Alternative titles; symbols
HGNC Approved Gene Symbol: ADAMTSL2
Cytogenetic location: 9q34.2 Genomic coordinates (GRCh38) : 9:133,532,164-133,575,519 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.2 | Geleophysic dysplasia 1 | 231050 | Autosomal recessive | 3 |
ADAMTS proteases are secreted enzymes with a conserved organization that includes a metalloprotease domain and an ancillary domain containing 1 or more thrombospondin (see 188060) type-1 repeats (TSRs). ADAMTSL2 belongs to the ADAMTS-like (ADAMTSL) subfamily, which comprises proteins containing ADAMTS ancillary domains but lacking the protease domain and, consequently, catalytic activity (summary by Le Goff et al., 2008).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) cloned ADAMTSL2, which they designated KIAA0605. The 5-prime region of the cDNA contains an Alu sequence, and the deduced 951-amino acid protein shares similarity with bovine procollagen I N-proteinase (ADAMTS2; 604539). RT-PCR detected high expression in kidney, liver, and lung, and low to moderate expression in all other tissues examined.
Hall et al. (2003) stated that the ADAMTSL2 gene contains an N-terminal thrombospondin type I domain, followed by a cysteine-rich domain, a spacer region, 6 additional thrombospondin type I repeats, and a C-terminal PLAC (protease and lacunin) domain.
By radiation hybrid analysis, Nagase et al. (1998) mapped the ADAMTSL2 gene to chromosome 9.
Le Goff et al. (2008) mapped the ADAMTSL2 gene to an interval on chromosome 9q34.2 defined by linkage analysis.
By in situ hybridization to human fetal tissue, Le Goff et al. (2008) demonstrated ADAMTSL2 mRNA expression in cardiomyocytes, epidermis, dermal blood vessels, tracheal wall, skeletal muscle, pulmonary arteries, and bronchioles of the lung. Strong expression was also observed in chondrocyte columns in the hypertrophic and reserve zones of the proximal femoral growth plate.
In a yeast 2-hybrid screen of a human muscle cDNA library, Le Goff et al. (2008) found that ADAMTSL2 bound to latent TGFB-binding protein-1 (LTBP1; 150390), which plays a major role in the storage of latent TGFB in the extracellular matrix and regulates its availability.
Le Goff et al. (2008) identified the ADAMTSL2 gene and 6 other genes within a critical interval on chromosome 9q34.2-q34.3 linked to geleophysic dysplasia-1 (GPHYSD1; 231050). Because geleophysic dysplasia belongs to the group of acromelic dysplasias that also includes the autosomal recessive form of Weill-Marchesani syndrome (277600), which is caused by mutations in ADAMTS10 (608990), Le Goff et al. (2008) considered ADAMTSL2 as the likely candidate among the genes within the interval. Le Goff et al. (2008) identified 4 missense and 1 nonsense mutation in the ADAMTSL2 gene in individuals with geleophysic dysplasia. Functional studies in HEK293 cells showed that ADAMTSL2 mutations lead to reduced secretion of the mutated proteins, possibly owing to the misfolding of ADAMTSL2. A yeast 2-hybrid screen showed that ADAMTSL2 interacts with latent TGF-beta-binding protein-1 (LTBP1; 150390). In addition, Le Goff et al. (2008) observed a significant increase in total and active TGF-beta (190180) in culture medium as well as nuclear localization of phosphorylated SMAD2 (601366) in fibroblasts from individuals with geleophysic dysplasia.
Allali et al. (2011) analyzed the ADAMTSL2 gene in an additional 33 patients with geleophysic dysplasia from 30 families, and identified 14 different homozygous or compound heterozygous mutations in 14 patients (see, e.g., 612277.0003, 612277.0006, and 612277.0007). All mutations cosegregated with disease in the respective families and were not found in 200 control chromosomes.
In affected members of 2 consanguineous Arab families with geleophysic dysplaisa-1, Ben-Salem et al. (2013) identified homozygous missense mutations in the ADAMTSL2 gene (see, e.g., 612277.0008) that segregated with the disorder in the families. The mutations were not found in the NHLBI EVS database or in ethnically matched controls.
In a 48-year-old man with GPHYSD1, one of the original patients described by Spranger et al. (1971), Legare et al. (2018) identified compound heterozygous mutations in the ADAMTSL2 gene (NM_014694.3): the previously identified D167N mutation and a 1-bp deletion (c.31delG) resulting in a frameshift and premature termination (Ala11ProfsTer10). The frameshift was predicted to be pathogenic based on ACMG criteria. The parents were not tested so there was a small possibility that the mutations occurred in cis; the authors considered this unlikely because the patient had 2 affected sibs.
In a consanguineous French Polynesian family segregating geleophysic dysplasia-1 (GPHYSD1; 231050), Le Goff et al. (2008) identified homozygosity for a C-to-T transition at nucleotide 440 in exon 5 of the ADAMTSL2 gene, resulting in a pro-to-leu substitution at codon 147 of the protein (P147L).
In 2 consanguineous families of North African descent, 1 from Morocco and 1 from Algeria, with geleophysic dysplasia-1 (GPHYSD1; 231050), Le Goff et al. (2008) identified homozygosity for a G-to-A transition at nucleotide 338 in exon 4 of the ADAMTSL2 gene, resulting in an arg-to-his substitution at codon 113 (R113H).
In affected members of a consanguineous Turkish family with geleophysic dysplasia-1 (GPHYSD1; 231050), Le Goff et al. (2008) identified homozygosity for a 340G-A transition in exon 4 of the ADAMTSL2 gene, resulting in a glu114-to-lys (E114K) substitution.
In an English patient with geleophysic dysplasia-1, Allali et al. (2011) identified compound heterozygosity for the E114K mutation in the cysteine-rich domain of the protein and a 215G-A transition in exon 2 of the ADAMTSL2 gene, resulting in an arg72-to-gln (R72Q; 612277.0006) substitution within the thrombospondin type 1 repeat. Allali et al. (2011) also identified the E114K mutation in a French woman with GPHYSD1, but a second mutation was not detected in that patient.
In a French child with geleophysic dysplasia-1 (GPHYSD1; 231050) from a nonconsanguineous family, Le Goff et al. (2008) identified compound heterozygosity for mutations in exon 16 of the ADAMTSL2 gene. One allele carried a G-to-A transition at nucleotide 2431, leading to a gly-to-arg substitution at codon 811 (G811R). The other allele carried a nonsense mutation (612277.0005).
In a French child with geleophysic dysplasia-1 (GPHYSD1; 231050) from a nonconsanguineous family, Le Goff et al. (2008) identified a G-to-A transition at nucleotide 2586 in exon 16 of the ADAMTSL2 gene, resulting in a trp-to-stop substitution at codon 862 (W862X). This mutation was found in compound heterozygosity with a missense mutation (612277.0004).
For discussion of the 215G-A transition in exon 2 of the ADAMTSL2 gene, resulting in an arg72-to-gln (R72Q) substitution, found in compound heterozygous state in an English patient with geleophysic dysplasia-1 (GPHYSD1; 231050) by Allali et al. (2011), see 612277.0003.
In 3 unrelated patients of Pakistani origin with geleophysic dysplasia-1 (GPHYSD1; 231050), Allali et al. (2011) identified homozygosity for a 661C-T transition in exon 6 of the ADAMTSL2 gene, resulting in an arg221-to-cys (R221C) substitution in the spacer module of the protein. The mutation segregated with disease in each family and was not found in 200 control chromosomes.
In a 2-year-old boy, born to consanguineous Pakistani parents, with geleophysic dysplasia-1 (GPHYSD1; 231050), Ben-Salem et al. (2013) identified homozygosity for a c.499G-A transition (c.499G-A, NM_001145320.1) in exon 6 of the ADAMTSL2 gene, resulting in an asp167-to-asn (D167N) substitution at a conserved residue. The mutation was found by Sanger sequencing of the ADAMTSL2 gene. The parents were heterozygous for the mutation, which was not found in the NHLBI EVS database or in ethnically matched controls.
Allali, S., Le Goff, C., Pressac-Diebold, I., Pfennig, G., Mahaut, C., Dagoneau, N., Alanay, Y., Brady, A. F., Crow, Y. J., Devriendt, K., Drouin-Garraud, V., Flori, E., and 18 others. Molecular screening of ADAMTSL2 gene in 33 patients reveals the genetic heterogeneity of geleophysic dysplasia. J. Med. Genet. 48: 417-421, 2011. [PubMed: 21415077] [Full Text: https://doi.org/10.1136/jmg.2010.087544]
Ben-Salem, S., Hertecant, J., Al-Shamsi, A. M., Ali, B. R., Al-Gazali, L. Novel mutations in ADAMTSL2 gene underlying geleophysic dysplasia in families from United Arab Emirates. Birth Defects Res. A Clin. Molec. Teratol. 97: 764-769, 2013. [PubMed: 24014090] [Full Text: https://doi.org/10.1002/bdra.23170]
Hall, N. G., Klenotic, P., Anand-Apte, B., Apte, S. ADAMTSL-3/punctin-2, a novel glycoprotein in extracellular matrix related to the ADAMTS family of metalloproteases. Matrix Biol. 22: 501-510, 2003. [PubMed: 14667842] [Full Text: https://doi.org/10.1016/s0945-053x(03)00075-1]
Le Goff, C., Morice-Picard, F., Dagoneau, N., Wang, L. W., Perrot, C., Crow, Y. J., Bauer, F., Flori, E., Prost-Squarcioni, C., Krakow, D., Ge, G., Greenspan, D. S., Bonnet, D., Le Merrer, M., Munnich, A., Apte, S. S., Cormier-Daire, V. ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-beta bioavailability regulation. Nature Genet. 40: 1119-1123, 2008. [PubMed: 18677313] [Full Text: https://doi.org/10.1038/ng.199]
Legare, J. M., Modaff, P., Strom, S. P., Pauli, R. M., Bartlett, H. L. Geleophysic dysplasia: 48 year clinical update with emphasis on cardiac care. Am. J. Med. Genet. 176A: 2237-2242, 2018. [PubMed: 30195254] [Full Text: https://doi.org/10.1002/ajmg.a.40377]
Nagase, T., Ishikawa, K., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5: 31-39, 1998. [PubMed: 9628581] [Full Text: https://doi.org/10.1093/dnares/5.1.31]
Spranger, J. W., Gilbert, E. F., Tuffli, G. A., Rossiter, F. P., Opitz, J. M. Geleophysic dwarfism--a 'focal' mucopolysaccharidosis? (Letter) Lancet 298: 97-98, 1971. Note: Originally Volume II. [PubMed: 4104008] [Full Text: https://doi.org/10.1016/s0140-6736(71)92073-3]