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Pseudoachondroplasia

Synonym: PSACH

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

Author Information

Initial Posting: ; Last Update: July 16, 2015.

Summary

Clinical 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, the growth rate falls below the standard growth curve by approximately age two years, 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; 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. Identification of a heterozygous pathogenic variant in COMP on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Analgesics for joint pain; osteotomy for lower-limb malalignment; C1-C2 fixation for symptoms and radiographic evidence of cervical spine instability; rarely, surgery for scoliosis; 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 symptomatic lower limb malalignment, kyphoscoliosis, symptomatic joint hypermobility, degenerative joint disease, and neurologic manifestations, particularly spinal cord compression secondary to odontoid hypoplasia.

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 pathogenic variant is unknown. Each child of an individual with pseudoachondroplasia and a reproductive partner with normal bone growth has a 50% chance of inheriting the pathogenic variant 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 pathogenic variant in the family is known.

Diagnosis

Suggestive Findings

Pseudoachondroplasia should be suspected in individuals with the following clinical findings and radiographic features.

Clinical findings

  • Normal length at birth
  • Normal facies
  • Waddling gait, recognized at the onset of walking
  • 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 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 features

  • 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).
Figure 1.

Figure 1.

Radiographs of a prepubertal child showing the changes typical of pseudoachondroplasia

Establishing the Diagnosis

The diagnosis of pseudoachondroplasia is established in a proband with the above clinical and radiographic features. The diagnosis is ideally confirmed 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). Identification of a heterozygous COMP pathogenic variant on molecular genetic testing (Table 1) establishes the diagnosis if clinical features are inconclusive.

Single-gene testing. Sequence analysis of COMP is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.

Table 1.

Molecular Genetic Testing Used in Pseudoachondroplasia

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
COMPSequence analysis 3>99% 4
Gene-targeted deletion/duplication analysis 5Very rare 6
Targeted analysis for pathogenic variants~30% 7
Unknown 8NASee footnote 9
1.
2.

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

3.

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.

4.
5.

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.

6.
7.

The pathogenic variant p.Asp473del (commonly referred to as p.Asp469del) is found in 30% of individuals with pseudoachondroplasia [Hecht et al 1995, Briggs et al 1998, Briggs & Chapman 2002, Mabuchi et al 2003].

8.
9.

No proven cases of classic PSACH are reported, but a recessive variant of PSACH not caused by pathogenic variants in COMP may exist.

Clinical Characteristics

Clinical Description

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].

Growth. Affected individuals are generally of normal length at birth. 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].

Facies. Head size and shape are normal, without dysmorphic features.

Gait. Often the presenting feature is a waddling gait, recognized at the onset of walking.

Extremities. Pseudoachondroplasia is a short-limb form of dwarfism. 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 generally necessary.

Genotype-Phenotype Correlations

A systematic analysis of the relationship between genotype and phenotype has recently been performed on 300 reported COMP pathogenic variants resulting in PSACH and/or MED [Briggs et al 2014]. The following are correlations from this study. (For repeat and domain structure, see Molecular Genetics, Normal gene product.)

  • Pathogenic missense variants of nucleotides encoding either the N- or C-type motifs within each of the type III calcium-binding domains showed no significant association with either MED or PSACH phenotype.
  • Pathogenic missense variants in nucleotides encoding the fourth and fifth (of 8 total) type III calcium-binding repeats (i.e. T34 and T35) showed significant association with the MED compared to the PSACH phenotype.
  • Pathogenic missense variants in nucleotides encoding the sixth through eighth type III calcium-binding repeats (i.e. T36, T37, and T38) were significantly associated with the PSACH phenotype.
  • The majority of pathogenic in-frame deletions, insertions, or indels lead to PSACH (n=74; 82%), whereas a smaller proportion cause MED (n=16; 18%); however, in several instances, the same pathogenic variant was reported to cause both PSACH and MED [Briggs et al 2014].

Correlations from prior studies:

Penetrance

Penetrance is 100%.

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.

Pseudoachondroplasia was referred to as pseudoachondroplastic dysplasia in the old literature.

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 but is less consistent than in pseudoachondroplasia (PSACH). Adult height is either in the lower range of normal or mildly shortened but in general greater than in PSACH. 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. Arthritis typically develops at an older age and is less severe than in PSACH. 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.

    A pathogenic variant in one of five genes causes autosomal dominant MED: COMP, COL9A1, COL9A2, COL9A3, and MATN3. However, in approximately 10%-20% of all samples analyzed from clinically confirmed cases, a pathogenic variant cannot be identified in any of the five genes above [Zankl et al 2007, Jackson et al 2012].

    Jackson et al [2012] reported pathogenic missense variants in COL2A1 in two individuals with suspected MED for whom there were limited clinical data and radiographic images on which to base an unambiguous diagnosis [Jackson et al 2012]. Both pathogenic variants were in exon 50 and resulted in a glycine substitution (Gly1179Arg and Gly1176Val). A recurrent missense variant (Gly1170Ser) in this exon has also been consistently associated with dominant Legg-Calvé-Perthes disease (LCPD), however the relationship between MED and LCPD remains to be determined.
  • 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 (e.g., clubfoot, clinodactyly, or rarely, cystic ear swelling) not seen in PSACH. Onset of articular pain is variable but usually occurs in late childhood – typically later in onset and of lower severity than in PSACH. 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 or absent. EDM4 is diagnosed on clinical and radiographic findings. SLC26A2 (DTDST) is the only gene in which pathogenic variants are known to cause EDM4. 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 pathogenic variant. 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).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with pseudoachondroplasia, the following evaluations are recommended:

  • Measurement of height and plotting growth on a disorder-specific growth chart
  • Evaluation by history and physical examination for skeletal manifestations, ligamentous laxity, and 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 potentially serious clinical complications associated with cervical spine instability [Shetty et al 2007], which can be assessed by flexion/extension radiographs or MRI, especially in persons with neurologic symptoms suggestive of cord compression.
  • 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.

Surgical treatment of scoliosis is rarely needed 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:

  • Symptomatic lower limb malalignment
  • Evidence of kyphoscoliosis
  • Symptoms related to joint hypermobility
  • Evidence of degenerative joint disease manifesting as joint pain or by radiographs
  • 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

Sibs of a proband

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 COMP pathogenic variant 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 pathogenic variant. When neither parent of a proband with pseudoachondroplasia has clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the COMP pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

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 COMP pathogenic variant 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: ContactUs@magicfoundation.org
  • Medline Plus
  • 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.

Pseudoachondroplasia: Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD
COMP19p13​.11Cartilage oligomeric matrix proteinCOMP databaseCOMP

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 Pseudoachondroplasia (View All in OMIM)

177170PSEUDOACHONDROPLASIA; PSACH
600310CARTILAGE OLIGOMERIC MATRIX PROTEIN; COMP

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

Benign allelic variants. A frequent single-nucleotide benign variant predicts a p.Asn386Asp substitution.

Pathogenic allelic variants. All individuals with pseudoachondroplasia (PSACH) appear to have COMP pathogenic variants [Jackson et al 2012]. Furthermore, all of the pathogenic variants 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). Pathogenic variants in the exons encoding the carboxyl-terminal globular domain have mostly been found in the remaining affected individuals (~15%; exons 14-19). Two variants in exons 7 and 8 encoding a type II repeat have been identified, but their pathogenesis has not been fully resolved [Jackson et al 2012, Briggs et al 2014].

Approximately 30% of individuals have the same pathogenic variant: deletion of a single aspartic acid codon (p.Asp469del) 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 of the protein. Most of the remaining individuals have a diverse range of single amino-acid substitution variants, small in-frame deletions, duplications, or indels. Interestingly, unlike the pathogenic variants in nucleotides of the type III repeats, pathogenic variants within the carboxyl terminal domain (exons 14-19) appear to cluster in three distinct regions and affect only a limited number of residues. These variant 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].

Recent evidence suggests that pathogenic variants in exons 7 and 8 encoding the type II repeats may be an uncommon cause of PSACH [Jackson et al 2012, Briggs et al 2014].

A single in-frame exon deletion and a single pathogenic variant 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

Variant ClassificationDNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
Benignc.1156A>Gp.Asn386AspNM_000095​.2
NP_000086​.2
Pathogenicc.1417_1419delGACp.Asp473del 2
(Asp469del)
c.1417_1419dupGACp.Asp473dup 2
(Asp469dup)
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 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 (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

Commonly referred to in the literature as p.Asp469del and p.Asp469dup, respectively.

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 consecutive type III (calmodulin-like calcium binding) repeats, and a carboxyl-terminal globular domain. The type III motifs typically are composed of both an N- and a C-type motif, although the third and fifth type III repeats lack the N-type motif. Domain structure of COMP is summarized by Briggs et al [2014]. COMP 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. Pathogenic variants 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, Coustry et al 2012]. 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 pathogenic variants in the exons encoding the C-terminal globular domain of COMP is not fully resolved, but these pathogenic variants 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 fibrillogenesis in cell culture models [Hansen et al 2011].

Three transgenic mouse models of the human COMP variant p.Asp469del (Table 2) were generated to study disease mechanisms in vivo [Schmitz et al 2008, Posey et al 2009, Posey et al 2012, 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 p.Asp469del COMP is retained in the ER of chondrocytes, causing premature cell death in the growth plate [Briggs et al 2015].

An orthologous mouse model of mild pseudoachondroplasia (p.Thr585Met) has also provided insight into disease mechanisms in vivo. This mutant COMP protein is efficiently secreted from the rER of chondrocytes and elicits a classic unfolded protein response. This ultimately results in decreased chondrocyte proliferation and increased and dysregulated apoptosis [Piróg-Garcia et al 2007].

Analysis of the cartilage proteome from two mouse models of PSACH (orthologous to human p.Thr585Met and p.Asp469del) show common and discrete disease signatures [Bell et al 2013]. Most notably there are genotype-specific changes in the extractability of a range of cartilage proteins, confirming that mutant COMP protein exerts a dominant-negative effect on cartilage structure and function and that this is likely to contribute to PSACH pathology and early onset osteoarthritis [Bell et al 2013, Briggs et al 2015].

A mild myopathy has been characterized in two mutant COMP mouse models (orthologous to the human p.Thr585Met and p.Asp469del), 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, Piróg et al 2013].

References

Literature Cited

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Suggested Reading

  • Coustry F, Posey KL, Liu P, Alcorn JL, Hecht JT. D469del-COMP retention in chondrocytes stimulates caspase-independent necroptosis. Am J Pathol. 2012;180:738–48. [PMC free article: PMC3349870] [PubMed: 22154936]
  • Piróg KA, Irman A, Young S, Halai P, Bell PA, Boot-Handford RP, Briggs MD. Abnormal chondrocyte apoptosis in the cartilage growth plate is influenced by genetic background and deletion of CHOP in a targeted mouse model of pseudoachondroplasia. PLoS One. 2014;9:e85145. [PMC free article: PMC3928032] [PubMed: 24558358]
  • Piróg KA, Katakura Y, Mironov A, Briggs MD. Mild myopathy is associated with COMP but not MATN3 mutations in mouse models of genetic skeletal diseases. PLoS One. 2013;8:e82412. [PMC free article: PMC3842254] [PubMed: 24312420]
  • Posey KL, Coustry F, Veerisetty AC, Liu P, Alcorn JL, Hecht JT. Chop (Ddit3) is essential for D469del-COMP retention and cell death in chondrocytes in an inducible transgenic mouse model of pseudoachondroplasia. Am J Pathol. 2012;180:727–37. [PMC free article: PMC3349877] [PubMed: 22154935]

Chapter Notes

Author History

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

Revision History

  • 16 July 2015 (me) Comprehensive update posted live
  • 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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