HGNC Approved Gene Symbol: COL9A3
Cytogenetic location: 20q13.33 Genomic coordinates (GRCh38) : 20:62,816,213-62,841,159 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.33 | {Intervertebral disc disease, susceptibility to} | 603932 | 3 | |
| Epiphyseal dysplasia, multiple, 3, with or without myopathy | 600969 | Autosomal dominant | 3 | |
| Stickler syndrome, type VI | 620022 | Autosomal recessive | 3 |
Brewton et al. (1995) identified cDNA and genomic clones that encode the entire alpha-3 chain of type IX collagen. Also see COL9A1 (120210).
By genomic amplification, Brewton et al. (1995) identified a SSCP that was used to map COL9A3 to 20q13.3 by linkage analysis. By fluorescence in situ hybridization, radiation hybrid mapping, and multipoint linkage analysis, Tiller et al. (1998) localized the COL9A3 gene to 20q13.3, 13 cM telomeric to D20S173.
Multiple Epiphyseal Dysplasia 3
Paassilta et al. (1999) identified a splice site mutation (120270.0001) in the COL9A3 gene in a family with multiple epiphyseal dysplasia (EDM3; 600969). Bonnemann et al. (2000) found a COL9A3 splice site mutation (120270.0002) in a family with multiple epiphyseal dysplasia and myopathy.
In a 3-generation Japanese family with EDM3, Nakashima et al. (2005) identified a heterozygous splice site mutation in the COL9A3 gene (120270.0004). Affected members had knee pain ('occasional' in females) but were of normal height and had no signs or symptoms of muscle weakness. Nakashima et al. (2005) commented that these cases were milder than those reported by Paassilta et al. (1999).
Stickler Syndrome, Type VI
In 3 Moroccan sibs with hearing loss, visual defects, and skeletal abnormalities (STL6; 620022), Faletra et al. (2014) identified homozygosity for a 23-bp deletion in the COL9A3 gene (120270.0005). Their unaffected first-cousin parents were heterozygous for the deletion, which was not found in 100 matched healthy controls or in public variant databases.
In a 12-year-old Indian boy with hearing loss, myopia, and epiphyseal abnormalities, Hanson-Kahn et al. (2018) identified homozygosity for a 1-bp duplication in the COL9A3 gene (120270.0006). The mutation segregated with disease in the family and was not found in public SNP variant databases.
In 2 sibs with hearing loss, myopia, and hypoplastic vitreous, 1 of whom also exhibited severe arthropathy, Nixon et al. (2019) identified homozygosity for a nonsense mutation in the COL9A3 gene (R471X; 120270.0007). Their parents, who were heterozygous for the mutation, exhibited some features of Stickler syndrome, including arthritis and myopia in the mother, and arthritis and sensorineural hearing loss in the father. However, because these symptoms are not very specific and occur in the general population with considerable frequency, the authors concluded that there was no solid evidence for carrier manifestation of heterozygous COL9 null alleles.
In a 3-year-old Russian boy with severe sensorineural hearing loss, high myopia, vitreoretinal degeneration, and early-onset arthropathy of the lower limbs, Markova et al. (2021) performed targeted sequencing in 166 genes associated with congenital skeletal disorders and identified compound heterozygosity for 2 nonsense mutations in the COL9A3 gene, R90X (120270.0008) and R577X (120270.0009). Sanger sequencing confirmed familial segregation.
By exome sequencing in 5 patients from 3 unrelated consanguineous Iranian families with high myopia, progressive moderate to profound sensorineural hearing loss, and variable skeletal changes, Rad et al. (2022) identified homozygosity for truncating mutations in the COL9A3 gene: a 10-bp deletion (120270.0010), a nonsense mutation (R402X; 120270.0011), and a 1-bp deletion (120270.0012). The authors reviewed previously reported cases of biallelic COL9A3 loss-of-function variants and noted that high myopia and moderate to severe hearing loss appeared to be consistent features among all cases, whereas skeletal findings were more variable.
Associations Pending Confirmation
For discussion of a possible association between susceptibility to intervertebral disc disease (see 603932) and variation in the COL9A3 gene, see 120270.0003.
In a canine model of oculoskeletal dysplasia in Labrador retrievers, termed drd1 (dwarfism with retinal dysplasia type 1), Goldstein et al. (2010) identified a homozygous 1-bp insertion in exon 1 of the COL9A3 gene that segregated with the phenotype. The mutation affects the COL3 domain of the gene. Northern blot analysis showed reduced RNA expression of the COL9A3 gene in affected retinas. The drd1 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 drd1 phenotype resembles human hereditary arthroophthalmopathies such as Stickler syndrome (108300), Kniest dysplasia (156550), and Marshall syndrome (154780).
In affected members of a 4-generation family with multiple epiphyseal dysplasia (EDM3; 600969), Paassilta et al. (1999) identified an A-to-T transversion in an acceptor splice site of intron 2 of the COL9A3 gene. The pedigree pattern in this family was consistent with linkage to the COL9A3 locus. The mutation led to skipping of exon 3 and an in-frame deletion of 12 amino acid residues in the COL3 domain of the alpha-3 chain of collagen IX. This appeared to be similar to the splice site mutation found in COL9A2 that causes skipping of exon 3 of the alpha-2 chain of collagen IX (120260.0001). All affected family members experienced knee pain and stiffness during childhood. They had difficulty walking as a result of these symptoms, and some developed hip arthrosis and required surgical hip replacement after age 50 years. Affected adults had normal hands and no spinal symptoms; their height was normal and did not differ from that of unaffected family members.
Bonnemann et al. (2000) studied a family with autosomal dominant multiple epiphyseal dysplasia (EDM3; 600969) affecting predominantly the knee joints and a mild proximal myopathy. Genetic linkage to the COL9A3 locus on chromosome 20q13.3 was established with a peak lod score of 3.87 for markers D20S93 and D20S164. RT-PCR performed on muscle biopsy revealed aberrant mRNA lacking exon 3, which predicted a protein lacking 12 amino acids from the COL3 domain of alpha-3(IX) collagen. Direct sequencing of genomic DNA confirmed the presence of a splice acceptor mutation in intron 2 of the COL9A3 gene only in affected family members. By electron microscopy, chondrocytes from epiphyseal cartilage exhibited dilated rough endoplasmic reticulum containing linear lamellae of alternating electron-dense and electron-lucent material, reflecting abnormal processing of mutant protein. Type IX collagen chains appeared normal in size and quantity but showed defective crosslinking by Western blot analysis. Bonnemann et al. (2000) suggested that the MED and mild myopathy was likely caused by a dominant-negative effect of the exon 3-skipping mutation. Patients with MED and a waddling gait but minimal radiographic hip involvement should be evaluated for a primary myopathy and a mutation in type IX collagen. The proband in the family reported by Bonnemann et al. (2000) was a 10-year-old boy referred for evaluation of proximal muscle weakness and mildly elevated serum creatine kinase. He walked at 1 year of age but at age 3 was noted to have difficulty walking and climbing stairs. He always had difficulty rising from the floor and sometimes used a one-handed Gowers maneuver. He tired easily, never ran well, and complained of knee pain. He had significant weakness of neck flexion, mild weakness of shoulder abduction and elbow extension, and proximal lower limb weakness (hamstrings weaker than quadriceps). His height was 145.5 cm (90th percentile), and his hands appeared normal. The family history was notable for childhood-onset osteoarthritis and complaints of knee pain and stiffness in his mother and several relatives. Eleven members were affected across 3 generations. By x-ray, the epiphyseal changes characteristic of MED were most marked in the knee joints, followed by the ankle joints. Affected family members likewise showed MED predominantly affecting the knee joints and sparing the hips. The proband's mother had weak neck flexors and minimal weakness of the proximal extremities.
Lohiniva et al. (2000) found this mutation in a propositus and 2 affected relatives of a 3-generation family with MED. The phenotype consisted mainly of epiphyseal dysplasia of the knees and other joints in childhood, and osteochondrosis dissecans and osteoarthritis of the knee joints in adulthood.
In Finland, Paassilta et al. (2001) investigated the frequency of sequence variations in the coding sequences and exon boundaries of the 3 collagen IX genes in 171 individuals with lumbar disc disease (see 603932) and 321 controls. Lumbar disc disease was evaluated clinically and by magnetic resonance imaging or computed tomography. They found an arg103-to-trp (R103W) substitution in the COL9A3 gene; the authors referred to the mutant allele as the trp3 allele. The trp3 allele was present in 12.2% of lumbar disc disease cases and in 4.7% of controls. It was estimated that the trp3 allele increased the risk of lumbar disc disease about 3-fold.
In a 3-generation Japanese family with multiple epiphyseal dysplasia (EDM3; 600969), Nakashima et al. (2005) identified a heterozygous G-to-A transition at +5 of the donor splice site in intron 3 of the COL9A3 gene. RNA analysis revealed that the mutation caused splicing variants that could skip exon 3 or exons 2 and 3, both predicted to cause in-frame deletions resulting in loss of the COL3 domain of the alpha-3 chain of collagen IX. Affected members had knee pain ('occasional' in females) but were of normal height and had no signs or symptoms of muscle weakness.
In 3 Moroccan sibs with hearing loss, visual defects, and skeletal abnormalities (STL6; 620022), Faletra et al. (2014) identified homozygosity for a 23-bp deletion (c.1176_1198del) in exon 23 of the COL9A3 gene, causing a frameshift predicted to result in a premature termination codon (Gln393CysfsTer25). Their unaffected parents were heterozygous for the deletion, which was not found in 100 matched healthy controls or in the dbSNP or NHLBI-ESP databases. The sibs also exhibited moderate to severe intellectual disability that the authors suggested was likely due to variation in another gene in this consanguineous family.
In a 12-year-old Indian boy (ISDR R08-308A) with hearing loss, myopia, and epiphyseal abnormalities (STL6; 620022), Hanson-Kahn et al. (2018) identified homozygosity for a 1-bp duplication (c.650dupC, NM_001853.3) in exon 13 of the COL9A3 gene, causing a frameshift predicted to result in a premature termination codon. The unaffected third-cousin parents and older sister were heterozygous for the duplication, which was not found in public SNP variant databases.
In 2 sibs with hearing loss, myopia, and hypoplastic vitreous, 1 of whom also exhibited severe arthropathy (STL6; 620022), Nixon et al. (2019) identified homozygosity for a c.1411C-T transition (c.1411C-T, NM_001853.3) in the COL9A3 gene, resulting in an arg471-to-ter (R471X) substitution. Their parents, who were heterozygous for the mutation, exhibited some features of the syndrome, including arthritis and myopia in the mother and arthritis and sensorineural hearing loss in the father. However, because these symptoms are not very specific and occur in the general population with considerable frequency, the authors concluded that there was no solid evidence for carrier manifestation of heterozygous COL9A3 null alleles.
In a 3-year-old Russian boy with severe sensorineural hearing loss, high myopia, vitreoretinal degeneration, and early-onset arthropathy of the lower limbs (STL6; 620022), Markova et al. (2021) performed targeted sequencing of 166 genes associated with congenital skeletal disorders and identified compound heterozygosity for 2 nonsense mutations in the COL9A3 gene: a c.268C-T transition (c.268C-T, NM_001853.4) in exon 5, resulting in an arg90-to-ter (R90X) substitution, and a c.1729C-T transition in exon 30, resulting in an arg577-to-ter (R577X; 120270.0009) substitution. Sanger sequencing confirmed familial segregation; his unaffected sibs did not carry the COL9A3 variant.
For discussion of the c.1729C-T transition (c.1729C-T, NM_001853.4) in exon 30 of the COL9A3 gene, resulting in an arg577-to-ter (R577X) substitution, that was found in compound heterozygous state in a 3-year-old Russian boy with severe sensorineural hearing loss, high myopia, vitreoretinal degeneration, and early-onset arthropathy of the lower limbs (STL6; 620022) by Markova et al. (2021), see 120270.0008.
In a 28-year-old Iranian woman (family 1) with high myopia, vitreoretinal degeneration, and severe progressive sensorineural hearing loss (STL6; 620022), Rad et al. (2022) identified homozygosity for a 10-bp deletion (c.107_116del, NM_001853.3) in exon 2 of the COL9A3 gene, causing a frameshift predicted to result in a premature termination codon (Pro36ArgfsTer49). Sanger sequencing confirmed familial segregation of the deletion, which was present in the gnomAD database in 2 carriers (minor allele frequency, 0.00001390) but was not found in the Iranome or GME databases.
In 2 Iranian brothers (family 2), ages 65 and 57 years, with severely reduced vision due to progressive vitreoretinal degeneration, and profound sensorineural hearing loss (STL6; 620022), Rad et al. (2022) identified homozygosity for a c.1204C-T transition (c.1204C-T, NM_001853.3) in exon 23 of the COL9A3 gene, resulting in an arg402-to-ter (R402X) substitution. Sanger sequencing confirmed familial segregation of the deletion, which was not found in the Iranome, GME, 1000 Genomes Project, or gnomAD databases.
In an 11-year-old Iranian boy and his 3-year-old sister (family 3) with high myopia, sensorineural hearing loss, and spondyloepiphyseal dysplasia (STL6; 620022), Rad et al. (2022) identified homozygosity for a 1-bp deletion (c.355delC, NM_001853.3) in exon 7 of the COL9A3 gene, causing a frameshift predicted to result in a premature termination codon (Leu119SerfsTer9). Sanger sequencing confirmed familial segregation of the deletion, which was not found in the Iranome, GME, 1000 Genomes Project, or gnomAD databases.
Bonnemann, C. G., Cox, G. F., Shapiro, F., Wu, J.-J., Feener, C. A., Thompson, T. G., Anthony, D. C., Eyre, D. R., Darras, B. T., Kunkel, L. M. A mutation in the alpha 3 chain of type IX collagen causes autosomal dominant multiple epiphyseal dysplasia with mild myopathy. Proc. Nat. Acad. Sci. 97: 1212-1217, 2000. [PubMed: 10655510] [Full Text: https://doi.org/10.1073/pnas.97.3.1212]
Brewton, R. G., Wood, B. M., Ren, Z.-X., Gong, Y., Tiller, G. E., Warman, M. L., Lee, B., Horton, W. A., Olsen, B. R., Baker, J. R., Mayne, R. Molecular cloning of the alpha-3 chain of human type IX collagen: linkage of the gene COL9A3 to chromosome 20q13.3. Genomics 30: 329-336, 1995. [PubMed: 8586434] [Full Text: https://doi.org/10.1006/geno.1995.9870]
Faletra, F., D'Adamo, A. P., Bruno, I., Athanasakis, E., Biskup, S., Esposito, L., Gasparini, P. Autosomal recessive Stickler syndrome due to a loss of function mutation in the COL9A3 gene. Am. J. Med. Genet. 164A: 42-47, 2014. [PubMed: 24273071] [Full Text: https://doi.org/10.1002/ajmg.a.36165]
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] [Full Text: https://doi.org/10.1007/s00335-010-9276-4]
Hanson-Kahn, A., Li, B., Cohn, D. H., Nickerson, D. A., Bamshad, M. J., University of Washington Center for Mendelian Genomics, Hudgins, L. Autosomal recessive Stickler syndrome resulting from a COL9A3 mutation. Am. J. Med. Genet. 176A: 2887-2891, 2018. [PubMed: 30450842] [Full Text: https://doi.org/10.1002/ajmg.a.40647]
Lohiniva, J., Paassilta, P., Seppanen, U., Vierimaa, O., Kivirikko, S., Ala-Kokko, L. Splicing mutations in the COL3 domain of collagen IX cause multiple epiphyseal dysplasia. Am. J. Med. Genet. 90: 216-222, 2000. [PubMed: 10678658]
Markova, T., Sparber, P., Borovikov, A., Nagornova, T., Dadali, E. Clinical and genetic characterization of autosomal recessive stickler syndrome caused by novel compound heterozygous mutations in the COL9A3 gene. Molec. Genet. Genomic Med. 9: e1620, 2021. [PubMed: 33570243] [Full Text: https://doi.org/10.1002/mgg3.1620]
Nakashima, E., Kitoh, H., Maeda, K., Haga, N., Kosaki, R., Mabuchi,A., Nishimura, G., Ohashi, H., Ikegawa, S. Novel COL9A3 mutation in a family with multiple epiphyseal dysplasia. Am. J. Med. Genet. 132A: 181-184, 2005. [PubMed: 15551337] [Full Text: https://doi.org/10.1002/ajmg.a.30411]
Nixon, T. R. W., Alexander, P., Richards, A., McNinch, A., Bearcroft, P. W. P., Cobben, J., Snead, M. P. Homozygous Type IX collagen variants (COL9A1, COL9A2, and COL9A3) causing recessive Stickler syndrome--Expanding the phenotype. Am. J. Med. Genet. 179A: 1498-1506, 2019. [PubMed: 31090205] [Full Text: https://doi.org/10.1002/ajmg.a.61191]
Paassilta, P., Lohiniva, J., Annunen, S., Bonaventure, J., Le Merrer, M., Pai, L., Ala-Kokko, L. COL9A3: a third locus for multiple epiphyseal dysplasia. Am. J. Hum. Genet. 64: 1036-1044, 1999. Note: Erratum: Am. J. Hum. Genet. 65: 1214 only, 1999. [PubMed: 10090888] [Full Text: https://doi.org/10.1086/302328]
Paassilta, P., Lohiniva, J., Goring, H. H. H., Perala, M., Raina, S. S., Karppinen, J., Hakala, M., Palm, T., Kroger, H., Kaitila, I., Vanharanta, H., Ott, J., Ala-Kokko, L. Identification of a novel common genetic risk factor for lumbar disk disease. JAMA 285: 1843-1849, 2001. [PubMed: 11308397] [Full Text: https://doi.org/10.1001/jama.285.14.1843]
Rad, A., Najafi, M., Suri, F., Abedini, S., Loum, S., Karimiani, E. G., Daftarian, N., Murphy, D., Doosti, M., Moghaddasi, A., Ahmadieh, H., Sabbaghi, H., Rajati, M., Hashemi, N., Vona, B., Schmidts, M. Identification of three novel homozygous variants in COL9A3 causing autosomal recessive Stickler syndrome. Orphanet J. Rare Dis. 17: 97, 2022. [PubMed: 35241111] [Full Text: https://doi.org/10.1186/s13023-022-02244-6]
Tiller, G. E., Warman, M. L., Gong, Y., Knoll, J. H. M., Mayne, R., Brewton, R. G. Physical and linkage mapping of the gene for the alpha-3 chain of type IX collagen, COL9A3, to human chromosome 20q13.3. Cytogenet. Cell Genet. 81: 205-207, 1998. [PubMed: 9730604] [Full Text: https://doi.org/10.1159/000015031]