HGNC Approved Gene Symbol: ADAMTS10
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38) : 19:8,580,240-8,610,715 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.2 | Weill-Marchesani syndrome 1, recessive | 277600 | Autosomal recessive | 3 |
ADAMTS10 is a member of the large ADAMTS family of zinc-dependent proteases. For a general description of the ADAMTS gene family, see ADAMTS1 (605174).
Dagoneau et al. (2004) reported that the ADAMTS10 gene encodes a protein of 1,103 amino acids that is composed of 1 disintegrin-like domain, 1 metalloprotease domain, 1 cysteine-rich domain, and 5 thrombospondin type 1 (THBS1; 188060) repeats. ADAMTS10 differs from other members of the ADAMTS family by the presence of its 5 THBS1 domains and a unique C-terminal PLAC (protease and lacunin) domain and is closely related to ADAMTS6 (605008). Studies of the normal expression of ADAMTS10 using RT-PCR, Northern blot, and dot-blot analyses showed that ADAMTS10 is expressed in skin, fetal chondrocytes, and fetal and adult heart.
Dagoneau et al. (2004) reported that the ADAMTS10 gene contains 24 coding exons.
On the basis of its predicted function as a member of the extracellular matrix protease family and its presence within the Weill-Marchesani syndrome (WMS1; 277600) critical interval on 19p13.3-p13.2, Dagoneau et al. (2004) considered the ADAMTS10 gene as a candidate gene for autosomal recessive WMS. They found 3 distinct mutations of the ADAMTS10 gene in 2 families from Lebanon and Saudi Arabia and in 1 sporadic WMS case, including 1 nonsense mutation and 2 splice mutations (608990.0001-608990.0003).
In affected individuals from 2 consanguineous Saudi Arabian families with Weill-Marchesani syndrome, Morales et al. (2009) identified homozygosity for 2 different missense mutations in the ADAMTS10 gene (608990.0006 and 608990.0007, respectively).
In a consanguineous Lebanese family with 3 individuals with Weill-Marchesani syndrome (WMS1; 277600) in 2 sibships related as double first cousins, Dagoneau et al. (2004) found a homozygous 709C-T transition in exon 6 of the ADAMTS10 gene, resulting in an arg237-to-stop (R237X) change in the amino acid structure of the protein.
In a consanguineous Saudi Arabian family in which 3 of 12 sibs had Weill-Marchesani syndrome (WMS1; 277600), Dagoneau et al. (2004) found homozygosity for a 1190+1G-A mutation at the donor splice site of intron 10. The mutation caused a frameshift and a stop 1 codon downstream.
In a nonconsanguineous French family, Dagoneau et al. (2004) found that a single affected member with Weill-Marchesani syndrome (WMS1; 277600) was compound heterozygous for the R237X mutation in ADAMTS10 (608990.0001) and an 810+1G-A transition in exon 6 causing a frameshift and a stop 20 codons downstream.
In an 86-year-old man with Weill-Marchesani syndrome (WMS1; 277600), Kutz et al. (2008) identified compound heterozygosity for 2 mutations in the ADAMTS10 gene: a 73G-A transition, resulting in an ala25-to-thr (A25T) substitution at the -1 position of the signal peptidase cleavage site, and a 952C-T transition, resulting in a gln318-to-ter (Q318X; 608990.0005) substitution. The A25T mutation was not identified in 200 control chromosomes, and the Q318X mutation resulted in nonsense-mediated mRNA decay. In vitro functional expression studies in HEK293 and COS-1 cells showed impaired cellular secretin of the full-length A25T mutant protein. However, a C-terminally truncated construct lacking the ancillary domain and containing only the mutant signal peptide, the propeptide, and the catalytic domain was efficiently secreted, indicating that the signal peptide was processed correctly. Kutz et al. (2008) concluded that folding of the complex C-terminal ancillary domain is the rate-limiting step in biosynthesis of ADAMTS10, and that it is sensitive to subtle changes in efficiency of signal peptide cleavage. The findings supported a model in which the initial cotranslational processing events during protein biosynthesis can have long-range effects on protein folding and secretion.
For discussion of the gln318-to-ter (Q318X) mutation in the ADAMTS10 gene that was found in compound heterozygous state in a patient with Weill-Marchesani syndrome (WMS1; 277600) by Kutz et al. (2008), see 608990.0004.
In an affected brother and sister from a consanguineous Saudi Arabian family with Weill-Marchesani syndrome (WMS1; 277600), Morales et al. (2009) identified homozygosity for a 1553G-A transition in the ADAMTS10 gene, resulting in a gly518-to-asp (G518D) substitution. The mutation was not found in 240 controls.
In an affected brother and sister from a consanguineous Saudi Arabian family with Weill-Marchesani syndrome (WMS1; 277600), Morales et al. (2009) identified homozygosity for a 2098G-T transversion in the ADAMTS10 gene, resulting in a gly700-to-cys (G700C) substitution. The mutation was not found in 240 controls.
Dagoneau, N., Benoist-Lasselin, C., Huber, C., Faivre, L., Megarbane, A., Alswaid, A., Dollfus, H., Alembik, Y., Munnich, A., Legeai-Mallet, L., Cormier-Daire, V. ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome. Am. J. Hum. Genet. 75: 801-806, 2004. [PubMed: 15368195] [Full Text: https://doi.org/10.1086/425231]
Kutz, W. E., Wang, L. W., Dagoneau, N., Odrcic, K. J., Cormier-Daire, V., Traboulsi, E. I., Apte, S. S. Functional analysis of an ADAMTS10 signal peptide mutation in Weill-Marchesani syndrome demonstrates a long-range effect on secretion of the full-length enzyme. Hum. Mutat. 29: 1425-1434, 2008. [PubMed: 18567016] [Full Text: https://doi.org/10.1002/humu.20797]
Morales, J., Al-Sharif, L., Khalil, D. S., Shinwari, J. M. A., Bavi, P., Al-Mahrouqi, R. A., Al-Rajhi, A., Alkuraya, F. S., Meyer, B. F., Al Tassan, N. Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Am. J. Hum. Genet. 85: 558-568, 2009. [PubMed: 19836009] [Full Text: https://doi.org/10.1016/j.ajhg.2009.09.011]