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Multiple Epiphyseal Dysplasia, Dominant

Includes: Multiple Epiphyseal Dysplasia 1 (EDM1), Multiple Epiphyseal Dysplasia 2 (EDM2), Multiple Epiphyseal Dysplasia 3 (EDM3), Multiple Epiphyseal Dysplasia 5 (EDM5), Multiple Epiphyseal Dysplasia 6 (EDM6)

, PhD, , MB, ChB, MSc, FRCP, and , MD, PhD.

Author Information
, PhD
Professor of Skeletal Genetics, Institute of Genetic Medicine
Newcastle University
International Centre for Life
Newcastle upon Tyne, United Kingdom
, MB, ChB, MSc, FRCP
Consultant Clinical Geneticist, Northern Genetics Service
Institute of Human Genetics
Newcastle upon Tyne, United Kingdom
, MD, PhD
Chairman, Department of Medical Genetics
Antwerp University Hospital
Antwerp, Belgium

Initial Posting: ; Last Update: July 25, 2013.

Summary

Disease characteristics. Autosomal dominant multiple epiphyseal dysplasia (MED) presents early in childhood, usually with pain in the hips and/or knees after exercise. Affected children complain of fatigue with long-distance walking. Waddling gait may be present. Adult height is either in the lower range of normal or mildly shortened. The limbs are relatively short in comparison to the trunk. Pain and joint deformity progress, resulting in early-onset osteoarthritis, particularly of the large weight-bearing joints.

Diagnosis/testing. The diagnosis of autosomal dominant MED is based on clinical and radiographic findings in the proband and other family members. In the initial stage of the disorder, often before the onset of clinical symptoms, delayed ossification of the epiphyses of the long tubular bones is found on radiographs. With the appearance of the epiphyses, the ossification centers are small with irregular contours, usually most pronounced in the hips and/or knees. The tubular bones may be mildly shortened. By definition, the spine is normal, although Schmorl bodies and irregular vertebral end plates may be observed. Mutations in five genes are known to cause MED: COMP, COL9A1, COL9A2, COL9A3, and MATN3. However, in approximately 10%-20% of all samples analyzed, a mutation cannot be identified in any of the five genes above, suggesting that mutations in other as-yet unidentified genes are also involved in the pathogenesis of dominant MED.

Management. Treatment of manifestations: For pain control, a combination of analgesics and physiotherapy including hydrotherapy; referral to a rheumatologist or pain specialist as needed; consideration of realignment osteotomy and/or acetabular osteotomy to limit joint destruction and development of osteoarthritis. Consider total joint arthroplasty if the degenerative hip changes cause uncontrollable pain/dysfunction; offer psychosocial support re short stature, chronic pain, disability, and employment.

Surveillance: Evaluation by an orthopedic surgeon for chronic pain and/or limb deformities (genu varum, genu valgum).

Agents/circumstances to avoid: Obesity; exercise causing repetitive strain on affected joints.

Genetic counseling. Dominant MED is inherited in an autosomal dominant manner. Many individuals with dominant MED have inherited the mutant allele from one parent. The prevalence of new gene mutations is not known. Each child of an individual with dominant MED has a 50% chance of inheriting the mutation. Prenatal diagnosis of pregnancies at increased risk is possible if the disease-causing mutation has been identified in an affected family member.

Diagnosis

Clinical Diagnosis

The diagnosis of autosomal dominant multiple epiphyseal dysplasia (MED) is based on the clinical and radiographic presentation in the proband and other family members.

Clinical findings

  • Pain in the hips and/or knees and fatigue, often after exercise (frequently starting in early childhood)
  • Adult height in the lower range of normal or mildly shortened
  • Restricted range of movement at the major joints (e.g., elbows)
  • Early-onset osteoarthritis, often requiring joint replacement in the second or third decade of life

Radiographic findings

Initially, often before the onset of clinical symptoms, delayed ossification of the epiphyses of the long tubular bones is observed. When the epiphyses appear, the ossification centers are small with irregular contours. Epiphyseal abnormalities are usually most pronounced in the knees and/or hips, where they may resemble bilateral Perthes disease (see Differential Diagnosis).

In childhood, the tubular bones may be mildly shortened. Ivory (very dense) epiphyses may be present in the hands. By definition, the spine is normal; however, Schmorl bodies (i.e., the displacement of intervertebral disk tissue into the vertebral bodies) and irregular vertebral end plates can be observed.

In adulthood, signs of osteoarthritis are usually observed. It is often impossible to make a diagnosis of MED on adult x-rays alone.

Molecular Genetic Testing

Genes. Mutations in five genes are known to cause autosomal dominant MED [Unger & Hecht 2001, Briggs & Chapman 2002]:

  • COMP
  • COL9A1
  • COL9A2
  • COL9A3
  • MATN3

Evidence for locus heterogeneity

  • Mutations remain undetected in approximately 10%-20% of individuals with MED, suggesting that mutations in additional, as-yet unidentified genes are also involved in the pathogenesis of MED.
  • In some families genetic linkage studies have excluded linkage to the five genes in which mutations are known to be causal; however, additional genetic loci for MED have not yet been determined.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Dominant Multiple Epiphyseal Dysplasia

Gene Symbol 1Proportion of Dominant MED Attributed to Mutation in This Gene 2, 3Test Method 4Mutations Detected
COMP~70%Sequence analysisSequence variants 5, 6
Sequence analysis of select exonsSee footnote 7
Deletion / duplication analysis 8, 9Unknown, none reported 10
COL9A1~10% 11Sequence analysisSequence variants 5
Sequence analysis of select exonsSee footnote 7
Deletion / duplication analysis 8Unknown, none reported 10
COL9A2Sequence analysisSequence variants 5, 12
Sequence analysis of select exonsSee footnote 7
Deletion / duplication analysis 8Unknown, none reported 10
COL9A3Sequence analysisSequence variants 5, 13
Sequence analysis of select exonsSee footnote 7
Deletion / duplication analysis 8Unknown, none reported 10
MATN3~20%Sequence analysis Sequence variants 5, 14
UnknownSequence analysis of select exonsSee footnote 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. In those cases of AD-MED in which a mutation in one of the five confirmed genes has been identified. However, the relative proportions are different depending on patient ethnicity. For example, a recent study by the European Skeletal Dysplasia Network (ESDN) [Jackson et al 2012] found that in 56 patients with molecularly confirmed MED, COMP mutations accounted for 66%, MATN3 for 24%, COL9A2 for 8%, and COL9A3 for 2%. In contrast, a recent study of a Korean patient cohort identified mutations in 55 patients [Kim et al 2011] as follows: COMP (43%), MATN3 (55%) and COL9A2 (2%). This is in close agreement with a Japanese study that identified mutations in 19 patients with MED: COMP (37%), MATN3 (47%), COL9A2 (11%) and COL9A3 (5%). The high prevalence of MATN3 mutations in these latter populations is believed to be the result of a common founder mutation (p.Arg121Trp), but this mutation is also common in European populations. None of the three studies identified mutations in COL9A1.

3. The proportion of COMP, MATN3, and COL9A1-3 mutations found in persons with MED is not well established. Previous studies have suggested frequencies of 10%-36% for COMP [Jakkula et al 2005, Kennedy et al 2005b], 10% for MATN3, and 5% for the type IX collagen genes [Briggs & Chapman 2002, Jackson et al 2004]. However, in a study by the ESDN the proportion of MED caused by mutations in COMP increased to 81% when a strict clinical-radiographic review was undertaken before molecular genetic testing was performed [Zankl et al 2007]. The success of this approach has been recently confirmed by Kim et al [2011], when pre-selection of cases resulted in a mutation detection rate of 87%.

4. See Molecular Genetics for information on allelic variants.

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Mutations in COMP are located in the exons encoding the type III repeats (exons 8-14) and C-terminal domain (exons 15-19) [Unger & Hecht 2001, Briggs & Chapman 2002]. More recently a putative mutation has been identified in exon 5 of COMP, which encodes residues of the second EGF-like repeat of COMP [Jackson et al 2012]. A previous study by Kennedy et al [2005b] demonstrated that approximately 70% of MED-causing mutations in COMP reside in exons 10, 11, and 13, a finding confirmed by a recent study [Jackson et al 2012], which also reaffirmed that MED mutations are not found in exons 15, 17 and 19 of COMP.

7. Selected exons analyzed may vary by laboratory.

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9. Mabuchi et al [2003]

10. No whole-gene deletions or duplications involving COMP, COL9A1, COL9A2, or COL9A3 have been reported to cause dominant multiple epiphyseal dysplasia.

11. Based on data from sequence analysis of the coding and flanking splice site regions of each gene

12. All mutations identified cluster in the splice donor site of exon 3.

13. All mutations identified are in the splice acceptor and/or donor site of exon 3.

14. See Molecular Genetics, MATN3.

Testing Strategy

To confirm/establish the diagnosis in a proband. Ideally a comprehensive clinical and radiographic review of the proband should precede molecular genetic testing. By confirming the clinical diagnosis of MED, the mutation detection rate can be significantly increased [Zankl et al 2007, Kim et al 2011, Jackson et al 2012].

For autosomal dominant MED, consideration should be given to the ethnicity of the affected individual to inform the order in which genes are tested and best reflect the relative contribution of each gene to the overall proportion of molecularly confirmed MED in that population.

Single gene testing. One strategy for molecular diagnosis of a proband suspected of having autosomal dominant MED is to perform single-gene tiered testing. Based on molecular findings [Kennedy et al 2005b, Zankl et al 2007] the following testing regime was recommended by the European Skeletal Dysplasia Network & Maeda et al [2005]:

  • Level 1: COMP (exons 10-15) and MATN3 (exon 2)
  • Level 2: COMP (exons 8 & 9 and 16-19)
  • Level 3: COL9A1 (exon 8), COL9A2 and COL9A3 (exon 3)

Note: In some situations, autosomal dominant MED may not be distinguishable from autosomal recessive forms of MED; therefore, it may be appropriate to test SCLA26A2 after testing COMP.

Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having MED is use of a multi-gene panel. The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Autosomal dominant multiple epiphyseal dysplasia (MED) was originally divided into a mild form called ‘Ribbing-type’ and a more severe form known as ‘Fairbank-type.’ However, much more clinical variability exists within the overall MED phenotype than is suggested by these two distinct entities. It is likely that the milder forms of MED either remain undiagnosed or are misdiagnosed as bilateral Perthes disease or even early-onset familial osteoarthritis.

The presenting symptom early in childhood is usually pain in the hips and/or knees after exercise.

Affected children complain of fatigue with long-distance walking. Waddling gait may be present. Angular deformities, including coxa vara and genu varum or genu valgum, are relatively rare. In contrast to the restricted mobility in the elbows, hypermobility in the knee and finger joints can be observed.

Adult height is either in the lower range of normal or mildly shortened. The shortness of the limbs relative to the trunk first becomes apparent in childhood.

The natural history of dominant MED is of progressively worsening pain and joint deformity resulting in early-onset osteoarthritis. In adulthood, the condition is characterized by early-onset osteoarthritis, particularly of the large weight-bearing joints. In some cases, the osteoarthritis is sufficiently severe to require joint replacement in early adult life.

Associated anomalies are absent. Intelligence is normal.

Genotype-Phenotype Correlations

Preliminary studies of genotype-phenotype correlations have been relatively successful and can be summarized briefly [Mortier et al 2001, Unger et al 2001]:

  • MED resulting from COMP mutations is characterized by significant involvement at the capital femoral epiphyses and irregular acetabuli [Unger et al 2001]. However, the recurrent p.Arg718Trp mutation in COMP appears to cause a mild form of the disorder, more consistent with MED caused by a type IX collagen gene mutation [Jakkula et al 2003].
  • Type IX collagen defects result in more severe involvement of the knees and relative sparing of the hips.
  • MATN3 mutations result in knee abnormalities that are similar to those in individuals with a COL9A2 mutation; the hip abnormalities are more severe (although not as severe as those in individuals with a COMP mutation) [Mortier et al 2001]. However, more intra- and interfamilial variability is evident in MED caused by MATN3 mutations. A mutation such as p.Arg121Trp can result in a spectrum of clinical and radiographic features, suggesting that other genetic and/or environmental factors modify the severity of this particular form of MED [Jackson et al 2004, Mäkitie et al 2004].

It is important to note that striking intra- and interfamilial variability can be observed in MED caused by mutations in MATN3 [Chapman et al 2001, Mortier et al 2001, Jackson et al 2004, Mäkitie et al 2004], in COL9A3 [Bonnemann et al 2000, Nakashima et al 2005], and in some instances, in COMP. These findings make the establishment of strong genotype-phenotype correlations in dominant MED less likely in the long term.

Penetrance

There is some evidence for reduced penetrance in MED caused by MATN3 mutations [Mortier et al 2001, Mäkitie et al 2004].

Anticipation

Anticipation is not observed.

Nomenclature

Multiple epiphyseal dysplasia was originally classified into the severe Fairbank type (MED-Fairbank) and milder Ribbing type (MED-Ribbing).

  • MED-Fairbank type is probably the same disease as 'enchondral dysostosis' described by Odman [1959], and 'microepiphyseal dysplasia' described by Elsbach [1959].
  • MED-Ribbing should not be confused with Ribbing disease (OMIM 601477), a form of multiple diaphyseal sclerosis.

Prevalence

Studies undertaken to determine the birth prevalence of skeletal dysplasias suggest a prevalence of dominant MED of at least one per 10,000 births. However, as MED is usually not diagnosed at birth, the figure is most likely an underestimate.

Differential Diagnosis

Three other disorders have features that overlap with those of autosomal dominant multiple epiphyseal dysplasia (MED).

Autosomal recessive MED (EDM4/rMED). Recessive multiple epiphyseal dysplasia is characterized by joint pain (usually in the hips and/or knees); malformations of hands, feet, and knees; and scoliosis. About 50% of affected individuals have some anomaly at birth, including clubfoot, cleft palate, cystic ear swelling, or clinodactyly. Onset of pain is variable, but usually occurs in late childhood. Stature is usually within the normal range prior to puberty; in adulthood, stature is only slightly diminished, with the median height shifting from 50th to the tenth percentile; range is between 150 and 180 cm. Functional disability is mild or absent. EDM4/rMED is diagnosed on clinical and radiographic findings. Of particular note is double-layered patella (i.e., presence of a separate anterior and posterior ossification center) observed on lateral knee radiographs in about 60% of individuals with EDM4/rMED. This finding appears to be age related and may not be apparent in adults. Diagnosis can be confirmed by molecular genetic testing of SLC26A2 (DTDST) [Superti-Furga et al 1999].

Bilateral Perthes disease (BPD). Legg-Calve-Perthes (LCP) disease (Perthes disease) (OMIM 150600) is a form of juvenile osteonecrosis of the femoral head, caused by a disruption of the blood supply during endochondral ossification. Perthes disease usually affects males between ages three and 15 years. Up to 20% of individuals with Perthes disease have bilateral involvement. Several studies have identified differences between bilateral and unilateral Perthes disease, prominent among which is the greater severity of BPD. The radiographic changes observed in Perthes disease differ from those of MED, with more involvement of the metaphyses and femoral neck. Some forms of Perthes disease have been shown to result from a recurrent p.Gly1170Ser mutation in exon 50 of COL2A1 [Liu et al 2005] while other COL2A1 mutations, such as p.Gly393Ser [Kannu et al 2011] and p.Gly717Ser [Miyamoto et al 2007], have also been associated with LCP disease and avascular necrosis of the femoral head.

Mild spondyloepiphyseal dysplasia congenta (SEDc). A recent study by Jackson et al [2012] identified COL2A1 missense mutations in two individuals with mild SEDc [OMIM 183900] who had MED-like features. Both mutations were in exon 50 and resulted in p.Gly1176Val or p.Gly1179Arg substitutions. There were limited clinical data and radiographic images on which to make an unambiguous diagnosis; however, both patients had phenotypic features consistent with MED.

Beukes familial hip dysplasia (BFHD). An inherited skeletal disorder that shares many clinical and radiographic features with MED, BFHD was first identified in 47 individuals in six generations of an Afrikaner family in South Africa [Cilliers & Beighton 1990]. The International Nosology and Classification of Genetic Skeletal Disorders –2006 Revision now recognizes BFHD as a form of MED [Superti-Furga & Unger 2007]. Genetic linkage studies determined that the as-yet unidentified gene in which mutation causes BFHD maps to an 11-cM region on 4q35 [Roby et al 1999].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with multiple epiphyseal dysplasia (MED), the following evaluations are recommended:

  • Elicitation of pain history
  • Assessment of joint mobility
  • Radiographs to determine the extent and severity of joint involvement
  • Medical genetics consultation

Treatment of Manifestations

For pain control, a combination of analgesics and physiotherapy including hydrotherapy is helpful to many affected individuals; however, pain can be difficult to control. Referral to a rheumatologist or pain specialist may be indicated.

Limitation of joint destruction and the development of osteoarthritis is a goal. Consultation with an orthopedic surgeon can determine if realignment osteotomy and/or acetabular osteotomy may be helpful in slowing the progression of symptoms.

In some individuals, total joint arthroplasty may be required if the degenerative hip changes are causing too much pain or dysfunction.

Psychosocial support addressing issues of short stature, chronic pain, disability, and employment is appropriate [Hunter 1998a, Hunter 1998b].

Surveillance

Evaluation by an orthopedic surgeon is recommended if the affected individual has chronic pain or limb deformities (genu varum, genu valgum).

Agents/Circumstances to Avoid

The following should be avoided:

  • Obesity, which increases stress on joints
  • Exercise that causes repetitive strain on affected joints

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Dominant multiple epiphyseal dysplasia (MED) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Many individuals with dominant MED have inherited the mutant allele from one parent.
  • A proband with dominant MED may have the disorder as the result of a de novo gene mutation. The prevalence of de novo gene mutations is not known.
  • When a diagnosis of MED is considered, it is sometimes worthwhile to evaluate both parents for signs of MED or early-onset osteoarthritis. If a disease-causing mutation has been identified in an affected family member, molecular genetic testing of the parents is possible.

Sibs of a proband

Offspring of a proband. Each child of an individual with dominant MED has a 50% chance of inheriting the mutation.

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

MED of unknown mode of inheritance

  • Until the mode of inheritance in an individual with MED can be determined, it may be appropriate to consider that the risk of transmitting the disorder to each of the offspring is as high as 50%.
  • A number of families in which one of the parents has germline mosaicism for a dominantly inherited mutation have been reported, resulting in a family history suggestive of autosomal recessive inheritance.

Testing of at-risk individuals during childhood. The testing of asymptomatic at-risk individuals younger than age 18 years is controversial. This testing can be justified only if it is believed that knowledge of the disease status of the child will influence care of that child. Since early orthopedic intervention and limitation of inappropriate exercise may ameliorate the severity of joint disease in the long term, it has been argued that predictive testing is justified in children at risk for MED.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Little People of America, Inc. (LPA)
    250 El Camino Real
    Suite 201
    Tustin CA 92780
    Phone: 888-572-2001 (toll-free); 714-368-3689
    Fax: 714-368-3367
    Email: info@lpaonline.org
  • Restricted Growth Association (RGA)
    PO Box 15755
    Solihull B93 3FY
    United Kingdom
    Phone: +44 0300 111 1970
    Fax: +44 0300 111 2454
    Email: office@restrictedgrowth.co.uk
  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
    Fax: 310-423-1528
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Email: info@esdn.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Multiple Epiphyseal Dysplasia, Dominant: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Multiple Epiphyseal Dysplasia, Dominant (View All in OMIM)

120210COLLAGEN, TYPE IX, ALPHA-1; COL9A1
120260COLLAGEN, TYPE IX, ALPHA-2; COL9A2
120270COLLAGEN, TYPE IX, ALPHA-3; COL9A3
132400EPIPHYSEAL DYSPLASIA, MULTIPLE, 1; EDM1
600204EPIPHYSEAL DYSPLASIA, MULTIPLE, 2; EDM2
600310CARTILAGE OLIGOMERIC MATRIX PROTEIN; COMP
600969EPIPHYSEAL DYSPLASIA, MULTIPLE, 3; EDM3
602109MATRILIN 3; MATN3
607078EPIPHYSEAL DYSPLASIA, MULTIPLE, 5; EDM5
614135EPIPHYSEAL DYSPLASIA, MULTIPLE, 6; EDM6

Molecular Genetic Pathogenesis

The five genes (COMP, COL9A1, COL9A2, COL9A3, and MATN3) in which mutations are known to cause dominant MED code for three structural macromolecules of the cartilage extracellular matrix (cartilage oligomeric matrix protein, type IX collagen, and matrilin-3) [Unger & Hecht 2001, Briggs & Chapman 2002]. These proteins have been shown to interact with each other and also with type II collagen both in vitro [Rosenberg et al 1998, Holden et al 2001, Thur et al 2001, Mann et al 2004, Budde et al 2005, Wagener et al 2005, Fresquet et al 2007, Fresquet et al 2008, Fresquet et al 2010] and in vivo [Budde et al 2005, Blumbach et al 2008, Zaucke & Grässel 2009].

Mutations in COMP exons encoding the type III repeats of COMP result in the misfolding of the protein and its retention in the rough endoplasmic reticulum (rER) of chondrocytes. This is thought to result in ER stress and an unfolded protein response (UPR), which ultimately causes increased cell death in vitro [Chen et al 2000, Maddox et al 2000, Unger & Hecht 2001, Kleerekoper et al 2002]. Several transgenic mouse models of COMP mutations have been developed to study disease mechanisms in vivo [Schmitz et al 2008, Posey et al 2009, Suleman et al 2012]. Although these models all have the same PSACH-causing COMP mutation (i.e., Asp469del) they nonetheless provide some insight into the disease mechanisms of MED caused by similar COMP mutations. For example, mutant COMP is retained in the ER of chondrocytes causing reduced chondrocyte proliferation and increased/dysregulated cell death [Suleman et al 2012].

The effect of mutations in the exons encoding the C-terminal domain of COMP is not fully resolved, but these mutations do not necessarily prevent the secretion of mutant COMP in vitro [Spitznagel et al 2004, Schmitz et al 2006] or in vivo [Pirog-Garcia et al 2007]. The generation of a mouse model of MED-PSACH with a p.Thr585Met mutation in the C-terminal domain has provided novel insight into disease mechanisms in vivo. Mutant COMP protein is efficiently secreted from the rER of chondrocytes, but still elicits a mild unfolded protein response (UPR). This ultimately results in decreased chondrocyte proliferation and increased and spatially dysregulated apoptosis that is possibly mediated by CHOP [Piróg -Garcia et al 2007]. More recently, a mild myopathy that originates from an underlying tendon and ligament pathology (which is a direct result of structural abnormalities to the collagen fibril architecture) has been demonstrated in this mouse model [Piróg & Briggs 2010, Piróg et al 2010].

The effect of MATN3 mutations appears similar to the effect caused by type III COMP mutations and results in the retention of mutant matrilin-3 in the rER of cells in vitro [Cotterill et al 2005, Otten et al 2005]. The study of a mouse model of MED harboring the p.Val194Asp mutation has demonstrated that the expression of this mutation causes ER stress and an unfolded protein response (UPR). Ultimately this results in a reduction in chondrocyte proliferation and dysregulated apoptosis [Leighton et al 2007, Nundlall et al 2010]. Interestingly, it has been recently demonstrated that retained mutant matrilin-3 forms non-native disulphide-bonded aggregates and that alanine substitution of the two terminal cysteine residues from the A-domain of p.Val194Asp matrilin-3 prevented aggregation, promoted mutant protein secretion in a cell culture model.

The pathologic effect of mutations in COL9A1, COL9A2, and COL9A3 is not well understood and a number of mechanisms have been proposed for these mutations including the degradation of mRNA from the mutant allele [Holden et al 1999, Spayde et al 2000], an accumulation of abnormal type IX collagen α-chains in the rER of chondrocytes [Bonnemann et al 2000], and/or the degradation of abnormal α-chains [van Mourik et al 1998]. However, the remarkable clustering of all COL9A1, COL9A2, and COL9A3 MED-causing mutations, which result in the in-frame deletion of equivalent regions of the COL3 domain of type IX collagen, led to the hypothesis that the deletion of these specific amino acids was a significant contributing factor to the development of the disease [Briggs & Chapman 2002]. Recent studies have confirmed that a COL9A3 mutation indeed abolishes binding of type IX collagen to matrilin-3 and type II collagen, thus identifying for the first time a molecular consequence of these mutations [Fresquet et al 2007].

COMP

Normal allelic variants. The coding sequence of COMP is organized into 19 exons spanning approximately 8.5 kb. The p.Asn386Asp allele has occasionally been seen in the heterozygous state in several unaffected individuals (allele frequency of 0.03) and is therefore likely to be a polymorphism.

Pathologic allelic variants. (EDM1: OMIM 132400). All of the pathogenic mutations identified in COMP that result in MED are either missense mutations or small in-frame deletions and duplications found in the type III or C-terminal domains of COMP. To date, nearly 100 different missense mutations have been reported in these two domains. The majority of mutations are in the type III repeats (~85%) with the remainder in the C-terminal domain (~15%) [Kennedy et al 2005a, Kennedy et al 2005b, Jackson et al 2012]. The small in-frame deletions (p.Arg367_Gly368del and p.Asn386del) and duplication (p.Asp473dup) are both in the type III repeat region of COMP, while a single-nucleotide deletion has been reported at codon 742 in the C-terminal domain. Recurrent mutations in the type III repeat region include p.Asp385Asn and p.Asn523Lys. A number of C-terminal missense mutations have been identified including p.Asn555Lys, p.Asp605Asn, p.Ser681Cys, p.Arg718Pro, and the recurrent p.Arg718Trp [Kennedy et al 2005a, Jackson et al 2012], while two mutations (p.Thr585Arg and p.Thr585Met) have been shown to result in either mild PSACH or MED, confirming that the two disorders are related. See Table 2.

Table 2. Selected COMP Allelic Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Normalc.1156A>Gp.Asn386AspNM_000095​.2
NP_000086​.2
Pathologicc.1099_1104delp.Arg367_Gly368del
c.1156_1158delp.Asn386del
c.1417_1419dupp.Asp473dup
c.1665C>Ap.Asn555Lys
c.1754C>Gp.Thr585Arg
c.1754C>Tp.Thr585Met
c.1813G>Ap.Asp605Asn
c.2042C>Gp.Ser681Cys
c.2153G>Cp.Arg718Pro
c.2152C>Tp.Arg718Trp

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. COMP is a 550-kd protein of 757 amino acids. It is a pentameric adhesive glycoprotein found predominantly in the extracellular matrix (ECM) of cartilage but also in tendon and ligament. It is the fifth member of the thrombospondin protein family and a modular and multifunctional protein, comprising a coiled-coil oligomerization domain, four type II (EGF-like) repeats, eight type III (CaM-like) repeats, and a large COOH-terminal globular domain. The type III repeats bind Ca2+ cooperatively and with high affinity, while the C-terminal globular domain has the ability to interact with both fibrillar (type I, II, and III) and nonfibrillar (type IX) collagens [Rosenberg et al 1998, Holden et al 2001, Thur et al 2001, Mann et al 2004], and fibronectin [Di Cesare et al 2002].

Abnormal gene product. Missense mutations in COMP result in misfolding of the gene product, which in some cases results in its retention in the rough endoplasmic reticulum (rER) of chondrocytes [Unger & Hecht 2001].

Collagen IX Genes

Normal allelic variants. The coding sequence of COL9A1 is organized into 38 exons spanning approximately 90 kb [Pihlajamaa et al 1998]; the coding sequence of COL9A2 and COL9A3 is organized into 32 exons spanning approximately 15 kb and 23 kb respectively [Paassilta et al 1999]. A number of non-pathogenic changes have been identified in the genes encoding type IX collagen, including an in-frame deletion and several synonymous changes [Paassilta et al 1999, Loughlin et al 2002].

Pathologic allelic variants. Mutations in the genes encoding type IX collagen and MED (EDM2: OMIM 600204; EDM3: OMIM 600969; EDM6). All mutations in the genes encoding type IX collagen reported in MED are clustered in either the splice donor site of exon 3 of COL9A2, the splice acceptor site of exon 3 of COL9A3, or the splice acceptor site of exon 8 of COL9A1. The mutations in COL9A2 and COL9A3 result in the skipping of exon 3 during RNA splicing; the resulting 36-bp deletion in the mRNA from COL9A2 and COL9A3 gives rise to a 12-amino acid in-frame deletion from the α2(IX) or α3(IX) chains. The single mutation identified in the splice acceptor site of exon 8 of COL9A1 results in a complex splicing pattern in which exon 8 (75 bp), exon 10 (63 bp), or both exons 8 and 10 (138 bp) are deleted, giving rise to the in-frame deletion of 25, 21, or 49 amino acids from the α1(IX) chain. All of the deletions are located in a similar region of the COL3 domain of type IX collagen and the precise location of the mutations demonstrates the importance of this domain [Unger & Hecht 2001, Briggs & Chapman 2002].

Normal gene product. Type IX collagen is an integral component of cartilage and a member of the FACIT (fibril-associated collagen with interrupted triple helix) group of collagens; it comprises three collagenous (COL) domains separated by non-collagenous (NC) domains. The amino-terminal NC domain (NC4) is encoded entirely by COL9A1. It is a heterotrimer [α1(IX)α2(IX)α3(IX)] of polypeptides derived from three distinct genes (COL9A1, COL9A2, and COL9A3). Type IX collagen comprises three collagenous (COL1-COL3) domains separated by four non-collagenous (NC1-NC4) domains and is closely associated with type II collagen fibrils, where it is thought to act as a molecular bridge between collagen fibrils and other cartilage matrix components.

Abnormal gene product. Exon skipping mutations in COL9A1, COL9A2, and COL9A3 result in the in-frame deletion of amino acids from the COL3 domain of type IX collagen, which may affect its ability to fold correctly or interact with other components of the cartilage extracellular matrix [Fresquet et al 2007].

MATN3

Normal allelic variants. The coding sequence of MATN3 is organized into eight exons spanning approximately 21 kb. The p.Glu252Lys allele has occasionally been seen in the heterozygous state in several unaffected individuals (allele frequency of 0.025) and is therefore likely to be a polymorphism.

Pathologic allelic variants (see Table 3)

Table 3. Selected MATN3 Allelic Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Normalc.754G>Ap.Glu252LysNM_002381​.4
NP_002372​.1
Pathologicc.209G>Ap.Arg70His
c.359C>Tp.Thr120Met
c.361C>Tp.Arg121Trp
c.400G>Ap.Glu134Lys
c.575T>Ap.Ile192Asn
c.581T>Ap.Val194Asp
c.584C>Ap.Thr195Lys
c.652T>Ap.Tyr218Asn
c.656C>Ap.Ala219Asp
c.908C>Tp.Thr303Met 1
c.910T>Ap.Cys304Ser 2

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. This mutation is associated with hand osteoarthritis and spinal disc degeneration.

2. This mutation is associated with spondyloepimetaphyseal dysplasia (SEMD).

Normal gene product. Matrilin-3 is the third member of a family of oligomeric multidomain ECM proteins comprising matrilin-1, -2, -3 and -4 [Wagener et al 2005]. The domain structure of the matrilin family of proteins is similar; each consists of one or two vWFA domains, a varying number of EGF-like repeats, and a coiled-coil domain, which facilitates oligomerization. Specifically, matrilin-3 is a protein of 486 amino acids, which comprises primarily a vWFA domain, four EGF-like repeats, and a coiled-coil domain [Belluoccio et al 1998]. Matrilins have been found in collagen-dependent and -independent filament networks within the tissues in which they are expressed and may perform analogous functions in these different tissues. Matrilin-3 has been shown to interact with COMP and other cartilage collagens through the A-domain [Mann et al 2004, Fresquet et al 2007, Fresquet et al 2008, Fresquet et al 2010].

Abnormal gene product. MATN3 mutations appear to delay the folding of the A-domain, which elicits an unfolded protein response and results in the retention of mutant matrilin-3 in the rER both in vitro [Cotterill et al 2005, Otten et al 2005] and in vivo [Leighton et al 2007, Nundlall et al 2010].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

  1. Annunen S, Paassilta P, Lohiniva J, Perala M, Pihlajamaa T, Karppinen J, Tervonen O, Kroger H, Lahde S, Vanharanta H, Ryhanen L, Goring HH, Ott J, Prockop DJ, Ala-Kokko L. An allele of COL9A2 associated with intervertebral disc disease. Science. 1999;285:409–12. [PubMed: 10411504]
  2. Belluoccio D, Schenker T, Baici A, Trueb B. Characterization of human matrilin-3 (MATN3). Genomics. 1998;53:391–4. [PubMed: 9799608]
  3. Blumbach K, Niehoff A, Paulsson M, Zaucke F. Ablation of collagen IX and COMP disrupts epiphyseal cartilage architecture. Matrix Biol. 2008;27:306–18. [PubMed: 18191556]
  4. Bonnemann CG, Cox GF, Shapiro F, Wu JJ, Feener CA, Thompson TG, Anthony DC, Eyre DR, Darras BT, Kunkel LM. 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. 2000;97:1212–7. [PMC free article: PMC15572] [PubMed: 10655510]
  5. Borochowitz ZU, Scheffer D, Adir V, Dagoneau N, Munnich A, Cormier-Daire V. Spondylo-epi-metaphyseal dysplasia (SEMD) matrilin 3 type: homozygote matrilin 3 mutation in a novel form of SEMD. J Med Genet. 2004;41:366–72. [PMC free article: PMC1735768] [PubMed: 15121775]
  6. Briggs MD, Chapman KL. Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations. Hum Mutat. 2002;19:465–78. [PubMed: 11968079]
  7. Budde B, Blumbach K, Ylöstalo J, Zaucke F, Ehlen HW, Wagener R, Ala-Kokko L, Paulsson M, Bruckner P, Grässel S. Altered integration of matrilin-3 into cartilage extracellular matrix in the absence of collagen IX. Mol Cell Biol. 2005;25:10465–78. [PMC free article: PMC1291247] [PubMed: 16287859]
  8. Chapman KL, Mortier GR, Chapman K, Loughlin J, Grant ME, Briggs MD. Mutations in the region encoding the von Willebrand factor A domain of matrilin-3 are associated with multiple epiphyseal dysplasia. Nat Genet. 2001;28:393–6. [PubMed: 11479597]
  9. Chen H, Deere M, Hecht JT, Lawler J. Cartilage oligomeric matrix protein is a calcium-binding protein, and a mutation in its type 3 repeats causes conformational changes. J Biol Chem. 2000;275:26538–44. [PubMed: 10852928]
  10. Cilliers HJ, Beighton P. Beukes familial hip dysplasia: an autosomal dominant entity. Am J Med Genet. 1990;36:386–90. [PubMed: 2389793]
  11. Cotterill SL, Jackson GC, Leighton MP, Wagener R, Makitie O, Cole WG, Briggs MD. Multiple epiphyseal dysplasia mutations in MATN3 cause misfolding of the A-domain and prevent secretion of mutant matrilin-3. Hum Mutat. 2005;26:557–65. [PMC free article: PMC2726956] [PubMed: 16287128]
  12. Di Cesare PE, Chen FS, Moergelin M, Carlson CS, Leslie MP, Perris R, Fang C. Matrix-matrix interaction of cartilage oligomeric matrix protein and fibronectin. Matrix Biol. 2002;21:461–70. [PubMed: 12225811]
  13. Elsbach L. Bilateral hereditary micro-epiphysial dysplasia of the hips. J Bone Joint Surg Br. 1959;41-B:514–23. [PubMed: 13849708]
  14. Fresquet M, Jackson GC, Loughlin J, Briggs MD. Novel mutations in exon 2 of MATN3 affect residues within the alpha-helices of the A-domain and can result in the intracellular retention of mutant matrilin-3. Hum Mutat. 2008;29:330. [PubMed: 18205203]
  15. Fresquet M, Jowitt TA, Stephen LA, Ylöstalo J, Briggs MD. Structural and functional investigations of Matrilin-1 A-domains reveal insights into their role in cartilage ECM assembly. J Biol Chem. 2010;285:34048–61. [PMC free article: PMC2962504] [PubMed: 20729554]
  16. Fresquet M, Jowitt TA, Ylöstalo J, Coffey P, Meadows RS, Ala-Kokko L, Thornton DJ, Briggs MD. Structural and functional characterization of recombinant matrilin-3 A-domain and implications for human genetic bone diseases. J Biol Chem. 2007;282:34634–43. [PMC free article: PMC2673055] [PubMed: 17881354]
  17. Gu J, Rong J, Guan F, Jiang L, Tao S, Guan G, Tao T. MATN3 gene polymorphism is associated with osteoarthritis in Chinese Han population: a community-based case-control study. Sci World J. 2012;2012:656084. [PMC free article: PMC3432353] [PubMed: 22973175]
  18. Holden P, Canty EG, Mortier GR, Zabel B, Spranger J, Carr A, Grant ME, Loughlin JA, Briggs MD. Identification of novel pro-alpha2(IX) collagen gene mutations in two families with distinctive oligo-epiphyseal forms of multiple epiphyseal dysplasia. Am J Hum Genet. 1999;65:31–8. [PMC free article: PMC1378072] [PubMed: 10364514]
  19. Holden P, Meadows RS, Chapman KL, Grant ME, Kadler KE, Briggs MD. 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. 2001;276:6046–55. [PubMed: 11087755]
  20. Hunter AG. Some psychological aspects of nonlethal chondrodysplasias: III. Self-esteem in children and adults. Am J Med Genet. 1998a;78:13–16. [PubMed: 9637416]
  21. Hunter AG. Some psycholgical aspects of nonlethal chondrodysplasias: II. Depression and anxiety. Am J Med Genet. 1998b;78:9–12. [PubMed: 9637415]
  22. Itoh T, Shirahama S, Nakashima E, Maeda K, Haga N, Kitoh H, Kosaki R, Ohashi H, Nishimura G, Ikegawa S. Comprehensive screening of multiple epiphyseal dysplasia mutations in Japanese population. Am J Med Genet A. 2006;140:1280–4. [PubMed: 16691584]
  23. 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. Missense mutations in the beta strands of the single A-domain of matrilin-3 result in multiple epiphyseal dysplasia. J Med Genet. 2004;41:52–9. [PMC free article: PMC1757268] [PubMed: 14729835]
  24. Jackson GC, Mittaz-Crettol L, Taylor JA, Mortier GR, Spranger J, Zabel B, LeMerrer 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. 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. 2012;33:144–57. [PMC free article: PMC3272220] [PubMed: 21922596]
  25. Jakkula E, Lohiniva J, Capone A, Bonafe L, Marti M, Schuster V, Giedion A, Eich G, Boltshauser E, Ala-Kokko L, Superti-Furga A. A recurrent R718W mutation in COMP results in multiple epiphyseal dysplasia with mild myopathy: clinical and pathogenetic overlap with collagen IX mutations. J Med Genet. 2003;40:942–8. [PMC free article: PMC1735347] [PubMed: 14684695]
  26. Jakkula E, Makitie O, Czarny-Ratacjzak M, Jackson GC, Damignani R, Susic M, Briggs MD, Cole WG, Ala-Kokko L. 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. 2005;13:292–301. [PubMed: 15523498]
  27. Kannu P, Irving M, Aftimos S, Savarirayan R. Two novel COL2A1 mutations associated with a Legg-Calvé-Perthes disease-like presentation. Clin Orthop Relat Res. 2011;469:1785–90. [PMC free article: PMC3094608] [PubMed: 21442341]
  28. Kennedy J, Jackson G, Barker FS, Nundlall S, Bella J, Wright MJ, Mortier GR, Neas K, Thompson E, Elles R, Briggs MD. Novel and recurrent mutations in the C-terminal domain of COMP cluster in two distinct regions and result in a spectrum of phenotypes within the pseudoachondroplasia -- multiple epiphyseal dysplasia disease group. Hum Mutat. 2005a;25:593–4. [PubMed: 15880723]
  29. Kennedy J, Jackson G, Ramsden S, Taylor J, Newman W, Wright MJ, Donnai D, Elles R, Briggs MD. COMP mutation screening as an aid for the clinical diagnosis and counselling of patients with a suspected diagnosis of pseudoachondroplasia or multiple epiphyseal dysplasia. Eur J Hum Genet. 2005b;13:547–55. [PMC free article: PMC2673054] [PubMed: 15756302]
  30. Kim OH, Park H, Seong MW, Cho TJ, Nishimura G, Superti-Furga A, Unger S, Ikegawa S, Choi IH, Song HR, Kim HW, Yoo WJ, Shim JS, Chung CY, Oh CW, Jeong C, Song KS, Seo SG, Cho SI, Yeo IK, Kim SY, Park S, Park SS. Revisit of multiple epiphyseal dysplasia: ethnic difference in genotypes and comparison of radiographic features linked to the COMP and MATN3 genes. Am J Med Genet A. 2011;155A:2669–80. [PubMed: 21965141]
  31. Kleerekoper Q, Hecht JT, Putkey JA. Disease-causing mutations in cartilage oligomeric matrix protein cause an unstructured Ca2+ binding domain. J Biol Chem. 2002;277:10581–9. [PubMed: 11782471]
  32. Leighton MP, Nundlall S, Starborg T, Meadows RS, Suleman F, Knowles L, Wagener R, Thornton DJ, Kadler KE, Boot-Handford RP, Briggs MD. 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. 2007;16:1728–41. [PMC free article: PMC2674230] [PubMed: 17517694]
  33. Liu YF, Chen WM, Lin YF, Yang RC, Lin MW, Li LH, Chang YH, Jou YS, Lin PY, Su JS, Huang SF, Hsiao KJ, Fann CS, Hwang HW, Chen YT, Tsai SF. Type II collagen gene variants and inherited osteonecrosis of the femoral head. N Engl J Med. 2005;352:2294–301. [PubMed: 15930420]
  34. Loughlin J, Mustafa Z, Dowling B, Southam L, Marcelline L, Raina SS, Ala-Kokko L, Chapman K. Finer linkage mapping of a primary hip osteoarthritis susceptibility locus on chromosome 6. Eur J Hum Genet. 2002;10:562–8. [PubMed: 12173034]
  35. Mabuchi A, Haga N, Maeda K, Nakashima E, Manabe N, Hiraoka H, Kitoh H, Kosaki R, Nishimura G, Ohashi H, Ikegawa S. Novel and recurrent mutations clustered in the von Willebrand factor A domain of MATN3 in multiple epiphyseal dysplasia. Hum Mutat. 2004;24:439–40. [PubMed: 15459972]
  36. Mabuchi A, Manabe N, Haga N, Kitoh H, Ikeda T, Kawaji H, Tamai K, Hamada J, Nakamura S, Brunetti-Pierri N, Kimizuka M, Takatori Y, Nakamura K, Nishimura G, Ohashi H, Ikegawa S. Novel types of COMP mutations and genotype-phenotype association in pseudoachondroplasia and multiple epiphyseal dysplasia. Hum Genet. 2003;112:84–90. [PubMed: 12483304]
  37. Maddox BK, Mokashi A, Keene DR, Bachinger HP. A cartilage oligomeric matrix protein mutation associated with pseudoachondroplasia changes the structural and functional properties of the type 3 domain. J Biol Chem. 2000;275:11412–7. [PubMed: 10753957]
  38. Maeda K, Nakashima E, Horikoshi T, Mabuchi A, Ikegawa S. 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. 2005;136:285–6. [PubMed: 15948199]
  39. Mäkitie O, Mortier GR, Czarny-Ratajczak M, Wright MJ, Suri M, Rogala P, Freund M, Jackson GC, Jakkula E, Ala-Kokko L, Briggs MD, Cole WG. Clinical and radiographic findings in multiple epiphyseal dysplasia caused by MATN3 mutations: description of 12 patients. Am J Med Genet A. 2004;125A:278–84. [PubMed: 14994237]
  40. Mann HH, Ozbek S, Engel J, Paulsson M, Wagener R. Interactions between the cartilage oligomeric matrix protein and matrilins. Implications for matrix assembly and the pathogenesis of chondrodysplasias. J Biol Chem. 2004;279:25294–8. [PubMed: 15075323]
  41. Min JL, Meulenbelt I, Riyazi N, Kloppenburg M, Houwing-Duistermaat JJ, Seymour AB, van Duijn CM, Slagboom PE. Association of matrilin-3 polymorphisms with spinal disc degeneration and osteoarthritis of the first carpometacarpal joint of the hand. Ann Rheum Dis. 2006;65:1060–6. [PMC free article: PMC1798238] [PubMed: 16396979]
  42. Miyamoto Y, Matsuda T, Kitoh H, Haga N, Ohashi H, Nishimura G, Ikegawa S. A recurrent mutation in type II collagen gene causes Legg-Calvé-Perthes disease in a Japanese family. Hum Genet. 2007;121:625–9. [PubMed: 17394019]
  43. Mortier GR, Chapman K, Leroy JL, Briggs MD. Clinical and radiographic features of multiple epiphyseal dysplasia not linked to the COMP or type IX collagen genes. Eur J Hum Genet. 2001;9:606–12. [PubMed: 11528506]
  44. Mostert AK, Dijkstra PF, Jansen BR, van Horn JR, de Graaf B, Heutink P, Lindhout D. Familial multiple epiphyseal dysplasia due to a matrilin-3 mutation: further delineation of the phenotype including 40 years follow-up. Am J Med Genet. 2003;120A:490–7. [PubMed: 12884427]
  45. Nakashima E, Kitoh H, Maeda K, Haga N, Kosaki R, Mabuchi A, Nishimura G, Ohashi H, Ikegawa S. Novel COL9A3 mutation in a family with multiple epiphyseal dysplasia. Am J Med Genet A. 2005;132A:181–4. [PubMed: 15551337]
  46. Nundlall S, Rajpar MH, Bell PA, Clowes C, Zeeff LA, Gardner B, Thornton DJ, Boot-Handford RP, Briggs MD. An unfolded protein response is the initial cellular response to the expression of mutant matrilin-3 in a mouse model of multiple epiphyseal dysplasia. Cell Stress Chaperones. 2010;15:835–49. [PMC free article: PMC3024081] [PubMed: 20428984]
  47. Odman P. Hereditary enchondral dysostosis; twelve cases in three generations mainly with peripheral location. Acta Radiol. 1959;52:97–113. [PubMed: 14428296]
  48. Otten C, Wagener R, Paulsson M, Zaucke F. Matrilin-3 mutations that cause chondrodysplasias interfere with protein trafficking while a mutation associated with hand osteoarthritis does not. J Med Genet. 2005;42:774–9. [PMC free article: PMC1735938] [PubMed: 16199550]
  49. Paassilta P, Lohiniva J, Goring HH, Perala M, Raina SS, Karppinen J, Hakala M, Palm T, Kroger H, Kaitila I, Vanharanta H, Ott J, Ala-Kokko L. Identification of a novel common genetic risk factor for lumbar disk disease. JAMA. 2001;285:1843–9. [PubMed: 11308397]
  50. Paassilta P, Pihlajamaa T, Annunen S, Brewton RG, Wood BM, Johnson CC, Liu J, Gong Y, Warman ML, Prockop DJ, Mayne R, Ala-Kokko L. Complete sequence of the 23-kilobase human COL9A3 gene. Detection of Gly-X-Y triplet deletions that represent neutral variants. J Biol Chem. 1999;274:22469–75. [PubMed: 10428822]
  51. Pihlajamaa T, Vuoristo MM, Annunen S, Perala M, Prockop DJ, Ala-Kokko L. Human COL9A1 and COL9A2 genes. Two genes of 90 and 15 kb code for similar polypeptides of the same collagen molecule. Matrix Biol. 1998;17:237–41. [PubMed: 9707347]
  52. Piróg KA, Briggs MD. Skeletal dysplasias associated with mild myopathy-a clinical and molecular review. J Biomed Biotechnol. 2010;2010:686457. [PMC free article: PMC2875749] [PubMed: 20508815]
  53. Piróg KA, Jaka O, Katakura Y, Meadows RS, Kadler KE, Boot-Handford RP, Briggs MD. A mouse model offers novel insights into the myopathy and tendinopathy often associated with pseudoachondroplasia and multiple epiphyseal dysplasia. Hum Mol Genet. 2010;19:52–64. [PMC free article: PMC2792148] [PubMed: 19808781]
  54. Piróg-Garcia KA, Meadows RS, Knowles L, Heinegård D, Thornton DJ, Kadler KE, Boot-Handford RP, Briggs MD. 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. 2007;16:2072–88. [PMC free article: PMC2674228] [PubMed: 17588960]
  55. Posey KL, Veerisetty AC, Liu P, Wang HR, Poindexter BJ, Bick R, Alcorn JL, Hecht JT. An inducible cartilage oligomeric matrix protein mouse model recapitulates human pseudoachondroplasia phenotype. Am J Pathol. 2009;175:1555–63. [PMC free article: PMC2751552] [PubMed: 19762713]
  56. Pullig O, Tagariello A, Schweizer A, Swoboda B, Schaller P, Winterpacht A. 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. 2007;66:279–80. [PMC free article: PMC1798488] [PubMed: 17242023]
  57. Roby P, Eyre S, Worthington J, Ramesar R, Cilliers H, Beighton P, Grant M, Wallis G. Autosomal dominant (Beukes) premature degenerative osteoarthropathy of the hip joint maps to an 11-cM region on chromosome 4q35. Am J Hum Genet. 1999;64:904–8. [PMC free article: PMC1377811] [PubMed: 10053028]
  58. Rosenberg K, Olsson H, Morgelin M, Heinegard D. Cartilage oligomeric matrix protein shows high affinity zinc-dependent interaction with triple helical collagen. J Biol Chem. 1998;273:20397–403. [PubMed: 9685393]
  59. Schmitz M, Becker A, Schmitz A, Weirich C, Paulsson M, Zaucke F, Dinser R. Disruption of extracellular matrix structure may cause pseudoachondroplasia phenotypes in the absence of impaired cartilage oligomeric matrix protein secretion. J Biol Chem. 2006;281:32587–95. [PubMed: 16928687]
  60. Schmitz M, Niehoff A, Miosge N, Smyth N, Paulsson M, Zaucke F. Transgenic mice expressing D469Delta mutated cartilage oligomeric matrix protein (COMP) show growth plate abnormalities and sternal malformations. Matrix Biol. 2008;27:67–85. [PubMed: 17889519]
  61. Spayde EC, Joshi AP, Wilcox WR, Briggs M, Cohn DH, Olsen BR. Exon skipping mutation in the COL9A2 gene in a family with multiple epiphyseal dysplasia. Matrix Biol. 2000;19:121–8. [PubMed: 10842095]
  62. Spitznagel L, Nitsche DP, Paulsson M, Maurer P, Zaucke F. Characterization of a pseudoachondroplasia-associated mutation (His587-->Arg) in the C-terminal, collagen-binding domain of cartilage oligomeric matrix protein (COMP). Biochem J. 2004;377:479–87. [PMC free article: PMC1223886] [PubMed: 14580238]
  63. 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. Genomewide scan for hand osteoarthritis: a novel mutation in matrilin-3. Am J Hum Genet. 2003;72:1448–59. [PMC free article: PMC1180305] [PubMed: 12736871]
  64. Suleman F, Gualeni B, Gregson HJ, Leighton MP, Piróg KA, Edwards S, Holden P, Boot-Handford RP, Briggs MD. A novel form of chondrocyte stress is triggered by a COMP mutation causing pseudoachondroplasia. Hum Mutat. 2012;33:218–31. [PMC free article: PMC3320758] [PubMed: 22006726]
  65. Superti-Furga A, Neumann L, Riebel T, Eich G, Steinmann B, Spranger J, Kunze J. Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation. J Med Genet. 1999;36:621–4. [PMC free article: PMC1762965] [PubMed: 10465113]
  66. Superti-Furga A, Unger S. Nosology and classification of genetic skeletal disorders: 2006 revision. Am J Med Genet A. 2007;143:1–18. [PubMed: 17120245]
  67. Thur J, Rosenberg K, Nitsche DP, Pihlajamaa T, Ala-Kokko L, Heinegard D, Paulsson M, Maurer P. 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. 2001;276:6083–92. [PubMed: 11084047]
  68. Unger S, Hecht JT. Pseudoachondroplasia and multiple epiphyseal dysplasia: New etiologic developments. Am J Med Genet. 2001;106:244–50. [PubMed: 11891674]
  69. Unger SL, Briggs MD, Holden P, Zabel B, Ala-Kokko L, Paassilta P, Lohiniva J, Rimoin DL, Lachman RS, Cohn DH. Multiple epiphyseal dysplasia: radiographic abnormalities correlated with genotype. Pediatr Radiol. 2001;31:10–8. [PubMed: 11200990]
  70. van Mourik JB, Buma P, Wilcox WR. Electron microscopical study in multiple epiphyseal dysplasia type II. Ultrastruct Pathol. 1998;22:249–51. [PubMed: 9793205]
  71. Wagener R, Ehlen HW, Ko YP, Kobbe B, Mann HH, Sengle G, Paulsson M. The matrilins--adaptor proteins in the extracellular matrix. FEBS Lett. 2005;579:3323–9. [PubMed: 15943978]
  72. 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. Preselection of cases through expert clinical and radiological review significantly increases mutation detection rate in multiple epiphyseal dysplasia. Eur J Hum Genet. 2007;15:150–4. [PMC free article: PMC2670452] [PubMed: 17133256]
  73. Zaucke F, Grässel S. Genetic mouse models for the functional analysis of the perifibrillar components collagen IX, COMP and matrilin-3: Implications for growth cartilage differentiation and endochondral ossification. Histol Histopathol. 2009;24:1067–79. [PubMed: 19554514]
  74. Zhao J, Xia W, Nie M, Zheng X, Wang Q, Wang X, Wang W, Ning Z, Huang W, Jiang Y, Li M, Wang O, Xing X, Sun Y, Luo L, He S, Yu W, Lin Q, Pei Y, Zhang F, Han Y, Tong Y, Che Y, Shen R, Hu Y, Zhou X, Chen Q, Xu L. A haplotype of MATN3 is associated with vertebral fracture in Chinese postmenopausal women: Peking Vertebral Fracture (PK-VF) study. Bone. 2012;50:917–24. [PubMed: 22270056]

Chapter Notes

Revision History

  • 25 July 2013 (me) Comprehensive update posted live
  • 1 February 2011 (me) Comprehensive update posted live
  • 18 April 2007 (me) Comprehensive update posted to live Web site
  • 24 January 2005 (me) Comprehensive update posted to live Web site
  • 8 January 2003 (me) Review posted to live Web site
  • 10 October 2002 (gm) Original submission
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