Disease relevance of COL4A5

• Alport (COL4A5) gene-disease database  
• In earlier studies, intragenic deletions of COL4A5 were detected in a subset of patients with Alport syndrome (AS), a hereditary defect of basement membranes [1].
• In the present study, we examined the expression of the alpha5(IV)/alpha6(IV) chains and the methylation profiles of the bidirectional promoter region of COL4A5/COL4A6 in colon cancer cell lines and colorectal tumor tissues [2].
• A subtype of X-linked Alport syndrome (XLAS) in which diffuse leiomyomatosis is an associated feature reflects deletion mutations involving the adjacent COL4A5 and COL4A6 genes [3].
• RESULTS: Hematuria in this family segregated with a haplotype at the COL4A3/COL4A4 locus (P = 0.031) but not with haplotypes at the COL4A5 locus [4].
• Three structural aberrations were found in COL4A5, in intragenic deletion, a Pst I site variant, and an uncharacterized abnormality, which appear to cause nephritis and deafness, with allele-specific severity, in three Alport syndrome kindreds in Utah [5].

Psychiatry related information on COL4A5

• We observed a family in which two boys were diagnosed with Alport syndrome, elliptocytosis, and mental retardation and carried a large deletion of the Xq22.3-q23 region, encompassing the COL4A5 gene [6].
• A score (ATS) was calculated by summing the percent lumen narrowing of all main vessels; alcohol consumption was quantitated by questionnaire [7].

High impact information on COL4A5

• Our recent discovery of the contiguous gene deletion syndrome ATS-MR (previously known as Alport syndrome, mental retardation, midface hypoplasia, elliptocytosis, OMIM #300194), characterized by Alport syndrome (ATS) and mental retardation (MR), indicated Xq22.3 as a region containing one mental retardation gene [8].
• Comparing the extent of deletion between individuals with ATS-MR and individuals with ATS alone allowed us to define a critical region for mental retardation of approximately 380 kb, containing four genes [8].
• The gene encoding alpha 6(IV) collagen, COL4A6, was identified on the human X chromosome in a head-to-head arrangement and within 452 base pairs of the alpha 5(IV) collagen gene, COL4A5 [1].
• A skewed pattern of X inactivation was demonstrated in DNA isolated from the patient's kidney and white blood cells: > 90% of the X chromosomes with the normal COL4A5 allele was inactivated [9].
• It is suggested that this skewed inactivation pattern is responsible for the absence of detectable normal COL4A5 mRNA and hence the severe phenotype in this woman [9].

Chemical compound and disease context of COL4A5

• De novo mutation in the COL4A5 gene converting glycine 325 to glutamic acid in Alport syndrome [10].
• A novel frameshift deletion in type IV collagen alpha 5 gene in a juvenile-type Alport syndrome patient: an adenine deletion (2940/2943 del A) in exon 34 of COL4A5 [11].
• Tumor-associated mucin-type glycoprotein (CA54/61) defined by two monoclonal antibodies (MA54 and MA61) in ovarian cancers [12].
• Leptomycin B (LMB), a secondary metabolite produced by Streptomyces sp. strain ATS 1287, with known antifungal and antitumor effects, inhibits the nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 regulatory protein Rev and exhibits significant antiproliferative activity [13].
• 105 patients of both sexes with mild bronchial asthma were included in this study and were subjected to methacholine test according to ATS standards [14].

Biological context of COL4A5

• However, the COL4A5 gene contains 51 exons, or one less than COL4A1 [15].
• The alpha5(IV) gene (COL4A5) and the alpha6(IV) gene (COL4A6) are on chromosome Xq22 and are regulated by a bidirectional promoter [2].
• In conclusion, the hypermethylation of the bidirectional promoter region of COL4A5/COL4A6 is one of the events that is responsible for the loss of expression of the alpha5(IV)/alpha6(IV) chains and the remodeling of the epithelial BM during cancer cell invasion [2].
• Recently, the target for alloantibodies from an X-linked Alport patient with complete COL4A5 gene deletion was determined to be the alpha 3 chain of type IV collagen [16].
• RESULTS: In four cases with the COL4A5 frameshift or missense mutations, the COL4A5 chain was either lacking from the EBM (male) or showed a focally negative pattern (female) [17].

Anatomical context of COL4A5

• BACKGROUND: Carriers of autosomal-recessive and X-linked Alport syndrome often have a thinned glomerular basement membrane (GBM) and have mutations in the COL4A3/COL4A4 and COL4A5 genes respectively [4].
• A 10.6-kb fragment upstream of COL4A5 directs expression in the esophagus [18].
• The COL4A5 chain was absent from all cochlear basement membranes except those in the vessels of the stria vascularis [19].
• This sequence was absent in all white blood cell RNA samples sequenced by us, indicating tissue specific splicing with the presence of an additional exon in kidney COL4A5 mRNA [20].
• Detection of mutations in the COL4A5 gene by analyzing cDNA of skin fibroblasts [21].

Associations of COL4A5 with chemical compounds

• After systematic analysis of all 51 exons of COL4A5, we have now identified 30 different mutations: 10 glycine substitutions in the triple helical domain of the protein, 9 frameshift mutations, 4 in-frame deletions, 1 start codon, 1 nonsense, and 5 splice-site mutations [22].
• The second mutation, located in exon 46, substituted a cysteine proximal to the NC1 domain of COL4A5 for an arginine [9].
• One mutation (G289V) occurred in exon 15 and converted a glycine in a collagenous domain of COL4A5 to a valine [9].
• In contrast, the xenograft from recipients treated with 5 doses of ATS still contained well-preserved islet tissue with many insulin and glucagon containing cells on the day of graft removal when blood glucose had returned to the hyperglycemic level [23].
• When transplanted into ATS-treated hamsters, the cells transformed by MNNG (0.01 mug/ml) and Ki-MSV produced tumors but MNNG (0.1 mug/ml) transformed cells did not produce tumors [24].

Other interactions of COL4A5

• Recently, several mutations in three other collagen genes (COL2A1, COL3A1, and COL4A5) have been found in probands with genetic diseases involving tissues rich in these collagens [25].
• Approximately 85% of patients with Alport syndrome (hereditary nephritis) have been estimated to have mutations in the X chromosomal COL4A5 collagen gene; the remaining cases are autosomal with mutations in the COL4A3 or COL4A4 genes located on chromosome 2 [26].
• The results establish the target for the alloantibodies from an autosomal recessive Alport patient with COL4A3 deletion as principally the alpha 3(IV) collagen chain, similar to the post-transplant alloantibodies from X-linked Alport patients with COL4A5 gene deletions [16].
• Other candidate collagen genes encoding basement membrane collagen (COL4A1/A2 and COL4A5/A6) were excluded by linkage analysis (13q33-q34 and Xq22), or by sequence (COL4A3) [27].
• X-linked Alport syndrome is much less common than TBMN and can often be identified in family members by its typical clinical features (including retinopathy), a lamellated GBM without the collagen alpha3(IV), alpha4(IV), and alpha5(IV) chains, and by gene linkage studies or the demonstration of a COL4A5 mutation [28].

Analytical, diagnostic and therapeutic context of COL4A5

• Differential expression of two basement membrane collagen genes, COL4A6 and COL4A5, demonstrated by immunofluorescence staining using peptide-specific monoclonal antibodies [29].
• Southern blot analysis with COL4A5 cDNA probes showed loss of a MspI restriction site [30].
• High mutation detection rate in the COL4A5 collagen gene in suspected Alport syndrome using PCR and direct DNA sequencing [26].
• Identification of COL4A5 defects in Alport's syndrome by immunohistochemistry of skin [17].
• METHODS: The index case and all available family members were examined for dysmorphic hematuria> 50,000/mL using phase contrast microscopy and for segregation of hematuria with the COL4A3/COL4A4 and COL4A5 loci using DNA satellite markers [4].

References