Alternative titles; symbols
HGNC Approved Gene Symbol: TLL1
Cytogenetic location: 4q32.3 Genomic coordinates (GRCh38): 4:165,873,237-166,104,457 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q32.3 | Atrial septal defect 6 | 613087 | Autosomal dominant | 3 |
Tolloid-like-1 is an astacin-like metalloprotease that shares structural similarity to the morphogenetically important proteases bone morphogenetic protein-1 (BMP1; 112264) and Drosophila Tolloid (TLD).
By use of a fragment of mouse Tll1 cloned by Takahara et al. (1996) to screen a human placenta genomic DNA library and by RT-PCR amplification of human fetal cartilage RNA, Scott et al. (1999) obtained a full-length human TLL1 sequence. TLL1 encodes a deduced 1,013-amino acid secreted protein with a molecular mass of 115 kD by SDS/PAGE.
By in situ hybridization, Scott et al. (1999) found extensive Tll1 mRNA expression in the hindlimb of the 15.5-day embryonic mouse and in the area of the femoral growth plate at postnatal day 21.
By fluorescence in situ hybridization, Scott et al. (1999) mapped the TLL1 gene to chromosome 4q32-q33. By interspecific backcross analysis, Takahara et al. (1996) mapped the mouse Tll1 gene to chromosome 8.
Scott et al. (1999) compared enzymatic activities and expression domains of 4 mammalian BMP1/TLD-like proteases and found differences in their ability to process fibrillar collagen precursors and to cleave chordin (603475). As previously demonstrated for BMP1 and TLD, TLL1 specifically processes procollagen C-propeptides at the physiologically relevant site, whereas TLL2 (606743) lacks this activity. BMP1 and TLL1 cleave chordin, at sites similar to procollagen C-propeptide cleavage sites, and counteract dorsalizing effects of chordin upon overexpression on Xenopus embryos. Proteases TLD and TLL2 do not cleave chordin.
Based on studies in mouse with a disrupted Tll1 allele, Clark et al. (1999) suggested that the TLL1 gene plays multiple roles in formation of the mammalian heart and is essential for formation of the interventricular septum.
Stanczak et al. (2009) sequenced the TLL1 gene in 19 unrelated patients with atrial septal defect (613087) with or without other cardiovascular anomalies, and identified heterozygosity for 3 missense mutations in 3 patients (606742.0001-606742.0003, respectively).
Clark et al. (1999) used gene targeting in embryonic stem cells to produce mice with a disrupted allele for Tll1. Homozygous mutants were embryonic lethal, with death at midgestation from cardiac failure and a constellation of developmental defects confined to the heart. Constant features were incomplete formation of the muscular interventricular septum and an abnormal and novel positioning of the heart and aorta.
In a 35-year-old man with an isolated type I atrial septal defect (ASD6; 613087) Stanczak et al. (2009) identified heterozygosity for a 1191A-C transversion in exon 5 of the TLL1 gene, resulting in a met182-to-leu (M182L) substitution at the first residue in the catalytic domain, which is conserved among all the astacins.
In a 70-year-old man with a type II atrial septal defect (ASD6; 613087), Stanczak et al. (2009) identified heterozygosity for a 1360T-C transition in exon 6 of the TLL1 gene, resulting in a val238-to-ala (V238A) substitution at a conserved residue within the catalytic domain, located just before the zinc-binding signature. The patient also had an aneurysm of the interatrial septum and atrial fibrillation requiring pacemaker implantation, and had suffered myocardial infarction as well as cerebrovascular accident.
In a 72-year-old man with a type II atrial septal defect (ASD6; 613087), Stanczak et al. (2009) identified heterozygosity for a 1885A-G transition in exon 15 of the TLL1 gene, resulting in an ile629-to-val (I629V) substitution. The patient also had an aneurysm of the interatrial septum and bradycardia.
Clark, T. G., Conway, S. J., Scott, I. C., Labosky, P. A., Winnier, G., Bundy, J., Hogan, B. L. M., Greenspan, D. S. The mammalian Tolloid-like 1 gene, Tll1, is necessary for normal septation and positioning of the heart. Development 126: 2631-2642, 1999. [PubMed: 10331975] [Full Text: https://doi.org/10.1242/dev.126.12.2631]
Scott, I. C., Blitz, I. L., Pappano, W. N., Imamura, Y., Clark, T. G., Steiglitz, B. M., Thomas, C. L., Maas, S. A., Takahara, K., Cho, K. W. Y., Greenspan, D. S. Mammalian BMP-1/tolloid-related metalloproteinases, including novel family member mammalian tolloid-like 2, have differential enzymatic activities and distributions of expression relevant to patterning and skeletogenesis. Dev. Biol. 213: 283-300, 1999. [PubMed: 10479448] [Full Text: https://doi.org/10.1006/dbio.1999.9383]
Scott, I. C., Clark, T. G., Takahara, K., Hoffman, G. G., Eddy, R. L., Haley, L. L., Shows, T. B., Greenspan, D. S. Assignment of TLL1 and TLL2, which encode human BMP-1/tolloid-related metalloproteases, to chromosomes 4q32-q33 and 10q23-q24 and assignment of murine Tll2 to chromosome 19. Cytogenet. Cell Genet. 86: 64-65, 1999. [PubMed: 10516436] [Full Text: https://doi.org/10.1159/000015412]
Stanczak, P., Witecka, J., Szydlo, A., Gutmajster, E., Lisik, M., Augusciak-Duma, A., Tarnowski, M., Czekaj, T., Czekaj, H., Sieron, A. L. Mutations in mammalian tolloid-like 1 gene detected in adult patients with ASD. Europ. J. Hum. Genet. 17: 344-351, 2009. [PubMed: 18830233] [Full Text: https://doi.org/10.1038/ejhg.2008.175]
Takahara, K., Brevard, R., Hoffman, G. G., Suzuki, N., Greenspan, D. S. Characterization of a novel gene product (mammalian tolloid-like) with high sequence similarity to mammalian tolloid/bone morphogenetic protein-1. Genomics 34: 157-165, 1996. [PubMed: 8661043] [Full Text: https://doi.org/10.1006/geno.1996.0260]