* 120260

COLLAGEN, TYPE IX, ALPHA-2; COL9A2


HGNC Approved Gene Symbol: COL9A2

Cytogenetic location: 1p34.2     Genomic coordinates (GRCh38): 1:40,300,489-40,317,286 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1p34.2 ?Stickler syndrome, type V 614284 AR 3
Epiphyseal dysplasia, multiple, 2 600204 AD 3

TEXT

Description

The COL9A2 gene encodes the alpha-2 subunit of collagen type IX. Type IX collagen, a heterotrimer of alpha-1 (COL9A1; 120210), alpha-2, and alpha-3 (COL9A3; 120270) chains specific for this type of collagen, is a cartilage-specific fibril-associated collagen (Perala et al., 1993).


Cloning and Expression

In the process of characterizing genomic clones for the mouse COL9A2 gene, Perala et al. (1993) also used 4 pairs of oligonucleotide primers designed for amplification of murine exon sequences to construct cDNA clones for the human gene spanning more than 90% of the coding region. The amino acid and nucleotide sequence identities between human and chick are 78 and 71%, respectively.


Mapping

Perala et al. (1993) assigned the human COL9A2 gene to chromosome 1 by study of a panel of DNAs from human/rodent somatic cell hybrids.

Warman et al. (1994) used fluorescence in situ hybridization to regionalize the COL9A2 gene to 1p33-p32.3. A single-strand conformation polymorphism within the murine gene was used to map Col9a2 to mouse chromosome 4. Since one form of multiple epiphyseal dysplasia (EDM2; 600204) maps to the same region of chromosome 1, COL9A2 was considered to be a candidate gene for that disorder.

Hellsten et al. (1995) demonstrated that the COL9A2 gene is in a 1-Mb contig, proximal to RLF (180610) and MYCL1 (164850).

Gross (2017) mapped the COL9A2 gene to chromosome 1p34.2 based on an alignment of the COL9A2 sequence (GenBank AF019406) with the genomic sequence (GRCh38).


Gene Function

The cartilage collagen fibrils are formed from fibrillar collagens II and XI (120280), while collagen IX is located on the fibril surface (see Figure 2 in Muragaki et al., 1996). The alpha-1(IX) chain contains a large N-terminal globular domain (NC4); a chondroitin sulfate chain is attached to the alpha-2(IX) chain (Muragaki et al., 1996).


Molecular Genetics

Multiple Epiphyseal Dysplasia 2

The usefulness of the candidate gene approach for identification of a basic gene defect was illustrated by the finding of a mutation in the COL9A2 gene (120260.0001) in a Dutch kindred with multiple epiphyseal dysplasia-2 (EDM2; 600204) showing linkage to DNA markers in the region of 1p32 (Muragaki et al., 1996). Muragaki et al. (1996) stated that the results provided by the EDM2 'experiment of nature' represent the first in vivo evidence for the role of collagen IX in human articular cartilage.

Holden et al. (1999) described 2 families with distinctive oligoepiphyseal forms of multiple epiphyseal dysplasia, in which heterozygosity for different mutations in the COL9A2 gene (120260.0002 and 120260.0003) was found. Both of these mutations resulted in the skipping of exon 3 from the COL9A2 mRNA, but the position of the mutation in the splice donor site determined the stability of the mRNA produced from the mutant allele.

Stickler Syndrome V

In a large 5-generation consanguineous pedigree of Asian Indian origin segregating autosomal recessive Stickler syndrome (STL5; 614284), Baker et al. (2011) analyzed 3 candidate collagen IX-related genes and identified homozygosity for an 8-bp deletion in the COL9A2 gene (120260.0006) that segregated with disease in the family.

Associations Pending Confirmation

For discussion of a possible association between intervertebral disc disease (IDD; 603932) and variation in the COL9A2 gene, see 120260.0004.


Animal Model

In a canine model of oculoskeletal dysplasia in Samoyed dogs, termed drd2 (dwarfism with retinal dysplasia type 2), Goldstein et al. (2010) identified a homozygous 1,267-bp deletion in the 5-prime end of the COL9A2 gene that segregated with the phenotype. The mutation affected the COL3 domain of the gene. Northern blot analysis showed reduced RNA expression of the COL9A2 gene in affected retinas. The drd2 phenotype is characterized by short-limb dwarfism and severe ocular defects, such as vitreous dysplasia, retinal detachment, and cataracts. Heterozygous carrier dogs may exhibit a milder ocular phenotype, such as vitreal strands or retinal dysplasia, but have a normal appendicular skeleton. Goldstein et al. (2010) noted that the drd2 phenotype resembles human hereditary arthroophthalmopathies such as Stickler syndrome, Kniest dysplasia (156550), and Marshall syndrome (154780).


ALLELIC VARIANTS ( 6 Selected Examples):

.0001 EPIPHYSEAL DYSPLASIA, MULTIPLE, 2

COL9A2, IVS3DS, T-C, +2
  
RCV000018680

Muragaki et al. (1996) demonstrated a mutation in affected members of a family with multiple epiphyseal dysplasia (EDM2; 600204) that showed linkage to the 1p32 region. Affected members were heterozygous for a splice site mutation causing exon skipping during RNA splicing and an in-frame loss of 12 amino acids within the alpha-2 (IX) collagen chain. The results provided the first in vivo evidence for the role of collagen IX in human articular cartilage. The clinical findings in the family were entirely characteristic of MED although hip complaints were less conspicuous than in many kindreds. The specific mutation was a T-to-C transition in the consensus donor splice site of intron 3, resulting in the skipping of exon 3.

Jackson et al. (2010) reported a large 4-generation family with autosomal dominant transmission of EDM2 associated with the T-to-C transition in intron 3 (186+2T-C) of the COL9A2 gene. The family had previously been reported by Versteylen et al. (1988). The proband was a 33-year-old woman with short stature who complained of stiff and painful hands and knees since age 4 years. Radiographs of the knees showed Blount disease (progressive varus deformity of the proximal tibia associated with internal torsion of the tibia) and of the spine showed mild spondyloarthrotic abnormalities in the thoracic region. Her sister had painful and swollen knees since age 4 years and developed severe osteochondritis dissecans as an adult. Two sons of the proband were also affected, showing pain in the knees during walking and clumsy walking. These boys also had frontal bossing, depressed nasal bridge, and were easily fatigued with mild muscle weakness. Radiographs of 1 son at age 3 years showed delayed ossification of the epiphyses, small proximal femoral epiphyses, and small femoral and tibial epiphyses around the knees. Skeletal muscle biopsy and mitochondrial studies showed no significant abnormalities, only mild variations in fiber size and slightly diminished ATP production. Jackson et al. (2010) commented on the mild myopathy present in the boys, and noted that EDM is characterized by clinical variability even within the same family. The mild myopathic and mitochondrial changes observed may be secondary to a tendonopathy and/or cell stress response resulting from expression of mutant collagen.


.0002 EPIPHYSEAL DYSPLASIA, MULTIPLE, 2

COL9A2, IVS3DS, 186G-A
  
RCV000489270...

In family K of Holden et al. (1999) with multiple epiphyseal dysplasia-2 (EDM2; 600204), the proband was a 17-year-old male of normal height who was diagnosed in childhood with pain in the joints, mostly the knees, and genu varum. Radiographs showed major epiphyseal changes in the knees and hands, and almost no changes in the hips. The spine also appeared normal. The molecular change was a G-to-A transition in the last nucleotide of exon 3, changing the last codon of exon 3 from CCG (pro) to CCA (also pro). Although there was no change in the amino acid, the change interfered with splicing.

Nakashima et al. (2005) identified the exon 3 G-to-A transition in the COL9A2 gene in affected members of a Japanese family with EDM2. The proband had bilateral double-layered patellae, indicating that this unusual feature is not unique to autosomal recessive multiple epiphyseal dysplasia with homozygous mutations in the DTDST gene (606718; see EDM4 226900).

Jackson et al. (2010) reported a patient with EDM2 characterized by onset at age 3 years of an abnormal gait associated with proximal muscle weakness. He had left-sided developmental dysplasia of the hip. The family history was positive for hypodontia and for osteochondritis dissecans. However, 2 affected adult family members showed improvement of the disorder after puberty. The proband was heterozygous for the 186G-A transition in the splice donor sequence of exon 3 of the COL9A2 gene.


.0003 EPIPHYSEAL DYSPLASIA, MULTIPLE, 2

COL9A2, IVS3DS, G-C, +5
  
RCV000018682

Family G reported by Holden et al. (1999) with an oligoepiphyseal form of multiple epiphyseal dysplasia (EDM2; 600204) and a mutation in the COL9A2 gene had affected members in 4 generations, of whom a mother and her 2 sons were available for study. They were slightly short in stature (adult height, 158 cm), and all 3 developed genu valgum, which required surgical correction. The mother started walking late and with a stiff gait that became more noticeable during ages 5 to 7 years. Her legs became increasingly bowed, and at age 17 she underwent tibial osteotomy. She had developed increasing problems with pain in her hands, lumbar spine, and ankles. Her 2 sons walked at age 2 years with a stiff gait. Epiphyseal dysplasia was recognized in them in early childhood, and they underwent tibial osteotomy for genu valgum at ages 14 and 13, respectively. They continued to have mild joint symptoms, including intermittent lumbar back pain and knee pain with swelling. Changes were not found clinically or radiographically in the hips. Affected members showed heterozygosity for a G-to-C transversion at position +5 of intron 3.


.0004 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

COL9A2, GLN326TRP
  
RCV000018683...

This variant, formerly titled INTERVERTEBRAL DISC DISEASE, SUSCEPTIBILITY TO, has been reclassified because its contribution to the disorder has not been confirmed.

In a study that examined for allelic variation in the COL9A2 gene in Finnish individuals with sciatica and radiologically documented intervertebral disc disease (IDD; 603932), Annunen et al. (1999) found a substitution of tryptophan for glutamine at codon 326. This change was found in 6 of 157 individuals with disc disease but in none of 174 controls. Further analysis of the families of 4 of the original patients revealed that all individuals heterozygous for the trp substitution demonstrated the disease phenotype. Many individuals within these families had IDD but not the trp allele. The authors invoked a high phenocopy rate to reconcile this observation with the conclusion that this sequence variant within COL9A2 contributes to the pathogenesis of disease. In the disease model chosen, this locus accounted for 10% of disease prevalence. Under these constraints, Annunen et al. (1999) demonstrated a lod score of 4.5 at a recombination fraction of 0.12. Subsequent linkage disequilibrium analysis conditional on linkage gave an additional lod score of 7.1. The authors did not exclude the possibility that a true disease locus may lie in close physical proximity to COL9A2.


.0005 EPIPHYSEAL DYSPLASIA, MULTIPLE, 2

COL9A2, IVS3DS, G-C, -1
  
RCV000018684...

In 12 affected members from a 4-generation family with a relatively hip-sparing multiple epiphyseal dysplasia phenotype (EDM2; 600204), Fiedler et al. (2002) identified a G-to-C mutation in the last nucleotide of exon 3 of the COL9A2 gene. The disorder was characterized by childhood onset of pain and stiffness in the knees. Finger joints, ankles, and elbows became symptomatic during early adult life. Some adult patients had free articular bodies which resulted in locking of the joints. Fiedler et al. (2002) noted that a G-to-A change at the same nucleotide had earlier been found to cause EDM2 (120260.0002).


.0006 STICKLER SYNDROME V (1 family)

COL9A2, 8-BP DEL, NT843
  
RCV000022493

In an affected sister and brother from a large 5-generation consanguineous pedigree of Asian Indian origin segregating autosomal recessive Stickler syndrome (STL5; 614284), Baker et al. (2011) identified homozygosity for an 8-bp deletion in the COL9A2 gene involving the last 4 nucleotides of exon 16 and the first 4 nucleotides of IVS16 (843_846+4del8). The deletion was predicted to cause a frameshift and downstream premature termination codon (Asp281GlnfsTer70). The mutation was detected in heterozygosity in the sibs' unaffected brother and parents.


REFERENCES

  1. Annunen, S., Paassilta, P. Lohiniva, J., Perala, M., Pihlajamaa, T., Karppinen, J., Tervonen, O., Kroger, H., Lahde, S., Vanharanta, H., Ryhanen, L., Goring, H. H. H., Ott, J., Prockop, D. J., Ala-Kokko, L. An allele of COL9A2 associated with intervertebral disc disease. Science 285: 409-412, 1999. [PubMed: 10411504, related citations] [Full Text]

  2. Baker, S., Booth, C., Fillman, C., Shapiro, M., Blair, M. P., Hyland, J. C., Ala-Kokko, L. A loss of function mutation in the COL9A2 gene cause autosomal recessive Stickler syndrome. Am. J. Med. Genet. 155A: 1668-1672, 2011. [PubMed: 21671392, related citations] [Full Text]

  3. Fiedler, J., Stove, J., Heber, F., Brenner, R. E. Clinical phenotype and molecular diagnosis of multiple epiphyseal dysplasia with relative hip sparing during childhood (EDM2). Am. J. Med. Genet. 112: 144-153, 2002. [PubMed: 12244547, related citations] [Full Text]

  4. Goldstein, O., Guyon, R., Kukekova, A., Kuznetsova, T. N., Pearce-Kelling, S. E., Johnson, J., Aguirre, G. D., Acland, G. M. COL9A2 and COL9A3 mutations in canine autosomal recessive oculoskeletal dysplasia. Mammalian Genome 21: 398-408, 2010. [PubMed: 20686772, images, related citations] [Full Text]

  5. Gross, M. B. Personal Communication. Baltimore, Md. 7/13/2017.

  6. Hellsten, E., Vesa, J., Heiskanen, M., Makela, T. P., Jarvela, I., Cowell, J. K., Mead, S., Alitalo, K., Palotie, A., Peltonen, L. Identification of YAC clones for human chromosome 1p32 and physical mapping of the infantile neuronal ceroid lipofuscinosis (INCL) locus. Genomics 25: 404-412, 1995. [PubMed: 7789974, related citations] [Full Text]

  7. Holden, P., Canty, E. G., Mortier, G. R., Zabel, B., Spranger, J., Carr, A., Grant, M. E., Loughlin, J. A., Briggs, M. D. Identification of novel pro-alpha-2(IX) collagen gene mutations in two families with distinctive oligo-epiphyseal forms of multiple epiphyseal dysplasia. Am. J. Hum. Genet. 65: 31-38, 1999. [PubMed: 10364514, related citations] [Full Text]

  8. Jackson, G. C., Marcus-Soekarman, D., Stolte-Dijkstra, I., Verrips, A., Taylor, J. A., Briggs, M. D. Type IX collagen gene mutations can result in multiple epiphyseal dysplasia that is associated with osteochondritis dissecans and a mild myopathy. Am. J. Med. Genet. 152A: 863-869, 2010. [PubMed: 20358595, images, related citations] [Full Text]

  9. Muragaki, Y., Mariman, E. C. M., van Beersum, S. E. C., Perala, M., van Mourik, J. B. A., Warman, M. L., Olsen, B. R., Hamel, B. C. J. A mutation in the gene encoding the alpha-2 chain of the fibril-associated collagen IX, COL9A2, causes multiple epiphyseal dysplasia (EDM2). Nature Genet. 12: 103-105, 1996. [PubMed: 8528240, related citations] [Full Text]

  10. Nakashima, E., Ikegawa, S., Ohashi, H., Kimizuka, M., Nishimura, G. Double-layered patella in multiple epiphyseal dysplasia is not exclusive to DTDST mutation. (Letter) Am. J. Med. Genet. 133A: 106-107, 2005. [PubMed: 15633184, related citations] [Full Text]

  11. Perala, M., Hanninen, M., Hastbacka, J., Elima, K., Vuorio, E. Molecular cloning of the human alpha-2(IX) collagen cDNA and assignment of the human COL9A2 gene to chromosome 1. FEBS Lett. 319: 177-180, 1993. [PubMed: 8454052, related citations] [Full Text]

  12. Versteylen, R. J., Zwemmer, A., Lorie, C. A. M., Schuur, K. H. Multiple epiphyseal dysplasia complicated by severe osteochondritis dissecans of the knee: incidence in two families. Skeletal Radiol. 17: 407-412, 1988. [PubMed: 3238439, related citations] [Full Text]

  13. Warman, M. L., McCarthy, M. T., Perala, M., Vuorio, E., Knoll, J. H. M., McDaniels, C. N., Mayne, R., Beier, D. R., Olsen, B. R. The genes encoding alpha-2(IX) collagen (COL9A2) map to human chromosome 1p32.3-p33 and mouse chromosome 4. Genomics 23: 158-162, 1994. [PubMed: 7829066, related citations] [Full Text]


Matthew B. Gross - updated : 07/13/2017
Ingrid M. Wentzensen - updated : 12/5/2014
Marla J. F. O'Neill - updated : 10/7/2011
Cassandra L. Kniffin - updated : 10/12/2005
Deborah L. Stone - updated : 11/11/2003
Harry C. Dietz - updated : 7/16/1999
Victor A. McKusick - updated : 6/28/1999
Creation Date:
Victor A. McKusick : 6/26/1987
carol : 12/06/2017
mgross : 07/13/2017
carol : 11/17/2016
carol : 01/05/2015
carol : 12/5/2014
alopez : 10/7/2011
terry : 10/7/2011
terry : 11/24/2010
wwang : 11/15/2010
ckniffin : 11/9/2010
wwang : 10/26/2005
wwang : 10/24/2005
ckniffin : 10/12/2005
tkritzer : 11/14/2003
tkritzer : 11/11/2003
tkritzer : 11/3/2003
carol : 6/17/2003
terry : 4/16/2002
alopez : 11/23/1999
carol : 11/4/1999
alopez : 7/16/1999
terry : 7/16/1999
carol : 7/9/1999
jlewis : 7/7/1999
terry : 6/28/1999
dkim : 12/9/1998
terry : 5/29/1998
mark : 1/8/1996
terry : 1/4/1996
terry : 3/7/1995
carol : 1/11/1995
supermim : 3/16/1992
supermim : 3/20/1990
ddp : 10/26/1989
marie : 3/25/1988

* 120260

COLLAGEN, TYPE IX, ALPHA-2; COL9A2


HGNC Approved Gene Symbol: COL9A2

Cytogenetic location: 1p34.2     Genomic coordinates (GRCh38): 1:40,300,489-40,317,286 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1p34.2 ?Stickler syndrome, type V 614284 Autosomal recessive 3
Epiphyseal dysplasia, multiple, 2 600204 Autosomal dominant 3

TEXT

Description

The COL9A2 gene encodes the alpha-2 subunit of collagen type IX. Type IX collagen, a heterotrimer of alpha-1 (COL9A1; 120210), alpha-2, and alpha-3 (COL9A3; 120270) chains specific for this type of collagen, is a cartilage-specific fibril-associated collagen (Perala et al., 1993).


Cloning and Expression

In the process of characterizing genomic clones for the mouse COL9A2 gene, Perala et al. (1993) also used 4 pairs of oligonucleotide primers designed for amplification of murine exon sequences to construct cDNA clones for the human gene spanning more than 90% of the coding region. The amino acid and nucleotide sequence identities between human and chick are 78 and 71%, respectively.


Mapping

Perala et al. (1993) assigned the human COL9A2 gene to chromosome 1 by study of a panel of DNAs from human/rodent somatic cell hybrids.

Warman et al. (1994) used fluorescence in situ hybridization to regionalize the COL9A2 gene to 1p33-p32.3. A single-strand conformation polymorphism within the murine gene was used to map Col9a2 to mouse chromosome 4. Since one form of multiple epiphyseal dysplasia (EDM2; 600204) maps to the same region of chromosome 1, COL9A2 was considered to be a candidate gene for that disorder.

Hellsten et al. (1995) demonstrated that the COL9A2 gene is in a 1-Mb contig, proximal to RLF (180610) and MYCL1 (164850).

Gross (2017) mapped the COL9A2 gene to chromosome 1p34.2 based on an alignment of the COL9A2 sequence (GenBank AF019406) with the genomic sequence (GRCh38).


Gene Function

The cartilage collagen fibrils are formed from fibrillar collagens II and XI (120280), while collagen IX is located on the fibril surface (see Figure 2 in Muragaki et al., 1996). The alpha-1(IX) chain contains a large N-terminal globular domain (NC4); a chondroitin sulfate chain is attached to the alpha-2(IX) chain (Muragaki et al., 1996).


Molecular Genetics

Multiple Epiphyseal Dysplasia 2

The usefulness of the candidate gene approach for identification of a basic gene defect was illustrated by the finding of a mutation in the COL9A2 gene (120260.0001) in a Dutch kindred with multiple epiphyseal dysplasia-2 (EDM2; 600204) showing linkage to DNA markers in the region of 1p32 (Muragaki et al., 1996). Muragaki et al. (1996) stated that the results provided by the EDM2 'experiment of nature' represent the first in vivo evidence for the role of collagen IX in human articular cartilage.

Holden et al. (1999) described 2 families with distinctive oligoepiphyseal forms of multiple epiphyseal dysplasia, in which heterozygosity for different mutations in the COL9A2 gene (120260.0002 and 120260.0003) was found. Both of these mutations resulted in the skipping of exon 3 from the COL9A2 mRNA, but the position of the mutation in the splice donor site determined the stability of the mRNA produced from the mutant allele.

Stickler Syndrome V

In a large 5-generation consanguineous pedigree of Asian Indian origin segregating autosomal recessive Stickler syndrome (STL5; 614284), Baker et al. (2011) analyzed 3 candidate collagen IX-related genes and identified homozygosity for an 8-bp deletion in the COL9A2 gene (120260.0006) that segregated with disease in the family.

Associations Pending Confirmation

For discussion of a possible association between intervertebral disc disease (IDD; 603932) and variation in the COL9A2 gene, see 120260.0004.


Animal Model

In a canine model of oculoskeletal dysplasia in Samoyed dogs, termed drd2 (dwarfism with retinal dysplasia type 2), Goldstein et al. (2010) identified a homozygous 1,267-bp deletion in the 5-prime end of the COL9A2 gene that segregated with the phenotype. The mutation affected the COL3 domain of the gene. Northern blot analysis showed reduced RNA expression of the COL9A2 gene in affected retinas. The drd2 phenotype is characterized by short-limb dwarfism and severe ocular defects, such as vitreous dysplasia, retinal detachment, and cataracts. Heterozygous carrier dogs may exhibit a milder ocular phenotype, such as vitreal strands or retinal dysplasia, but have a normal appendicular skeleton. Goldstein et al. (2010) noted that the drd2 phenotype resembles human hereditary arthroophthalmopathies such as Stickler syndrome, Kniest dysplasia (156550), and Marshall syndrome (154780).


ALLELIC VARIANTS 6 Selected Examples):

.0001   EPIPHYSEAL DYSPLASIA, MULTIPLE, 2

COL9A2, IVS3DS, T-C, +2
SNP: rs1569763139, ClinVar: RCV000018680

Muragaki et al. (1996) demonstrated a mutation in affected members of a family with multiple epiphyseal dysplasia (EDM2; 600204) that showed linkage to the 1p32 region. Affected members were heterozygous for a splice site mutation causing exon skipping during RNA splicing and an in-frame loss of 12 amino acids within the alpha-2 (IX) collagen chain. The results provided the first in vivo evidence for the role of collagen IX in human articular cartilage. The clinical findings in the family were entirely characteristic of MED although hip complaints were less conspicuous than in many kindreds. The specific mutation was a T-to-C transition in the consensus donor splice site of intron 3, resulting in the skipping of exon 3.

Jackson et al. (2010) reported a large 4-generation family with autosomal dominant transmission of EDM2 associated with the T-to-C transition in intron 3 (186+2T-C) of the COL9A2 gene. The family had previously been reported by Versteylen et al. (1988). The proband was a 33-year-old woman with short stature who complained of stiff and painful hands and knees since age 4 years. Radiographs of the knees showed Blount disease (progressive varus deformity of the proximal tibia associated with internal torsion of the tibia) and of the spine showed mild spondyloarthrotic abnormalities in the thoracic region. Her sister had painful and swollen knees since age 4 years and developed severe osteochondritis dissecans as an adult. Two sons of the proband were also affected, showing pain in the knees during walking and clumsy walking. These boys also had frontal bossing, depressed nasal bridge, and were easily fatigued with mild muscle weakness. Radiographs of 1 son at age 3 years showed delayed ossification of the epiphyses, small proximal femoral epiphyses, and small femoral and tibial epiphyses around the knees. Skeletal muscle biopsy and mitochondrial studies showed no significant abnormalities, only mild variations in fiber size and slightly diminished ATP production. Jackson et al. (2010) commented on the mild myopathy present in the boys, and noted that EDM is characterized by clinical variability even within the same family. The mild myopathic and mitochondrial changes observed may be secondary to a tendonopathy and/or cell stress response resulting from expression of mutant collagen.


.0002   EPIPHYSEAL DYSPLASIA, MULTIPLE, 2

COL9A2, IVS3DS, 186G-A
SNP: rs1085307973, gnomAD: rs1085307973, ClinVar: RCV000489270, RCV001807641

In family K of Holden et al. (1999) with multiple epiphyseal dysplasia-2 (EDM2; 600204), the proband was a 17-year-old male of normal height who was diagnosed in childhood with pain in the joints, mostly the knees, and genu varum. Radiographs showed major epiphyseal changes in the knees and hands, and almost no changes in the hips. The spine also appeared normal. The molecular change was a G-to-A transition in the last nucleotide of exon 3, changing the last codon of exon 3 from CCG (pro) to CCA (also pro). Although there was no change in the amino acid, the change interfered with splicing.

Nakashima et al. (2005) identified the exon 3 G-to-A transition in the COL9A2 gene in affected members of a Japanese family with EDM2. The proband had bilateral double-layered patellae, indicating that this unusual feature is not unique to autosomal recessive multiple epiphyseal dysplasia with homozygous mutations in the DTDST gene (606718; see EDM4 226900).

Jackson et al. (2010) reported a patient with EDM2 characterized by onset at age 3 years of an abnormal gait associated with proximal muscle weakness. He had left-sided developmental dysplasia of the hip. The family history was positive for hypodontia and for osteochondritis dissecans. However, 2 affected adult family members showed improvement of the disorder after puberty. The proband was heterozygous for the 186G-A transition in the splice donor sequence of exon 3 of the COL9A2 gene.


.0003   EPIPHYSEAL DYSPLASIA, MULTIPLE, 2

COL9A2, IVS3DS, G-C, +5
SNP: rs1569763108, ClinVar: RCV000018682

Family G reported by Holden et al. (1999) with an oligoepiphyseal form of multiple epiphyseal dysplasia (EDM2; 600204) and a mutation in the COL9A2 gene had affected members in 4 generations, of whom a mother and her 2 sons were available for study. They were slightly short in stature (adult height, 158 cm), and all 3 developed genu valgum, which required surgical correction. The mother started walking late and with a stiff gait that became more noticeable during ages 5 to 7 years. Her legs became increasingly bowed, and at age 17 she underwent tibial osteotomy. She had developed increasing problems with pain in her hands, lumbar spine, and ankles. Her 2 sons walked at age 2 years with a stiff gait. Epiphyseal dysplasia was recognized in them in early childhood, and they underwent tibial osteotomy for genu valgum at ages 14 and 13, respectively. They continued to have mild joint symptoms, including intermittent lumbar back pain and knee pain with swelling. Changes were not found clinically or radiographically in the hips. Affected members showed heterozygosity for a G-to-C transversion at position +5 of intron 3.


.0004   RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

COL9A2, GLN326TRP
SNP: rs137853213, ClinVar: RCV000018683, RCV000710925

This variant, formerly titled INTERVERTEBRAL DISC DISEASE, SUSCEPTIBILITY TO, has been reclassified because its contribution to the disorder has not been confirmed.

In a study that examined for allelic variation in the COL9A2 gene in Finnish individuals with sciatica and radiologically documented intervertebral disc disease (IDD; 603932), Annunen et al. (1999) found a substitution of tryptophan for glutamine at codon 326. This change was found in 6 of 157 individuals with disc disease but in none of 174 controls. Further analysis of the families of 4 of the original patients revealed that all individuals heterozygous for the trp substitution demonstrated the disease phenotype. Many individuals within these families had IDD but not the trp allele. The authors invoked a high phenocopy rate to reconcile this observation with the conclusion that this sequence variant within COL9A2 contributes to the pathogenesis of disease. In the disease model chosen, this locus accounted for 10% of disease prevalence. Under these constraints, Annunen et al. (1999) demonstrated a lod score of 4.5 at a recombination fraction of 0.12. Subsequent linkage disequilibrium analysis conditional on linkage gave an additional lod score of 7.1. The authors did not exclude the possibility that a true disease locus may lie in close physical proximity to COL9A2.


.0005   EPIPHYSEAL DYSPLASIA, MULTIPLE, 2

COL9A2, IVS3DS, G-C, -1
SNP: rs1085307973, gnomAD: rs1085307973, ClinVar: RCV000018684, RCV001851921

In 12 affected members from a 4-generation family with a relatively hip-sparing multiple epiphyseal dysplasia phenotype (EDM2; 600204), Fiedler et al. (2002) identified a G-to-C mutation in the last nucleotide of exon 3 of the COL9A2 gene. The disorder was characterized by childhood onset of pain and stiffness in the knees. Finger joints, ankles, and elbows became symptomatic during early adult life. Some adult patients had free articular bodies which resulted in locking of the joints. Fiedler et al. (2002) noted that a G-to-A change at the same nucleotide had earlier been found to cause EDM2 (120260.0002).


.0006   STICKLER SYNDROME V (1 family)

COL9A2, 8-BP DEL, NT843
SNP: rs606231376, ClinVar: RCV000022493

In an affected sister and brother from a large 5-generation consanguineous pedigree of Asian Indian origin segregating autosomal recessive Stickler syndrome (STL5; 614284), Baker et al. (2011) identified homozygosity for an 8-bp deletion in the COL9A2 gene involving the last 4 nucleotides of exon 16 and the first 4 nucleotides of IVS16 (843_846+4del8). The deletion was predicted to cause a frameshift and downstream premature termination codon (Asp281GlnfsTer70). The mutation was detected in heterozygosity in the sibs' unaffected brother and parents.


REFERENCES

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Contributors:
Matthew B. Gross - updated : 07/13/2017
Ingrid M. Wentzensen - updated : 12/5/2014
Marla J. F. O'Neill - updated : 10/7/2011
Cassandra L. Kniffin - updated : 10/12/2005
Deborah L. Stone - updated : 11/11/2003
Harry C. Dietz - updated : 7/16/1999
Victor A. McKusick - updated : 6/28/1999

Creation Date:
Victor A. McKusick : 6/26/1987

Edit History:
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carol : 1/11/1995
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