Alternative titles; symbols
HGNC Approved Gene Symbol: ADAMTSL4
SNOMEDCT: 419237004;
Cytogenetic location: 1q21.2 Genomic coordinates (GRCh38) : 1:150,549,408-150,560,937 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.2 | Ectopia lentis et pupillae | 225200 | Autosomal recessive | 3 |
| Ectopia lentis, isolated, autosomal recessive | 225100 | Autosomal recessive | 3 |
ADAMTSL4 belongs to a family of proteins that share significant similarity with the ADAMTS family of metalloprotease (see ADAMTS1; 605174). However, ADAMTS-like proteins lack the zinc-binding metalloprotease domain of ADAMTS proteins and are therefore secreted glycoproteins rather than enzymes (summary by Gabriel et al., 2012).
By database analysis and PCR analysis of mouse brain, Buchner and Meisler (2003) cloned Adamtsl4, which they called Tsrc1. By database searching with the mouse Adamtsl4 sequence, they identified human ADAMTSL4. The deduced human and mouse proteins contain 1,074 and 1,036 amino acids, respectively, and share 76% sequence identity. The proteins contain 7 predicted thrombospondin type 1 (TSP1) repeats, 6 of which are clustered at the C-terminal end. The thrombospondin domains are most closely related to the ADAMTS (a disintegrin-like and metalloproteinase with thrombospondin type 1 repeats) subfamily. Northern blot analysis detected a 4.4-kb mouse Adamtsl4 transcript in muscle, brain, and other tissues; RT-PCR analysis confirmed expression in all fetal and adult tissues examined.
Ahram et al. (2009) amplified first-strand cDNA from adult human tissue and found expression of ADAMTSL4 in colon, heart, leukocyte, liver, lung, skeletal muscle, spleen, testis, and placenta; expression was weaker in bone marrow, brain tissue, kidney, and pancreas. Expression studies in fetal tissue revealed strong expression in heart, kidney, liver, lung, and skeletal muscle, but weaker expression in brain and skin.
Using Western blot and immunohistochemical analyses, Gabriel et al. (2012) found that ADAMTSL4 was widely expressed in normal human eye and was associated with both cells and extracellular medium. Western blot analysis of conditioned medium from transfected HEK293F cells showed that ADAMTSL4 was secreted as a major N- and O-glycosylated species with an apparent molecular mass of 150 kD.
Using in situ hybridization, Collin et al. (2015) found that Adamtsl4 was highly expressed in lens epithelium at the lens equator throughout mouse embryonic development and in adults. Adamtsl4 was more modestly expressed in other tissues of anterior and posterior eye segments, but not in the ciliary body.
Buchner and Meisler (2003) determined that the ADAMTSL4 gene contains 17 coding exons and 2 untranslated exons and spans about 10 kb of genomic DNA.
By sequence analysis, Buchner and Meisler (2003) mapped the human ADAMTSL4 gene to chromosome 1q21. They mapped the mouse Adamtsl4 gene in a region of syntenic homology on chromosome 3.
Fibroblasts secrete fibrillin-1 (FBN1; 134797) and deposit it into microfibrils after a period of confluence. Gabriel et al. (2012) showed that conditioned medium containing human ADAMTSL4 accelerated the deposition of Fbn1 into microfibrils by fetal bovine nunchal ligament fibroblasts.
In a large consanguineous Arab family of Jordanian origin with isolated ectopia lentis mapping to chromosome 1p13.2-q21.1 (ECTOL2; 225100), originally reported by Al-Salem (1990), Ahram et al. (2009) identified homozygosity for a nonsense mutation in the ADAMTSL4 gene (610113.0001) that segregated with the phenotype and was not found in 380 ethnically matched control chromosomes.
In 2 Turkish brothers with isolated ectopia lentis who were negative for mutation in the FBN1 gene (134797), Greene et al. (2010) identified homozygosity for a splice site mutation in the ADAMTSL4 gene (610113.0002).
In 10 affected individuals from 5 Norwegian families with ectopia lentis et pupillae (225200), Christensen et al. (2010) identified homozygosity for a 20-bp deletion in the ADAMTSL4 gene (610113.0003). There was evidence for a founder effect in this population. In 1 family, 1 of the 3 affected individuals had bilateral downward dislocation of the lenses but normally positioned pupils.
In 6 patients with FBN1-negative ectopia lentis, including 1 who had ectopia lentis et pupillae, Aragon-Martin et al. (2010) identified homozygous or compound heterozygous mutations in the ADAMTSL4 gene, including the 20-bp deletion reported by Christensen et al. (2010) (see, e.g., 610113.0003-610113.0005).
In 8 patients from 7 German families with isolated ectopia lentis, Neuhann et al. (2011) identified homozygosity for the 20-bp deletion in the ADAMTSL4 gene. A 4-SNP haplotype was consistently associated with the mutation, suggestive of a founder mutation.
Chandra et al. (2012) identified mutations in the ADAMTSL4 gene in 8 Caucasian British probands with isolated ectopia lentis, including 6 who were homozygous for the 20-bp deletion and 1 who was compound heterozygous for the 20-bp deletion and a 1-bp deletion (610113.0006). Another Caucasian British proband, who had ectopia lentis et pupillae, was found to be compound heterozygous for the 20-bp deletion and a 1-bp duplication in ADAMTSL4 (610113.0007).
Collin et al. (2015) reported tvrm267 mice, which were generated by N-ethyl-N-nitrosourea mutagenesis and harbor a gln609-to-ter (Q609X) nonsense mutation in the Adamtsl4 gene. Eyes of homozygous tvrm267 mice appeared normal at birth, but they developed age-dependent ectopia lentis due to ciliary zonule detachment from the lens capsule. Homozygous tyrm367 mice also showed age-dependent dedifferentiation of retinal pigment epithelial (RPE) cells, with downregulation of RPE-specific genes, including Lrat (604863), Rgr (600342), and Rpe65 (180069), and upregulation of Col18a1 (120328). Electroretinography confirmed RPE functional defects in homozygous tvrm267 mice. Some homozygous tvrm267 mice also showed increased axial length.
In affected members of a large consanguineous Arab family of Jordanian origin with isolated ectopia lentis (ECTOL2; 225100), originally reported by Al-Salem (1990), Ahram et al. (2009) identified homozygosity for a 1785T-G transversion in exon 11 of the ADAMTSL4 gene, resulting in a tyr595-to-ter (Y595X) substitution at an evolutionarily conserved residue, predicted to generate a truncated protein of 594 residues lacking 6 of the 7 TSP1 repeats. The mutation, which segregated with the phenotype in the family, was not found in 380 ethnically matched control chromosomes.
In 2 Turkish boys with isolated ectopia lentis (ECTOL2; 225100), born of consanguineous parents, Greene et al. (2010) identified homozygosity for a -1G-A transition in intron 4 of the ADAMTSL4 gene that abolishes the splice acceptor site and creates a premature stop codon. Their unaffected parents were heterozygous for the mutation, which was not found in the SNP database and was not described as a physiologic splice variant in the Ensembl, UCSC, or Browser fast.db databases.
In 10 affected individuals from 5 Norwegian families with ectopia lentis et pupillae (225200), Christensen et al. (2010) identified homozygosity for a 20-bp deletion (767_786del20) in the ADAMTSL4 gene, causing a frameshift predicted to result in a stop codon and premature termination 113 bp downstream. RT-PCR analysis of ADAMTSL4 mRNA confirmed the presence of a transcript truncated by 20 bp. Obligate heterozygotes had no ocular abnormalities. Homozygosity mapping in the 5 Norwegian families from Hordaland County in western Norway was compatible with a common ancestor 150 generations (4,000 years) earlier, and the mutation was found in heterozygosity in 3 of 190 local blood donors, corresponding to a prevalence for homozygosity of approximately 1:16,000 in this population. In 1 family, 1 of the 3 affected individuals had bilateral downward dislocation of the lenses but normally positioned pupils.
In a 15-year-old boy with isolated ectopia lentis (ECTOL2; 252100), Aragon-Martin et al. (2010) identified homozygosity for the 20-bp deletion in exon 6 of the ADAMTSL4 gene. The 20-bp deletion was also identified in compound heterozygosity with an 11-bp deletion (826_836del11; 610113.0004) in ADAMTSL4 in 2 affected members of a Caucasian British family with ectopia lentis and in an 8-year-old Swedish boy with ectopia lentis et pupillae.
In 8 patients from 7 German families with isolated ectopia lentis, Neuhann et al. (2011) identified homozygosity for the 20-bp deletion in the ADAMTSL4 gene, which they designated 759_778del20. The mutation was found in heterozygosity in unaffected parents and sibs, as well as in 2 of 360 controls. A 4-SNP haplotype was consistently associated with the mutation, suggestive of a founder mutation.
In 6 Caucasian British patients with isolated ectopia lentis, Chandra et al. (2012) identified homozygosity for the ADAMTSL4 20-bp deletion (Gln256ProfsTer38). Two more Caucasian British patients, 1 with isolated ectopia lentis and 1 with ectopia lentis et pupillae, were found to be compound heterozygous for the 20-bp deletion and 2 different frameshift mutations: a 1-bp deletion (237delC, Pro80ArgfsTer53; 610113.0006) and a 1-bp duplication (2270dupG, Gly758TrpfsTer59; 610113.0007), respectively, in the ADAMTSL4 gene.
For discussion of the 11-bp deletion in the ADAMTSL4 gene (826_836del11) that was found in compound heterozygous state in patients with isolated ectopia lentis (ECTOL2; 252100) and in a patient with ectopia lentis et pupillae (225200) by Aragon-Martin et al. (2010), see 610113.0003.
In 2 sibs from a Caucasian British family with autosomal recessive isolated ectopia lentis (ECTOL2; 242100), Aragon-Martin et al. (2010) identified homozygosity for a 2008C-T transition in exon 12 of the ADAMTSL4 gene, resulting in an arg670-to-ter (R670X; 610113.0004) substitution.
For discussion of the 1-bp deletion (237delC) in the ADAMTSL4 gene that was found in compound heterozygous state in a patient with isolated ectopia lentis (ECTOL2; 252100) by Chandra et al. (2012), see 610113.0003.
For discussion of the 1-bp duplication (2270dupG) in the ADAMTSL4 gene that was found in compound heterozygous state in a patient with ectopia lentis et pupillae (225200) by Chandra et al. (2012), see 610113.0003.
Ahram, D., Sato, T. S., Kohilan, A., Tayeh, M., Chen, S., Leal, S., Al-Salem, M., El-Shanti, H. A homozygous mutation in ADAMTSL4 causes autosomal-recessive isolated ectopia lentis. Am. J. Hum. Genet. 84: 274-278, 2009. [PubMed: 19200529] [Full Text: https://doi.org/10.1016/j.ajhg.2009.01.007]
Al-Salem, M. Autosomal recessive ectopia lentis in two Arab family pedigrees. Ophthalmic Paediat. Genet. 11: 123-127, 1990. [PubMed: 2377351] [Full Text: https://doi.org/10.3109/13816819009012957]
Aragon-Martin, J. A., Ahnood, D., Charteris, D. G., Saggar, A., Nischal, K. K., Comeglio, P., Chandra, A., Child, A. H., Amo, G. Role of ADAMTSL4 mutations in FBN1 mutation-negative ectopia lentis patients. Hum. Mutat. 31: E1622, 2010. Note: Electronic Article. [PubMed: 20564469] [Full Text: https://doi.org/10.1002/humu.21305]
Buchner, D. A., Meisler, M. H. TSRC1, a widely expressed gene containing seven thrombospondin type I repeats. Gene 307: 23-30, 2003. [PubMed: 12706885] [Full Text: https://doi.org/10.1016/s0378-1119(03)00423-2]
Chandra, A., Aragon-Martin, J. A., Hughes, K., Gati, S., Reddy, M. A., Deshpande, C., Cormack, G., Child, A. H., Charteris, D. G., Arno, G. A genotype-phenotype comparison of ADAMTSL4 and FBN1 in isolated ectopia lentis. Invest. Ophthal. Vis. Sci. 53: 4889-4896, 2012. [PubMed: 22736615] [Full Text: https://doi.org/10.1167/iovs.12-9874]
Christensen, A. E., Fiskerstrand, T., Knappskog, P. M., Boman, H., Rodahl, E. A novel ADAMTSL4 mutation in autosomal recessive ectopia lentis et pupillae. Invest. Ophthal. Vis. Sci. 51: 6369-6373, 2010. [PubMed: 20702823] [Full Text: https://doi.org/10.1167/iovs.10-5597]
Collin, G. B., Hubmacher, D., Charette, J. R., Hicks, W. L., Stone, L., Yu, M., Naggert, J. K., Krebs, M. P., Peachey, N. S., Apte, S. S., Nishina, P. M. Disruption of murine Adamtsl4 results in zonular fiber detachment from the lens and in retinal pigment epithelium dedifferentiation. Hum. Molec. Genet. 24: 6958-6974, 2015. [PubMed: 26405179] [Full Text: https://doi.org/10.1093/hmg/ddv399]
Gabriel, L. A. R., Wang, L. W., Bader, H., Ho, J. C., Majors, A. K., Hollyfield, J. G., Traboulsi, E. I., Apte, S. S. ADAMTSL4, a secreted glycoprotein widely distributed in the eye, binds fibrillin-1 microfibrils and accelerates microfibril biogenesis. Invest. Ophthal. Vis. Sci. 53: 461-469, 2012. [PubMed: 21989719] [Full Text: https://doi.org/10.1167/iovs.10-5955]
Greene, V. B., Stoetzel, C., Pelletier, V., Perdomo-Trujillo, Y., Liebermann, L., Marion, V., De Korvin, H., Boileau, C., Dufier, J. L., Dollfus, H. Confirmation of ADAMTSL4 mutations for autosomal recessive isolated bilateral ectopia lentis. Ophthal. Genet. 31: 47-51, 2010. [PubMed: 20141359] [Full Text: https://doi.org/10.3109/13816810903567604]
Neuhann, T. M., Artelt, J., Neuhann, T. F., Tinschert, S., Rump, A. A homozygous microdeletion within ADAMTSL4 in patients with isolated ectopia lentis: evidence of a founder mutation. Invest. Ophthal. Vis. Sci. 52: 695-700, 2011. [PubMed: 21051722] [Full Text: https://doi.org/10.1167/iovs.10-5740]