackson GC, Crettol LM, Taylor J, Elles R, Mortier GR, Spranger J, Zabel B, Unger S, Merrer ML, Cormier-Daire V, Hall CM, Wright MJ, Bonafe L, Superti-Furga A, Briggs MD (2007) Preselection of cases through expert clinical and radiological review significantly increases mutation detection rate in multiple epiphyseal dysplasia. Eur J Hum Genet 15(2):150–154

    Article  CAS  PubMed  Google Scholar 

  • Zaucke F (2016) Cartilage glycoproteins. In: Grässel S, AszĂ³di A (eds) Cartilage: volume 1: physiology and development. Springer International Publishing, Cham, pp 55–81. doi:10.1007/978-3-319-29568-8_3

    Google Scholar 

  • Zhang Y, Chen Q (2000) Changes of matrilin forms during endochondral ossification. Molecular basis of oligomeric assembly. J Biol Chem 275(42):32628–32634

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK

    Michael D. Briggs, Peter Bell & Katarzyna A. PirĂ³g

Authors
  1. Michael D. Briggs
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Bell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katarzyna A. PirĂ³g
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael D. Briggs .

Editor information

Editors and Affiliations

  1. Orthopädische Klinik fĂ¼r die Universität Regensburg, Universitätsklinikum Regensburg, Regensburg, Germany

    Susanne Grässel

  2. Department of General, Trauma, and Reconstruction Surgery, Ludwig-Maximilians-University, Munich, Germany

    Attila AszĂ³di

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Briggs, M.D., Bell, P., PirĂ³g, K.A. (2017). Pseudoachondroplasia and Multiple Epiphyseal Dysplasia: Molecular Genetics, Disease Mechanisms and Therapeutic Targets. In: Grässel, S., AszĂ³di, A. (eds) Cartilage. Springer, Cham. https://doi.org/10.1007/978-3-319-45803-8_7

Download citation

Publish with us

Policies and ethics

Search

Navigation