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Missense mutations in the β strands of the single A-domain of matrilin-3 result in multiple epiphyseal dysplasia
  1. G C Jackson1,10,
  2. F S Barker1,
  3. E Jakkula2,
  4. M Czarny-Ratajczak3,4,
  5. O Mäkitie5,
  6. W G Cole5,
  7. M J Wright6,
  8. S F Smithson7,
  9. M Suri8,
  10. P Rogala4,
  11. G R Mortier9,
  12. C Baldock1,
  13. A Wallace10,
  14. R Elles10,
  15. L Ala-Kokko2,3,
  16. M D Briggs1
  1. 1Wellcome Trust Centre for Cell Matrix Research, School of Biological Sciences, University of Manchester, Manchester, UK
  2. 2Collagen Research Unit, Biocenter and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland
  3. 3Center for Gene Therapy and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
  4. 4Karol Marcinkowski University of Medical Sciences, Poznan, Poland
  5. 5Hospital for Sick Children, Toronto, Ontario, Canada
  6. 6Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne, UK
  7. 7Department of Clinical Genetics, St Michael’s Hospital, Bristol, UK
  8. 8Clinical Genetic Service, Nottingham City Hospital, Nottingham, UK
  9. 9Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium
  10. 10National Genetics Reference Laboratory (Manchester), Regional Genetics Service, St Mary’s Hospital, Manchester, UK
  1. Correspondence to:
 Dr M Briggs
 Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, 2.205 Stopford Building, Oxford Road, Manchester M13 9PT, UK;

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Multiple epiphyseal dysplasia (MED) is a relatively mild and clinically variable osteochondrodysplasia in which the hip and knee joints are most frequently affected. Both autosomal dominant and autosomal recessive forms of MED are recognised. The more severe forms of MED are often described as the “Fairbank type”, whereas the milder cases are known as the “Ribbing type”. However, this classification belies a much greater clinical spectrum in which characteristics such as radiographic features, age of onset, degree of lower limb deformity, stature, and long term morbidity such as osteoarthritis are extremely variable.1–4 It is therefore not surprising that MED is genetically heterogeneous, and to date mutations in six different genes have been shown to cause MED.5,6 Mutations in the genes encoding cartilage oligomeric matrix protein (COMP), the α1, α2, and α3 chains of type IX collagen (COL9A1, COL9A2, and COL9A3) and matrilin-3 (MATN3) all result in autosomal dominant MED,7–11 whereas specific mutations in the sulphate transporter 26A2 (SLC26A2 /DTDST) have been shown to result in an autosomal recessive form of MED.12,13 Preliminary genotype–phenotype correlations have suggested that the more severe forms of autosomal dominant MED often result from COMP mutations, while the milder forms are more probably caused by mutations in the genes encoding type IX collagen or matrilin-3.14,15 However, the number of patients available for comparative study, particularly those with type IX collagen and matrilin-3 defects, has remained too limited to date to allow any in depth correlations to be derived.

The matrilins are a four member family of extracellular matrix proteins; matrilin-1 and -3 are specifically expressed in cartilaginous tissues, while matrilin-2 and -4 have a wider pattern of expression in a variety of extracellular matrices including non-skeletal tissues.16,17 Each member of the family comprise …

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