Alternative titles; symbols
HGNC Approved Gene Symbol: AEBP1
SNOMEDCT: 1255121003;
Cytogenetic location: 7p13 Genomic coordinates (GRCh38): 7:44,104,345-44,114,560 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p13 | Ehlers-Danlos syndrome, classic-like, 2 | 618000 | Autosomal recessive | 3 |
Vascular smooth muscle cells originate from diverse cell types during embryonic development and acquire different phenotypes in disease states. The interactions of these cells with the extracellular matrix (ECM) are important in governing these processes. By screening a human aortic smooth muscle cell expression library for proteins that interact with the E47 product of E2A (TCF3; 147141), Layne et al. (1998) isolated a full-length cDNA encoding ACLP. The deduced 1,158-amino acid ACLP protein contains a putative signal peptide; an 11-residue lys/pro-rich motif repeated 4 times in the N terminus; a domain with 30% identity to the slime mold adhesion protein discoidin I; and a C-terminal 500-amino acid domain with 39% identity to carboxypeptidase E (CPE; 114855). Northern blot analysis detected a 4.0-kb ACLP transcript. Immunoblot analysis showed expression of a 175-kD ACLP protein. Western blot analysis and in situ hybridization established that expression of ACLP is largely restricted to aorta, particularly to smooth muscle cells. Immunofluorescence microscopy demonstrated perinuclear staining in mouse aortic smooth muscle cells.
By genomic sequence analysis, Layne et al. (2001) determined that the mouse Aclp gene contains 21 exons.
Gross (2018) mapped the AEBP1 gene to chromosome 7p13 based on an alignment of the AEBP1 sequence (GenBank AF053944) with the genomic sequence (GRCh38).
By purification of aortic smooth muscle cells from day-18.5 mouse embryos, followed by immunoblot analysis, Layne et al. (2001) showed that Aclp is a secreted protein that associates with the ECM, as predicted from its primary structure. Immunohistochemistry of day-15.5 mouse embryos revealed wide expression of Aclp in vascular smooth muscle cells, in bony and cartilaginous skeleton (skull, vertebrae, and ribs), in the basement membrane of lung airways, and in the dermis.
Blackburn et al. (2018) performed binding assays and observed that the discoidin domain of ACLP binds to most collagens, but has a preference for collagens I (see 120150), III (120180), and V (see 120215). Binding to collagen I was also shown to be dependent on glycosylation, with reduced binding to deglycosylated forms. When full-length recombinant ACLP was added to denatured collagen I, it significantly enhanced collagen polymerization under physiologic conditions. The authors suggested that ACLP is involved in organization and remodeling of the extracellular matrix through direct binding of collagens and modulation of collagen fibrillogenesis.
In 2 sibs from a consanguineous Saudi family with classic-like Ehlers-Danlos syndrome (EDSCLL2; 618000), Alazami et al. (2016) performed whole-exome sequencing and identified homozygosity for a splice site mutation in the AEBP1 gene (602981.0001) that segregated fully with disease in the family.
In 2 unrelated men with classic-like Ehlers-Danlos syndrome, Blackburn et al. (2018) identified compound heterozygosity and homozygosity, respectively, for mutations in the AEBP1 gene (602981.0002-602981.0004).
By exome sequencing in 2 adult sibs (family D) with classic-like Ehlers-Danlos syndrome, Hebebrand et al. (2019) identified homozygosity for a nonsense mutation in the AEBP1 gene (Y306X; 602981.0005).
By homologous recombination, Layne et al. (2001) generated Aclp -/- mice. Although heterozygotes were phenotypically normal, most Aclp -/- mice succumbed around the time of birth with gastroschisis, an extrusion of the abdominal viscera through the ventral body wall. Gastroschisis appeared as early as day 13.5. Many dead neonates were pale and had missing abdominal organs, such as liver and intestine. Aclp -/- mice that survived to adulthood had large, nonhealing skin lesions, deficient wound repair, and poor fibroblast proliferation. Layne et al. (2001) concluded that ACLP has important roles in both embryonic development and adult tissue repair.
Layne et al. (1998) found that the C terminus of ACLP is highly homologous to AEBP1, which was originally identified in mouse by He et al. (1995) as a factor that specifically binds AE1 and acts as a repressor of aP2 gene (600434) expression. Aebp1 contains a region that is 40% identical to the regulatory carboxypeptidases CPH/E, CPN (212070), and CPM (114860). He et al. (1995) found that CP activity was important for the transcriptional repression activity of Aebp1 and suggested that Aebp1 regulates transcription by cleavage of factors involved in transcription. Ohno et al. (1996) identified human AEBP1 as a gene whose cDNAs were found exclusively in osteoblast and adipose tissue libraries. The predicted 845-amino acid human AEBP1 protein is 95% identical to mouse Aebp1 except for an additional 105 amino acids in the N terminus of the human protein. This N-terminal extension contains a nuclear targeting signal. Northern blot analysis of various human tissues detected a 3-kb AEBP1 mRNA only in osteoblasts and adipose tissues.
Song and Fricker (1997), however, reported that AEBP1 has no carboxypeptidase activity; in contrast, CPZ (603105), CPE, and CPD (603102) were found to have modest or abundant activity. Layne et al. (1998) determined that the Aebp1 sequence described by He et al. (1995) lacks a G residue 11 bases 5-prime of the proposed start codon and is likely an incomplete clone of mouse Aclp. Northern blot analysis, even with Aepb1-derived probes, detected a single 4.0-kb transcript, which is consistent with the size of the human and mouse ACLP cDNAs. Furthermore, Layne (2001) stated that they have never detected nuclear localization of ACLP, nor have they detected any ACLP splice variants that might account for the discrepant data, suggesting that the human sequence reported by Ohno et al. (1996) is also a truncated clone.
In a 14-year-old Saudi girl and her 21-year-old brother (family 1, ID 14DG1601) with classic-like Ehlers-Danlos syndrome (EDSCLL2; 618000), Alazami et al. (2016) identified homozygosity for a splice site mutation (c.1630+1G-A, NM_001129.3) in intron 13 of the AEBP1 gene that segregated fully with disease in the family. RT-PCR revealed skipping of the last 22 bp of exon 13, causing a frameshift resulting in premature termination. Blackburn et al. (2018) stated that the c.1630+1G-A variant had been observed in 9 individuals in the gnomAD database, with a minor allele frequency of 3.313 x 10(-5).
In a 35-year-old man of German and Panamanian ancestry (family A) with classic-like Ehlers-Danlos syndrome (EDSCLL2; 618000), Blackburn et al. (2018) identified compound heterozygosity for a 1-bp deletion (c.1470delC, NM_001129.4) in exon 12 of the AEBP1 gene, causing a frameshift predicted to result in a premature termination codon (Asn490LysfsTer6) within the discoidin domain, and a c.1743C-A transversion in exon 15, resulting in a cys581-to-ter (C581X; 602981.0003) substitution within the carboxypeptidase-like domain. His unaffected parents and an unaffected brother were each heterozygous for 1 of the mutations. The 1-bp deletion was not found in the gnomAD or dbSNP databases, whereas the C581X variant was present in the gnomAD database at an allele frequency of 1/264,694. Sequencing of the PCR product of the 1-bp deletion revealed that the cDNA fragment retained all 103 bp of intron 12, with in-frame continuation of exon 13; the amino acid sequence derived from mRNA showed loss of the last 6 amino acids encoded by exon 12 due to the shift in reading frame, and inclusion of 40 aberrant amino acids before returning to in-frame translation of exon 13, which the authors designated as Asn490_Met495delins(40).
For discussion of the c.1743C-A transversion (c.1743C-A, NM_001129.4) in exon 15 of the AEBP1 gene, resulting in a cys581-to-ter (C581X) substitution, that was found in compound heterozygous state in a patient with classic-like Ehlers-Danlos syndrome (EDSCLL2; 618000) by Blackburn et al. (2018), see 602981.0002.
In a 41-year-old man of Italian ancestry (family B) with classic-like Ehlers-Danlos syndrome (EDSCLL2; 618000), Blackburn et al. (2018) identified homozygosity for a 7-bp deletion (c.1320_1326delGACCCAG, NM_001129.4) in exon 11 of the AEBP1 gene, causing a frameshift predicted to result in a premature termination codon (Arg440SerfsTer3). Analysis of patient fibroblasts showed no ACLP protein by Western blot analysis, suggesting that the variant results in nonsense-mediated decay and is a null variant.
In 2 sibs (family D) with classic-like Ehlers-Danlos syndrome (EDSCLL2; 618000), Hebebrand et al. (2019) identified homozygosity for a 1-bp duplication at nucleotide 917 (c.917dup, NM_001129.4) of the AEBP1 gene, causing a tyr306-to-ter substitution (Y306X). The phenotypically normal mother was heterozygous for the variant, but the father could not be tested. Chromosome microarray showed that the variant was located in a region of homozygosity, suggesting a common origin. RT-PCR analysis of the carrier mother showed monoallelic expression of the normal transcript, suggesting nonsense-mediated mRNA decay and a null variant in the sibs.
Alazami, A. M., Al-Qattan, S. M., Faqeih, E., Alhashem, A., Alshammari, M., Alzahrani, F., Al-Dosari, M. S., Patel, N., Alsagheir, A., Binabbas, B., Alzaidan, H., Alssiddiky, A., and 12 others. Expanding the clinical and genetic heterogeneity disorders of connective tissue. Hum. Genet. 135: 525-540, 2016. [PubMed: 27023906] [Full Text: https://doi.org/10.1007/s00439-016-1660-z]
Blackburn, P. R., Xu, Z., Tumelty, K. E., Zhao, R. W., Monis, W. J., Harris, K. G., Gass, J. M., Cousin, M. A., Boczek, N. J., Mitkov, M. V., Cappel, M. A., Francomano, C. A., Parisi, J. E., Klee, E. W., Faqeih, E., Alkuraya, F. S., Layne, M. D., McDonnell, N. B., Atwal, P. S. Bi-allelic alterations in AEBP1 lead to defective collagen assembly and connective tissue structure resulting in a variant of Ehlers-Danlos syndrome. Am. J. Hum. Genet. 102: 696-705, 2018. [PubMed: 29606302] [Full Text: https://doi.org/10.1016/j.ajhg.2018.02.018]
Gross, M. B. Personal Communication. Baltimore, Md. 6/4/2018.
He, G.-P., Muise, A., Li, A. W., Ro, H.-S. A eukaryotic transcriptional repressor with carboxypeptidase activity. Nature 378: 92-96, 1995. [PubMed: 7477299] [Full Text: https://doi.org/10.1038/378092a0]
Hebebrand, M., Vasileiou, G., Krumbiegel, M., Kraus, C., Uebe, S., Ekici, A. B., Thiel, C. T., Reis, A., Popp, B. A biallelic truncating AEBP1 variant causes connective tissue disorder in two siblings. Am. J. Med. Genet. 179: 50-56, 2019. [PubMed: 30548383] [Full Text: https://doi.org/10.1002/ajmg.a.60679]
Layne, M. D., Endege, W. O., Jain, M. K., Yet, S.-F., Hsieh, C.-M., Chin, M. T., Perrella, M. A., Blanar, M. A., Haber, E., Lee, M.-E. Aortic carboxypeptidase-like protein, a novel protein with discoidin and carboxypeptidase-like domains, is up-regulated during vascular smooth muscle cell differentiation. J. Biol. Chem. 273: 15654-15660, 1998. [PubMed: 9624159] [Full Text: https://doi.org/10.1074/jbc.273.25.15654]
Layne, M. D., Yet, S.-F., Maemura, K., Hsieh, C.-M., Bernfield, M., Perrella, M. A., Lee, M.-E. Impaired abdominal wall development and deficient wound healing in mice lacking aortic carboxypeptidase-like protein. Molec. Cell. Biol. 21: 5256-5261, 2001. [PubMed: 11438679] [Full Text: https://doi.org/10.1128/MCB.21.15.5256-5261.2001]
Layne, M. Personal Communication. Baltimore, Md. 7/6/2001.
Ohno, I., Hashimoto, J., Shimizu, K., Takaoka, K., Ochi, T., Matsubara, K., Okubo, K. A cDNA cloning of human AEBP1 from primary cultured osteoblasts and its expression in a differentiating osteoblastic cell line. Biochem. Biophys. Res. Commun. 228: 411-414, 1996. [PubMed: 8920928] [Full Text: https://doi.org/10.1006/bbrc.1996.1675]
Song, L., Fricker, L. D. Cloning and expression of human carboxypeptidase Z, a novel metallocarboxypeptidase. J. Biol. Chem. 272: 10543-10550, 1997. [PubMed: 9099699] [Full Text: https://doi.org/10.1074/jbc.272.16.10543]