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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Pseudoachondroplasia

Synonyms: PSACH, Pseudoachondroplastic Dysplasia

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

Author Information
, PhD
Professor of Skeletal Genetics & Wellcome Trust Senior Research Fellow, Institute of Genetic Medicine
Newcastle University
International Centre for Life
Newcastle upon Tyne, United Kingdom
, MB, ChB, MSc, FRCP
Consultant in Clinical Genetics, Northern Genetics Service
Newcastle upon Tyne Hospitals
Newcastle upon Tyne, United Kingdom

Initial Posting: ; Last Update: February 28, 2013.

Summary

Disease characteristics. Pseudoachondroplasia is characterized by normal length at birth and normal facies. Often the presenting feature is a waddling gait, recognized at the onset of walking. Typically, by approximately age two years, the growth rate falls below the standard growth curve, leading to a moderately severe form of disproportionate short-limb short stature. Joint pain during childhood, particularly in the large joints of the lower extremities, is common. Degenerative joint disease is progressive and approximately 50% of individuals with pseudoachondroplasia eventually require hip replacement surgery.

Diagnosis/testing. The diagnosis of pseudoachondroplasia can be made on the basis of clinical findings and radiographic features. Pseudoachondroplasia results almost exclusively from dominant mutations in COMP, which encodes cartilage oligomeric matrix protein.

Management. Treatment of manifestations: Analgesics for joint pain; osteotomy for lower-limb malalignment; rarely, surgery for scoliosis or C1-C2 fixation for symptoms and radiographic evidence of cervical spine instability; attention to and social support for psychosocial issues related to short stature for affected individuals and their families.

Prevention of secondary complications: Physical activities that do not cause excessive wear and/or damage to the joints

Surveillance: Regular examinations for evidence of degenerative joint disease, kyphoscoliosis, symptomatic lower limb malalignment, symptomatic joint hypermobility and neurologic manifestations, particularly spinal cord compression secondary to odontoid hypoplasia and consequent cervical spine instability.

Agents/circumstances to avoid: In those with odontoid hypoplasia, extreme neck flexion and extension should be avoided.

Genetic counseling. Pseudoachondroplasia is inherited in an autosomal dominant manner. Some individuals diagnosed with pseudoachondroplasia have an affected parent; the proportion of pseudoachondroplasia resulting from a de novo mutation is unknown. Each child of an individual with pseudoachondroplasia and a reproductive partner with normal bone growth has a 50% chance of inheriting the mutation and having pseudoachondroplasia. Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with pseudoachondroplasia may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. Prenatal testing for pregnancies at increased risk for pseudoachondroplasia is possible if the disease-causing mutation in the family is known.

Diagnosis

Clinical Diagnosis

The diagnosis of pseudoachondroplasia can be made on the basis of clinical findings and radiographic features. Although typical forms [Maroteaux & Lamy 1959, McKusick & Scott 1971] and mild forms [Maroteaux et al 1980, Rimoin et al 1994] of pseudoachondroplasia are recognized, the spectrum of clinical severity is continuous.

Clinical findings

  • Normal length at birth
  • Normal facies
  • Waddling gait, recognized at the onset of walking
  • Typically, decline in growth rate to below the standard growth curve by approximately age two years, leading to moderately severe disproportionate short-limb short stature
  • Moderate brachydactyly
  • Ligamentous laxity and joint hyperextensibility, particularly in the hands, knees, and ankles
  • Mild myopathy has been reported for some individuals
  • Restricted extension at the elbows and hips
  • Valgus, varus, or windswept deformity of the lower limbs
  • Mild scoliosis
  • Lumbar lordosis (~50% of affected individuals)
  • Joint pain during childhood, particularly in the large joints of the lower extremities; may be the presenting symptom in mildly affected individuals

Radiographic diagnosis of pseudoachondroplasia is ideally made based on radiographs obtained in prepubertal individuals. At a minimum, AP views of the hips, knees, and hands and wrists and a lateral view of the spine are required (see Figure 1). Findings include the following:

Figure 1

Figure

Figure 1. Radiographs of a prepubertal child showing the changes typical of pseudoachondroplasia

  • Delayed epiphyseal ossification with irregular epiphyses and metaphyses of the long bones (consistent)
  • Small capital femoral epiphyses, short femoral necks and irregular, flared metaphyseal borders; small pelvis and poorly modeled acetabulae with irregular margins that may be sclerotic, especially in older individuals
  • Significant brachydactyly; short metacarpals and phalanges that show small or cone shaped epiphyses and irregular metaphyses; small, irregular carpal bones
  • Anterior beaking or tonguing of the vertebral bodies on lateral view. This distinctive appearance of the vertebrae normalizes with age, emphasizing the importance of obtaining in childhood the radiographs to be used in diagnosis (Figure 1).

Molecular Genetic Testing

Gene. COMP, encoding cartilage oligomeric matrix protein, is the only gene in which mutations are known to cause pseudoachondroplasia [Briggs et al 1995, Hecht et al 1995, Briggs & Chapman 2002].

Clinical testing

  • Sequence analysis of selected exons. All mutations characterized to date have been sequence variants found in the exons encoding the eight type III calcium-binding repeats (exons 8-14) or the carboxyl-terminal globular domain (exons 14-19). If mutations are not identified in these exons, sequence analysis of the remaining exons can be considered; recently novel sequence variants have been identified in exons 5 and 7 in individuals with pseudoachondroplasia (or the related disease, multiple epiphyseal dysplasia (MED) (see Genetically Related Disorders), but their pathogenicity has not been fully confirmed [Jackson et al 2012].

Table 1. Summary of Molecular Genetic Testing Used in Pseudoachondroplasia

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
COMPSequence analysisp.Asp473del 2~30%
Sequence variants 3 in exons 1-19 4100% 5
Sequence analysis / mutation scanning of select exons 6Sequence variants 3 in the select exons 8-19 7>96% 5
Deletion / duplication analysis 8Exonic and/or whole-gene deletionsVery rare 9

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Approximately 30% of individuals with pseudoachondroplasia [Briggs et al 1998, Briggs & Chapman 2002, Mabuchi et al 2003] have the same recurrent mutation, p.Asp473del, deletion of a single GAC (c.1417_1419delGAC) codon within a run of five consecutive GAC codons in exon 13 [Hecht et al 1995], corresponding to the seventh type III calcium-binding repeat domain of the protein.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. Mutations are either missense (~65%) small in-frame deletions (~30%) or deletions/insertions (~5%); typically sequence analysis does not detect exonic or whole-gene deletions/duplications.

5. Jackson et al [2012]

6. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.

7. Exons sequenced 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]

Interpretation of test results

  • For issues to consider in interpretation of sequence analysis results, click here.
  • In a simplex case (i.e., a single occurrence in a family), analysis of parental DNA can be used to distinguish polymorphisms from the causative mutation.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. A recent analysis of COMP mutations identified in 35 individuals with pseudoachondroplasia demonstrated that they are distributed in seven exons in the following order of prevalence: 13, 14, 9/10, 18, and 11/16 [Kennedy et al 2005a, Jackson et al 2012].

Note that several mutations have been detected in exons 1-7, but their pathogenicity remains unclear [Jackson et al 2012].

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.

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

Pseudoachondroplasia is characterized by disproportionate short-limb short stature. Intrafamilial and interfamilial variability are observed.

Natural history is well documented [Wynne-Davies et al 1986, McKeand et al 1996]. Affected individuals are generally of normal length at birth. Often the presenting feature is a waddling gait, recognized at the onset of walking. Typically, the growth rate falls below the standard growth curve by approximately age two years. Growth curves for pseudoachondroplasia have been developed [Horton et al 1982]. Mean adult height is 116 cm for females and 120 cm for males [McKeand et al 1996].

Pseudoachondroplasia is a short-limb form of dwarfism. Head size and shape are normal, without dysmorphic features. Extension at the elbows may be limited, and the elbows and knees may appear large. Scoliosis/lordosis can be observed in childhood and may persist into adulthood.

Osteoarthritis of the upper extremities and the spine may occur in early adult life. Degenerative joint disease is progressive and approximately 50% of individuals with pseudoachondroplasia eventually require hip replacement surgery.

Odontoid hypoplasia is not a common finding but does sometimes occur. Cervical spine instability can result, but C1-C2 fixation is not commonly necessary.

Genotype-Phenotype Correlations

A systematic analysis of the relationship between gene mutation and phenotype has not been performed. In particular there is little correlation between the type and location of a mutation and the resulting phenotype, with the following notable exceptions:

  • Individuals with mutations in the seventh type III calcium binding repeat are reported to have more severe short stature than those with mutations in the other type III repeats [Mabuchi et al 2003].
  • Individuals heterozygous for the common p.Asp473del mutation, present in approximately 30% of affected individuals, have a consistent, typical form of the disorder and are severely short [Mabuchi et al 2003]. In contrast, the insertion of a GAC codon at the same region p.Asp473dup results in mild MED [Délot et al 1999, Zankl et al 2007, Jackson et al 2012].
  • Specific missense mutations that result in pseudoachondroplasia (as opposed to MED) affect residues in the C-type motif of the type III calcium binding repeats, whereas missense mutations in the N-type motif of the type III repeats generally result in MED [Jackson et al 2012]. In-frame deletions are found equally between the N-type and C-type motifs of the type III repeats [Jackson et al 2012] and can cause both pseudoachondroplasia and MED.

A range of intrafamilial variability has been observed, indicating that there are modifiers of phenotypic expression. Interfamilial variability is much wider, likely reflecting mutation-specific determinants of phenotypic severity as well as the effect of genetic modifiers.

Penetrance

Penetrance is 100%.

Anticipation

Anticipation has not been observed in families with pseudoachondroplasia.

Nomenclature

In the past, four subtypes of pseudoachondroplasia, including dominant and recessive forms, were recognized under the term pseudoachondroplasia. The current classification recognizes a single, dominantly inherited phenotype.

Prevalence

No firm data on the prevalence of pseudoachondroplasia are available; it is estimated at 1:30,000 [Genetics Home Reference].

Differential Diagnosis

Multiple epiphyseal dysplasias

  • 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 during long 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. The diagnosis of dominant MED is based on the clinical and radiographic presentation in the proband and other family members.

    In the initial stage of the disorder, often before the onset of clinical symptoms, radiographs show delayed ossification of the epiphyses of the long tubular bones. 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. The spine is by definition normal, although Schmorl bodies and irregular vertebral end plates may be observed.

    Mutations in one of five genes cause autosomal dominant MED: COMP, COL9A1, COL9A2, COL9A3, and MATN3. However, in approximately 20% of all samples analyzed from clinically confirmed cases, a mutation cannot be identified in any of the five genes above [Zankl et al 2007]. Moreover, differences in ascertainment, diagnosis, and genetic testing have suggested previously that up to 50% of individuals with MED do not have a mutation in one of the five known genes [Unger et al 2001, Jakkula et al 2005, Kennedy et al 2005a].
  • Recessive multiple epiphyseal dysplasia (EDM4/rMED) is characterized by joint pain (usually in the hips or knees); malformations of hands, feet, and knees; and scoliosis. Approximately 50% of affected individuals have some abnormal finding at birth including clubfoot, cleft palate, 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, with the median height shifting from the 50th to the tenth percentile; range is 150-180 cm. Functional disability is mild or absent. EDM4/rMED is diagnosed on clinical and radiographic findings. SLC26A2 (DTDST) is the only gene known to be associated with EDM4/rMED. Diagnosis can be confirmed by molecular genetic testing of SLC26A2.

Other forms of spondyloepimetaphyseal dysplasia (SEMD). Many different skeletal dysplasias have abnormalities of the spine, metaphyses, and epiphyses apparent on x-ray. For example, Spranger et al [2005] described a severe form of SEMD with some radiographic similarity to pseudoachondroplasia but without a COMP mutation. Generally, a complete genetic skeletal survey can distinguish these phenotypes from pseudoachondroplasia.

Another resource to help diagnose skeletal dysplasias using radiographic images is available online (registration or subscription required).

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 in an individual diagnosed with pseudoachondroplasia, the following evaluations are recommended:

  • Measurement of height and plotting on growth chart, preferably disorder-specific growth chart
  • Evaluation by history and physical examination for skeletal manifestations, including arthritis
  • “Genetic” skeletal survey including: AP views of the hips, knees and hands, as well as lateral views of the knees and spine
  • Evaluation of the cervical vertebrae because of the serious potential clinical complications associated with cervical spine instability [Shetty et al 2007]. This can be assessed by flexion/extension MRI, especially in persons with neurologic symptoms suggestive of cord compression.
  • Assessment of ligamentous laxity and its clinical implications
  • Medical genetics consultation

Treatment of Manifestations

Joint pain may be controlled with analgesics, but no systematic studies have evaluated the effectiveness of various forms of pain control in pseudoachondroplasia.

Osteotomy to treat the lower limb malalignment is common during childhood. The need for subsequent revision is also common, which most likely reflects the severe joint instability that can be present in some affected individuals [Hunter 1999, Li et al 2007].

Very few examples of extended limb lengthening have been reported for pseudoachondroplasia; thus, the outcome of this procedure in pseudoachondroplasia is not known.

The need for surgical treatment of scoliosis is uncommon but may be effective in severe situations. Surgical methods are standard.

In persons with neurologic symptoms and radiographic evidence of cervical spine instability or cord compression, C1-C2 fixation is the recommended surgical procedure.

Awareness of psychosocial issues related to short stature, including stigmatization and discrimination, is important in caring for the individual. Social support organizations, including the Little People of America and other similar organizations in other countries (see Resources), may be of great benefit in providing information to affected individuals and their families.

Prevention of Secondary Complications

The articular cartilage of individuals with pseudoachondroplasia is likely to be severely disrupted; therefore, directing the individual toward physical activities that do not accelerate joint degeneration will be beneficial.

Surveillance

Affected individuals should be examined regularly for the following by a medical geneticist and/or orthopedist familiar with the phenotype:

  • Evidence of degenerative joint disease manifesting as joint pain or by radiographs
  • Symptomatic lower limb malalignment
  • Evidence of kyphoscoliosis
  • Symptoms related to joint hypermobility
  • Neurologic manifestations, particularly spinal cord compression secondary to odontoid hypoplasia

Agents/Circumstances to Avoid

In the small fraction of individuals with odontoid hypoplasia, extreme neck flexion and extension should be avoided.

Evaluation of Relatives at Risk

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

Pregnancy Management

For females with pseudoachondroplasia, delivery by cesarean section is often necessary because of the small size of the pelvis.

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.

Other

Growth hormone treatment is ineffective in pseudoachondroplasia [Kanazawa et al 2003].

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

Pseudoachondroplasia is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with pseudoachondroplasia have an affected parent.
  • A proband with pseudoachondroplasia may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations has not been accurately determined, but a study by Kennedy and colleagues indicated that in at least 22% of individuals with molecularly confirmed pseudoachondroplasia, a COMP mutation had arisen de novo [Kennedy et al 2005a].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include physical examination and radiographs. If a COMP mutation has been identified in the proband, molecular genetic testing of the parents could detect somatic mosaicism for the mutation in one of the parents. Awareness of the possibility that somatic mosaicism for the mutation could be detected in the unaffected parent is important.

Note: If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the disease-causing mutation identified in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. The risk to the sibs of the proband depends on the probability of germline mosaicism in a parent of the proband and the spontaneous mutation rate of COMP. Germline mosaicism for a COMP mutation has been reported [Hall et al 1987, Ferguson et al 1997], but the frequency is unknown and the empiric risk to sibs of a proband has not been determined.

Offspring of a proband

  • Each child of an individual with pseudoachondroplasia and a reproductive partner with normal bone growth has a 50% chance of inheriting the mutation and having pseudoachondroplasia.
  • Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with pseudoachondroplasia may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals may be distinct from those of the parents [Unger et al 2001, Flynn & Pauli 2003].
  • If both partners have a dominantly inherited bone growth disorder, the offspring have a 25% chance of having the maternal bone growth disorder, a 25% chance of having the paternal bone growth disorder, a 25% chance of having average stature and bone growth and a 25% chance of having double heterozygosity for the two disorders.

Other family members of a proband. 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

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has 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.

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.

Requests for prenatal testing for conditions which (like pseudoachondroplasia) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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.

  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
    Email: hgf1@hgfound.org
  • 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
  • MAGIC Foundation
    6645 West North Avenue
    Oak Park IL 60302
    Phone: 800-362-4423 (Toll-free Parent Help Line); 708-383-0808
    Fax: 708-383-0899
    Email: info@magicfoundation.org
  • Medline Plus
  • 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. Pseudoachondroplasia: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
COMP19p13​.11Cartilage oligomeric matrix proteinCOMP homepage - Mendelian genesCOMP

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 Pseudoachondroplasia (View All in OMIM)

177170PSEUDOACHONDROPLASIA; PSACH
600310CARTILAGE OLIGOMERIC MATRIX PROTEIN; COMP

Normal allelic variants. The coding sequence of COMP is organized into 19 exons distributed over approximately 8.5 kilobases of genomic DNA. A frequent single-nucleotide normal variant predicts a p.Asn386Asp substitution.

Pathologic allelic variants. All individuals with pseudoachondroplasia appear to have COMP mutations [Jackson et al 2012]. Furthermore, all of the mutations predict an alteration in the primary structure of the protein, with the majority found in the exons encoding the eight type III calcium-binding repeats of the protein (~85%; exons 8-14). Mutations in the exons encoding the carboxyl-terminal globular domain have mostly been found in the remaining affected individuals (~15%; exons 14-19). A mutation in exon 7 has been identified but pathogenesis has not been fully resolved [Jackson et al 2012]. Approximately 30% of individuals have the same mutation: deletion of a single aspartic acid codon (p.Asp473del) within a run of five consecutive GAC (Asp encoding) codons in exon 13 [Hecht et al 1995, Briggs & Chapman 2002], corresponding to the seventh type III calcium-binding repeat domain of the protein. Most of the remaining individuals have a diverse range of single amino-acid substitution mutations, small in-frame deletions, duplications or indels. Interestingly, unlike the type III mutations, the carboxyl terminal domain (CTD) mutations (exons 14-19) appear to cluster in 3 distinct regions and affect only a limited number of residues. These mutation clusters include p.Thr529Ile, p.Glu583Lys, p.Thr585Met, p.Thr585Arg, p.Thr585Lys, p.His587Arg, and [p.Gly719Ser; p.Gly719Asp] and point to an important role for these residues in the structure and/or function of COMP [Briggs et al 1998, Deere et al 1998, Hecht et al 1998, Deere et al 1999, Mabuchi et al 2001, Kennedy et al 2005a, Kennedy et al 2005b, Jackson et al 2012].

A single in-frame exon deletion and a single mutation predicting synthesis of a truncated protein have also been characterized, but not analyzed in-depth [Mabuchi et al 2003].

Table 2. Selected COMP Allelic Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
Normalc.1156A>Gp.Asn386AspNM_000095​.2
NP_000086​.2
Pathologicc.1417_1419delGACp.Asp473del
(p.469delD)
c.1417_1419dupGACp.Asp473dup
c.1747G>Ap.Glu583Lys
c.1754C>Tp.Thr585Met
c.1754C>Gp.Thr585Arg
c.1754C>Ap.Thr585Lys
c.1760A>Gp.His587Arg
c.1679A>Gp.Thr527Ala
c.1586C>Tp.Thr529Ile
c.2155G>Ap.Gly719Ser
c.2156G>Ap.Gly719Asp

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. Variant designation that does not conform to current naming conventions

Normal gene product. Cartilage oligomeric matrix protein (COMP) is a 757-amino acid protein [Newton et al 1994] composed of an amino-terminal coiled-coil domain, four type II (EGF-like) repeats, eight type III (calmodulin-like calcium binding) repeats, and a carboxyl-terminal globular domain. It is a 550-kd homopentameric adhesive glycoprotein found predominantly in the cartilage extracellular matrix [Hedbom et al 1992]. COMP is also found in tendon, ligament, and muscle. It is the fifth member of the thrombospondin protein family and is also known as thrombospondin 5 (TSP5). COMP is a modular, multifunctional structural protein. The type III repeats bind calcium cooperatively and the carboxyl-terminal globular domain interacts with both fibrillar (types I, II, and III) and non-fibrillar (type IX) collagens.

Abnormal gene product. Mutations in the exons encoding the type III repeats of COMP result in the misfolding of the mutant protein and its retention in the rough endoplasmic reticulum (rER) of chondrocytes. This protein retention results in ER stress that ultimately causes increased cell death in vitro [Chen et al 2000, Maddox et al 2000, Unger & Hecht 2001, Kleerekoper et al 2002]. Three transgenic mouse models of the common p.Asp473del (p.Asp469del) COMP mutation have been generated to study disease mechanisms in vivo [Schmitz et al 2008, Posey et al 2009, Suleman et al 2012]. Although there are some model-specific differences in the disease pathology and genetic pathways affected, all three models confirm that mutant COMP is retained in the ER of chondrocytes causing premature cell death. The retained protein in cartilage samples from patients can have a diagnostic lamellar appearance by transmission electron microscopy [Maynard et al 1972].

The effect of mutations in the exons encoding the C-terminal domain of COMP is not fully resolved, but these mutations are not thought to prevent the secretion of mutant COMP in vitro [Spitznagel et al 2004, Schmitz et al 2006]. Furthermore, they are believed to affect collagen fibrillogensis in cell culture models [Hansen et al 2011]. A mouse model of mild pseudoachondroplasia with the c.1754C>T (p.Thr585Met) mutation has also provided insight into disease mechanisms in vivo. Mutant COMP protein is efficiently secreted from the rER of chondrocytes and elicits a classic unfolded protein response (UPR). This ultimately results in decreased chondrocyte proliferation and increased and dysregulated apoptosis [Piróg-Garcia et al 2007]. Interestingly, mild myopathy has been characterized in this mouse model, originating from an underlying tendon and ligament pathology that is a direct result of structural abnormalities in the collagen fibril architecture [Piróg et al 2010].

References

Literature Cited

  1. 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]
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Chapter Notes

Author History

Michael D Briggs, PhD (2013-present)
Daniel H Cohn, PhD; University of California, Los Angeles (2004-2013)
Michael Wright, MB, ChB, MSc, FRCP (2013-present)

Revision History

  • 28 February 2013 (me) Comprehensive update posted live
  • 13 April 2010 (me) Comprehensive update posted live
  • 11 December 2006 (me) Comprehensive update posted to live Web site
  • 20 August 2004 (ca) Review posted to live Web site
  • 6 April 2004 (dc) Original submission
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