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Multiple Epiphyseal Dysplasia, Autosomal Dominant

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

Author Information

Initial Posting: ; Last Update: November 19, 2015.

Summary

Clinical characteristics.

Autosomal dominant multiple epiphyseal dysplasia (MED) presents in early 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. Identification of a heterozygous pathogenic variant in COMP, MATN3, COL9A1, COL9A2, or COL9A3 establishes the diagnosis if clinical and radiographic features are inconclusive.

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 addressing issues of 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.

Many individuals with autosomal dominant MED have inherited the pathogenic variant from a parent. The prevalence of de novo pathogenic variants is not known. Each child of an individual with autosomal dominant MED has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis of pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member.

Diagnosis

Suggestive Findings

Autosomal dominant multiple epiphyseal dysplasia (MED) should be suspected in individuals with the following clinical and radiographic findings:

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.

Establishing the Diagnosis

The diagnosis of autosomal dominant MED is established in a proband with the above clinical and radiographic findings. Identification of a heterozygous pathogenic variant in one of the genes listed in Table 1 establishes the diagnosis if clinical and radiographic features are inconclusive.

Molecular testing approaches can include serial single-gene testing, use of a multi-gene panel, and genomic testing.

Table 1.

Molecular Genetic Testing Used in Autosomal Dominant Multiple Epiphyseal Dysplasia

Gene 1Proportion of Autosomal Dominant MED Attributed to Pathogenic Variants in This Gene 2, 3Proportion of Pathogenic Variants 4 Detected by Test Method
Sequence analysis 5Gene-targeted deletion/duplication analysis 6
COMP50%100% 7None reported 8, 9
MATN320%See footnote 10Unknown 11
COL9A110%100%None reported 8
COL9A2100% 12None reported 8
COL9A3100% 13None reported 8
Unknown 14~20%?NA
1.
2.

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

3.

The proportion of COMP, MATN3, and COL9A1-3 pathogenic variants 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 pathogenic variants 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 resulted in a variant detection rate of 87%.

4.

See Molecular Genetics for information on allelic variants detected in this gene.

5.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

Pathogenic variants 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 variant has been identified in exon 5 of COMP, which encodes residues of the second epidermal growth factor (EGF)-like repeat of COMP [Jackson et al 2012]. A previous study by Kennedy et al [2005b] demonstrated that approximately 70% of MED-causing variants 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-causing variants are not found in exons 15, 17 and 19 of COMP.

8.

No whole-gene deletions or duplications involving COMP, COL9A1, COL9A2, or COL9A3 have been reported to cause autosomal dominant MED.

9.
10.

See Molecular Genetics, MATN3.

11.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

12.

All pathogenic variants identified cluster in the splice donor site of exon 3.

13.

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

14.

Pathogenic variants remain undetected in approximately 20% of individuals with MED. In some families genetic linkage studies have excluded linkage to the five genes in which pathogenic variants are known to be causal; however, additional genetic loci for MED have not yet been determined.

Clinical Characteristics

Clinical Description

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 autosomal 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 individuals, the osteoarthritis is sufficiently severe to require joint replacement in early adult life.

No other anomalies are associated with autosomal dominant MED. 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 pathogenic variants is characterized by significant involvement at the capital femoral epiphyses and irregular acetabula [Unger et al 2001]. However, the recurrent p.Arg718Trp pathogenic variant in COMP appears to cause a mild form of the disorder, more consistent with MED caused by a type IX collagen gene variant [Jakkula et al 2003].
  • Type IX collagen defects result in more severe involvement of the knees and relative sparing of the hips.
  • MATN3 pathogenic variants result in knee abnormalities that are similar to those in individuals with a COL9A2 pathogenic variant; the hip abnormalities are more severe (although not as severe as those in individuals with a COMP pathogenic variant) [Mortier et al 2001]. However, more intra- and interfamilial variability is evident in MED caused by MATN3 pathogenic variants. A pathogenic variant 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 pathogenic variants in MATN3 [Chapman et al 2001, Mortier et al 2001, Jackson et al 2004, Mäkitie et al 2004], in COL9A3 [Bönnemann et al 2000, Nakashima et al 2005], and in some instances, in COMP. These findings make the establishment of strong genotype-phenotype correlations in autosomal dominant MED a challenge.

Briggs et al [2014] reviewed 300 COMP variants and the resulting phenotypes published between 1995 and 2014 and concluded that pathogenic variants in specific residues and/or regions of the type III repeats of COMP are significantly associated with either MED or pseudoachondroplasia.

Penetrance

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

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 autosomal 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).

Multiple epiphyseal dysplasia, recessive (EDM4/rMED) is characterized by joint pain (usually in the hips and/or knees); malformations of hands, feet, and knees; and scoliosis. Approximately 50% of affected individuals have an abnormal finding at birth, including clubfoot, clinodactyly, or (rarely) cystic ear swelling. Onset of articular 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 and ranges from 150 to 180 cm. Functional disability is mild. 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 layer) 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.

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

Mild spondyloepiphyseal dysplasia congenita (SEDc). A study by Jackson et al [2012] identified COL2A1 missense variants in two individuals with mild SEDc (OMIM 183900) who had MED-like features. Both variants 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 individuals had phenotypic features consistent with MED.

Beukes familial hip dysplasia (BFHD) (OMIM 142669). An autosomal dominant 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 –2015 Revision recognized BFHD as a form of MED [Bonafe et al 2015]. A UFSP2 pathogenic variant was recently identified in affected individuals in this South African family with BFHAD [Watson et al 2015].

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
  • Consultation with a medical geneticist and/or genetic counselor

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.

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

Sibs of a proband

  • The risk to sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband has autosomal dominant MED, the risk to each sib of the proband is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism; germline mosaicism has been reported in a number of families [Jackson et al 2004].
  • The sibs of a proband with clinically unaffected parents are still at increased risk for autosomal dominant MED because of the possibility of reduced penetrance in a parent (see Penetrance).

Offspring of a proband. Each child of an individual with autosomal dominant MED has a 50% chance of inheriting the COMP, MATN3, COL9A1, COL9A2, or COL9A3 pathogenic variant.

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 may be 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 pathogenic variant have been reported, resulting in a family history suggestive of autosomal recessive inheritance.

Testing of asymptomatic at-risk individuals younger than age 18 years is controversial. Testing may be appropriate 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 pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the COMP, MATN3, COL9A1, COL9A2, or COL9A3 pathogenic variant has been identified in an affected family member, prenatal testing or preimplantation genetic diagnosis for a pregnancy at increased risk for autosomal dominant multiple epiphyseal dysplasia may be an option that a couple may wish to consider.

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
    UCLA
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Email: AZargaryan@mednet.ucla.edu
  • 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 from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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, MATN3, COL9A1, COL9A2, and COL9A3) in which a pathogenic variant is known to cause autosomal dominant multiple epiphyseal dysplasia (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].

Pathogenic variants 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, 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 pathogenic variants 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 pseudoachondroplasia-causing COMP pathogenic variant (i.e., Asp469del) they nonetheless provide some insight into the disease mechanisms of MED caused by similar COMP pathogenic variants. 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 pathogenic variants in the exons encoding the C-terminal domain of COMP is not fully resolved, but these pathogenic variants do not necessarily prevent the secretion of mutant COMP in vitro [Spitznagel et al 2004, Schmitz et al 2006] or in vivo [Piróg-Garcia et al 2007]. The generation of a mouse model of MED-pseudoachondroplasia with a p.Thr585Met pathogenic variant 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. 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 a MATN3 pathogenic variant appears similar to the effect caused by a type III COMP pathogenic variant 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 pathogenic variant has demonstrated that the expression of this pathogenic variant causes ER stress and an unfolded protein response. 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 and promoted mutant protein secretion in a cell culture model.

The pathogenic effect of variants in COL9A1, COL9A2, and COL9A3 is not well understood and a number of mechanisms have been proposed for mutation of these genes, 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 [Bönnemann 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 variants, 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]. Studies have confirmed that a COL9A3 pathogenic variant 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 pathogenic variants [Fresquet et al 2007].

COMP

Gene structure. The coding sequence of COMP is organized into 19 exons spanning approximately 8.5 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Benign allelic variants. 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.

Pathogenic allelic variants. (EDM1: OMIM 132400). All of the pathogenic variants identified in COMP that result in MED are either missense variants or small in-frame deletions and duplications found in the type III or C-terminal domains of COMP. To date, nearly 100 different pathogenic missense variants have been reported in these two domains. The majority of pathogenic variants 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 pathogenic variants in the type III repeat region include p.Asp385Asn and p.Asn523Lys. A number of C-terminal missense variants have been identified; they include p.Asn555Lys, p.Asp605Asn, p.Ser681Cys, p.Arg718Pro, and the recurrent p.Arg718Trp [Kennedy et al 2005a, Jackson et al 2012], while two variants (p.Thr585Arg and p.Thr585Met) have been shown to result in either mild pseudoachondroplasia or MED, confirming that the two disorders are related. See Table 2.

Table 2.

Selected COMP Allelic Variants

Variant ClassificationDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Benignc.1156A>Gp.Asn386AspNM_000095​.2
NP_000086​.2
Pathogenicc.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 authors. 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. Pathogenic missense variants in COMP result in misfolding of the gene product, which in some cases results in its retention in the rER of chondrocytes [Unger & Hecht 2001].

MATN3

Gene structure. The coding sequence of MATN3 is organized into eight exons spanning approximately 21 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Benign allelic variants (see Table 3). 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 benign allelic variant.

Pathogenic allelic variants (see Table 3)

Table 3.

Selected MATN3 Allelic Variants

Variant ClassificationDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Benignc.754G>Ap.Glu252LysNM_002381​.4
NP_002372​.1
Pathogenicc.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 authors. 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 pathogenic variant is associated with hand osteoarthritis and spinal disc degeneration.

2.

This pathogenic variant is associated with spondyloepimetaphyseal dysplasia (SEMD) See Genetically Related Disorders.

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 pathogenic variants 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].

Collagen IX Genes

Gene structure. 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]. For a detailed summary of gene and protein information, see Table A, Gene.

Benign allelic variants. 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].

Pathogenic allelic variants. Pathogenic variants in the genes encoding type IX collagen and MED (EDM2: OMIM 600204; EDM3: OMIM 600969; EDM6). All pathogenic variants 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 pathogenic variants 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 pathogenic variant 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 pathogenic variants 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 pathogenic variants 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].

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Chapter Notes

Revision History

  • 19 November 2015 (me) Comprehensive update posted live
  • 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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Bookshelf ID: NBK1123PMID: 20301302

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