Disease relevance of ACVRL1

• In some families in whom a form of idiopathic pulmonary arterial hypertension cosegregated with HHT, mutations in the ACVRL1 gene were present [1].
• Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease characterized by arteriovenous malformations and resulting from mutations in two major genes: ENG and ACVRL1 [2].
• Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia [3].
• METHODS: The coding sequence (in 44 patients with AVMs and 27 with aneurysms) and the 5' end and the polyA site (in 53 patients with AVMs) of the ACVRL1 gene were analyzed for sequence variations using direct sequencing and single-strand conformational polymorphism analysis [4].
• One ENG and three ACVRL1 gene polymorphisms were genotyped using restriction enzyme-based analysis in 101 patients with sporadic AVMs and DAVFs of the CNS, 79 patients treated for intracranial aneurysms, and 202 control volunteers [4].

Psychiatry related information on ACVRL1

• In endothelial cells, TGF-beta binds to two distinct type I receptor serine-threonine kinases, ALK-5 and ALK-1; the latter activates the same R-Smads that are activated by BMP and induces synthesis of Id (inhibitor of differentiation or inhibitor of DNA binding) proteins [5].

High impact information on ACVRL1

• In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations [6].
• RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1 [6].
• CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1 [6].
• We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension [6].
• Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries [6].

Chemical compound and disease context of ACVRL1

• Therapeutic action of tranexamic acid in hereditary haemorrhagic telangiectasia (HHT): Regulation of ALK-1/endoglin pathway in endothelial cells [7].
• The translocation t(2;5)(p23;q35), discovered in CD30+ anaplastic large cell (ALC) lymphomas, creates a potentially oncogenic fusion gene, part of which is contributed by a novel tyrosine kinase, ALK [8].
• A chemically defined medium in which Streptococcus mutans strains AHT, BHT, GS-5, JC-2, Ingbritt, At6T, At9T, 6715, and OMZ-176 and Streptococcus salivarius strain HHT grew rapidly to high turbidities was formulated [9].
• Formalin-fixed, paraffin-embedded archival tissues were stained for HHV-8 and ALK with immunohistochemistry [10].
• Density-defined macrophages isolated from fluids of patients with liver cirrhosis mainly generated the 5-lipoxygenase products leukotriene B4 (LTB4, 16%) and 5-hydroxy-eicosatetraenoic acid (5-HETE, 24%) and the cyclooxygenase products 12-hydroxyheptadecatrienoic acid (HHT, 22%) and thromboxane B2 (TXB2, 18%) [11].

Biological context of ACVRL1

• Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype [12].
• Mutations in ACVRL1 cluster largely in exons 7 and 8, but ENG mutations were widely distributed within that gene [13].
• Interestingly, the majority of ACVRL1 mutations represented missense mutations, whereas mutations in ENG mostly resulted in a shortened protein [14].
• A second locus, designated ORW2, was mapped to chromosome 12 [15].
• Levels were also normal in a HUVEC with deletion of S232 in the ATP binding site of ALK-1 [16].

Anatomical context of ACVRL1

• Our data suggest a critical role for ALK1 in the control of blood vessel development or repair [15].
• It includes the activin receptor like kinase 1 gene (ACVRLK1 or ALK1), a member of the serine-threonine kinase receptor family expressed in endothelium [15].
• Using a novel polyclonal antibody to ALK-1, we measured ALK-1 expression on human umbilical vein endothelial cells (HUVEC) of newborns from HHT families whose affected members had normal endoglin levels [16].
• Interestingly, endoglin up-regulation was deficient in activated monocytes of both HHT1 and HHT2 patients compared with controls [17].
• Because searches of the human genome for genes with sequence homology to known serine/threonine kinase receptors failed to reveal uncharacterized receptor genes, GDF9 likely interacts with the known type II and type I activin receptor-like kinase (ALK) receptors in granulosa cells [18].

Associations of ACVRL1 with chemical compounds

• Human cDNA clones encoding four novel putative transmembrane protein serine/threonine kinases, denoted activin receptor-like kinase (ALK) -1, -2, -3 and -4, were obtained using a polymerase chain reaction (PCR)-based strategy [19].
• However, the sequence identities are higher (60-79%) between ALK-1, -2, -3 and -4, suggesting that they form a subfamily among the putative receptor serine/threonine kinases [19].
• Further analysis by competitive quantitative RT-PCR and Western blot demonstrated that DHT did not affect the level of expression of ALK-1 and -2 in LNCaP cells [20].
• Blockage of ligand-receptor binding using extracellular domain (ECD) of BMP type I receptors revealed that ECDs to activin receptor-like kinase (ALK)-2 and ALK-3 significantly reduced the aldosterone production induced by Ang II [21].
• Renal ALK-5 and TbetaRII protein expressions in the losartan-treated group were found to be significantly increased (P<0.05), whereas TGF-beta1, ALK-1, and alpha-SMA protein expressions were not changed by losartan treatment [22].

Physical interactions of ACVRL1

• Their structural properties suggest that ALK-1 to -4 are receptors that may bind ligands that are members of the TGF-beta superfamily [19].
• Using the two-hybrid system, we identified an ALK1-binding protein encoded by an ancient retroviral/retrotransposon element integrated as a single copy gene known as PEG10 on human chromosome 7q21 [23].
• Interestingly, SKR-3 could interact with both CUL-1 and its close paralog CUL-6 [24].

Other interactions of ACVRL1

• We report three mutations in the coding sequence of the ALK1 gene in those families which show linkage of the ORW phenotype to chromosome 12 [15].
• In HUVEC, ALK-1 was not detectable in the TGF-beta1 or -beta3 receptor complexes [16].
• TEK and ACVRL1 could essentially be excluded [25].
• DNA from the proband of each family was sequenced for the ACVRL1, ENG, and MADH4 genes [26].
• In COS-1 transfected cells, ALK-1 was found in the TGF-beta1 and -beta3 receptor complexes in association with endoglin and TbetaRII, but not in activin receptor complexes containing endoglin [16].

Analytical, diagnostic and therapeutic context of ACVRL1

• However, in the absence of ligand, ALK-1 and endoglin interactions were observed by immunoprecipitation/western blot in HUVEC from normal as well as HHT1 and HHT2 patients [16].
• We report here on the genetic and molecular heterogeneity found in the HHT population in the Netherlands. Probands of 104 apparently unrelated families were studied and we performed sequence analysis on both the ENG gene and ALK-1 gene [27].
• To identify downstream genes implicated in ALK-1 cellular responses, we next performed a cDNA array analysis of the expressed genes [28].
• We performed temperature gradient capillary electrophoresis and full gene sequencing of both ACVRL1 and ENG genes [29].
• The high rate of detection of mutations by genomic sequencing of ALK-1 suggests that this will be a useful diagnostic test for HHT2, particularly where preliminary linkage to chromosome 12q13 can be established [30].

References