HGNC Approved Gene Symbol: ADAMTS17
Cytogenetic location: 15q26.3 Genomic coordinates (GRCh38) : 15:99,971,437-100,341,975 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q26.3 | Weill-Marchesani 4 syndrome, recessive | 613195 | Autosomal recessive | 3 |
ADAMTS17 is a member of the large ADAMTS family of zinc-dependent proteases. For a general description of the ADAMTS gene family, see ADAMTS1 (605174).
Using homology with the metalloprotease domain of ADAMTS proteins, Cal et al. (2002) identified ADAMTS17 within a genomic database. They obtained the full-length clone by PCR and 5-prime and 3-prime RACE of fetal tissue cDNA libraries. The deduced protein contains an N-terminal signal peptide, followed by a propeptide; a metalloprotease catalytic domain that includes the Zn-binding motif; a disintegrin-like domain; a central thrombospondin I (THBS1; 188060)-like motif; a cysteine-rich domain; a spacer region; 3 C-terminal THBS1 repeats; and a protease-lacunin (PLAC)-like domain. It also has 7 N-glycosylation sites. ADAMTS17 shares 56% sequence identity with ADAMTS19 (607513), including 88% identity within the catalytic domains. PCR analysis revealed that ADAMTS17 is expressed in fetal lung and in adult brain, prostate, and liver.
Morales et al. (2009) analyzed ADAMTS17 expression in cDNA libraries from various adult and fetal tissues and found that transcripts of both a longer 'a' isoform, spanning 22 exons and coding for 1,095 amino acids, and a shorter 'b' isoform, spanning 16 exons and coding for 502 amino acids, showed high expression in adult lung, brain, whole eye, and retina. Isoform 'a' showed weaker expression in heart, kidney, and skeletal muscle, and was not expressed at all in bone marrow, whereas expression of isoform 'b' was weak in kidney, bone marrow, and skeletal muscle. Both transcripts demonstrated high expression of ADAMTS17 in fetal brain, heart, kidney, and whole eye, whereas expression was weak in the liver. Immunohistochemistry showed strong staining for ADAMTS17 in the spleen and testis, moderate staining in liver, kidney, placenta, and lymph node, and weak expression in heart, lung, colon, ovary, and uterine wall smooth muscle; there was no expression in pancreas or thyroid gland. Eye sections from mouse embryos showed diffuse expression of Adamts17 within the area of the future ciliary body.
By genomic sequence analysis, Cal et al. (2002) mapped the ADAMTS17 gene to chromosome 15q24.
Hartz (2009) mapped the ADAMTS17 gene to chromosome 15q26.3 based on an alignment of the ADAMTS17 sequence (GenBank AA884550) with the genomic sequence (GRCh37).
In 4 affected sibs from a consanguineous Saudi Arabian family with features of Weill-Marchesani syndrome (WMS4; 613195) mapping to chromosome 15q26.3, Morales et al. (2009) identified homozygosity for a 1-bp insertion in the ADAMTS17 gene (607511.0001) that fully segregated with the phenotype. Screening of the ADAMTS17 gene in similar WMS patients identified a homozygous truncating mutation (607511.0002) in 2 affected sisters from another Saudi Arabian family, and a homozygous splice site mutation in a sporadic case (607511.0003).
In a sister and brother with WMS from a consanguineous Saudi family, Khan et al. (2012) sequenced the candidate gene ADAMTS17 and identified a 1-bp deletion (607511.0004) that segregated fully with disease.
In an Indian woman with WMS, Shah et al. (2014) identified homozygosity for a splice site mutation in the ADAMTS17 gene (607511.0005) that segregated with disease and was not found in 50 ethnically matched controls or in public variant databases.
In 4 affected sibs from a consanguineous Saudi Arabian family with features of Weill-Marchesani syndrome (WMS4; 613195), Morales et al. (2009) identified homozygosity for a 1-bp insertion, 2458insG, in exon 18 of the ADAMTS17 gene, predicted to cause a frameshift and result in premature termination of the protein. The unaffected parents were heterozygous for the mutation, which was not found in 300 ethnically matched controls.
In 2 affected sisters from a consanguineous Saudi Arabian family with Weill-Marchesani syndrome (WMS4; 613195), Morales et al. (2009) identified homozygosity for a 760C-T transition in exon 4 of the ADAMTS17 gene, resulting in a gln254-to-ter (Q254X) substitution. The unaffected parents were heterozygous for the mutation, which was not found in 300 ethnically matched controls.
In a 33-year-old man with Weill-Marchesani syndrome (WMS4; 613195), Morales et al. (2009) identified homozygosity for a 1721+1G-A transition in intron 12 of the ADAMTS17 gene. The mutation was not found in 300 ethnically matched controls. In mRNA analysis, 3 aberrant transcripts were detected, all of which harbored a frameshift and were predicted to produce truncated proteins of 579 and 574 amino acids, respectively.
In a sister and brother with spherophakia and short stature (WMS4; 613195), Khan et al. (2012) identified a 1-bp deletion (c.652delG, NM_139057.2), causing a frameshift predicted to result in a premature termination codon (Asp218ThrfsTer41). The mutation segregated fully with disease in the family.
In an Indian woman with microspherophakia, short stature, and brachydactyly (WMS4; 613195), Shah et al. (2014) identified homozygosity for a splice site mutation (c.873+1G-T, NM_139057.2) in intron 5 of the ADAMTS17 gene. The mutation segregated fully with disease in the family and was not found in 50 ethnically matched controls or in the 1000 Genomes or NHLBI Exome Variant Server databases. Sanger sequencing of RT-PCR products from the proband showed deletion of the entire exon 5, resulting in a predicted protein of 1,067 amino acids, due to deletion of 28 amino acids from residue 264 to 291 within the reprolysin domain.
Cal, S., Obaya, A. J., Llamazares, M., Garabaya, C., Quesada, V., Lopez-Otin, C. Cloning, expression analysis, and structural characterization of seven novel human ADAMTSs, a family of metalloproteinases with disintegrin and thrombospondin-1 domains. Gene 283: 49-62, 2002. [PubMed: 11867212] [Full Text: https://doi.org/10.1016/s0378-1119(01)00861-7]
Hartz, P. A. Personal Communication. Baltimore, Md. 12/28/2009.
Khan, A. O., Aldahmesh, M. A., Al-Ghadeer, H., Mohamed, J. Y., Alkuraya, F. S. Familial spherophakia with short stature caused by a novel homozygous ADAMTS17 mutation. Ophthalmic Genet. 33: 235-239, 2012. [PubMed: 22486325] [Full Text: https://doi.org/10.3109/13816810.2012.666708]
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]
Shah, M. H., Bhat, V., Shetty, J. S., Kumar, A. Whole exome sequencing identifies a novel splice-site mutation in ADAMTS17 in an Indian family with Weill-Marchesani syndrome. Molec. Vision 20: 790-796, 2014. [PubMed: 24940034]