Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alport syndrome (AS), an X-linked kidney disorder, has been shown to be caused by mutations in the gene for the alpha 5-chain of type IV collagen (COL4A5), which maps to Xq22. On the basis of the results of conventional Southern blot analysis of AS patient DNAs, we employed pulsed-field gel electrophoresis to characterize further three gene rearrangements at the 3'-end of alpha 5(IV). We were able to construct long-range restriction maps for all three of these patients and deduce the extent and nature of each rearrangement. One of these mutations is a 450-kb simple deletion that includes 12 kb of the alpha 5(IV) gene. A second mutation has been shown to be a direct duplication of 35 kb of alpha 5(IV) genomic DNA, and a third mutation involves a complex insertion/deletion event resulting in an overall loss of 25 kb.
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PMID:DNA rearrangements in the alpha 5(IV) collagen gene (COL4A5) of individuals with Alport syndrome: further refinement using pulsed-field gel electrophoresis. 133 Aug 89

A large kindred with adult-type X-linked Alport syndrome was studied with regard to a defect in the recently described COL4A5 collagen gene. Southern blot analysis with COL4A5 cDNA probes showed loss of a MspI restriction site. Direct sequencing of cDNA amplified from lymphoblast mRNA demonstrated a single-base substitution converting a glycine codon to arginine at position 325 in the alpha 5 chain of type IV collagen. The triple-helical collagenous domain of alpha 5(IV), characterized by a Gly-X-Y repeat sequence, is interrupted 22 times by noncollagenous sequences. The mutation creates an additional interruption in the Gly-X-Y repeat motif, between interruptions 4 and 5. It is interesting that such glycine substitutions inside the COL1A1 or COL1A2 genes have been associated with many cases of osteogenesis imperfecta. This gly325-to-arg substitution presumably alters the triple-helix formation, and, in turn, modifies the ultrastructural and functional characteristics of the type IV collagen network inside the glomerular basement membrane.
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PMID:Substitution of arginine for glycine 325 in the collagen alpha 5 (IV) chain associated with X-linked Alport syndrome: characterization of the mutation by direct sequencing of PCR-amplified lymphoblast cDNA fragments. 137 65

We review the recent progress achieved on the understanding of the molecular basis of Alport's syndrome. This inherited disease is defined as progressive nephritis with sensorineural hearing loss. In 80%-85% of the families, inheritance is compatible with X-linked dominant transmission, whereas in the remaining cases autosomal dominant transmission is assumed. Histology studies demonstrated that the main defect is within the glomerular basement membrane (GBM). In addition, evidence for an altered GBM antigenicity came from immunofluorescence studies which showed a reduced or absent binding of anti-GBM autoantibodies or monoclonal antibodies to the "Goodpasture antigen" in some families. Subsequent studies added substantial evidence that Alport's syndrome is a type IV collagen disease. Genetic linkage analyses coherently identified an Alport locus at the X-chromosomal region Xq21.3-22. Recently, a previously unknown alpha 5 chain of type IV collagen was identified, and the corresponding gene was also mapped to Xq22. Subsequent studies on Alport families by various groups identified more than 25 COL4A5 lesions. Segregation in linkage with the Alport phenotype could be shown in large kindreds. Mainly deletions and only a few point mutations were described. Most lesions reported so far are heterogeneous. We were able to identify two deletions and one point mutation involving a 3' splice site in 20 Alport families from Germany. One of the patients with a COL4A5 deletion and the patient with the splice site mutation developed anti-GBM antibodies after renal transplantation. In contrast, no COL4A5 lesions have been found in 2 further patients with posttransplant anti-GBM nephritis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular aspects of Alport's syndrome. 145 Jun 36

Alport syndrome (AS) is an hereditary glomerulonephritis that is mainly inherited as a dominant X-linked trait. Structural abnormalities in the type IV collagen alpha 5 chain gene (COL4A5), which maps to Xq22, have recently been detected in several patients with AS. The association of AS with diffuse esophageal leiomyomatosis (DL) has been reported in 24 patients, most of them also suffering from congenital cataract. The mode of transmission and the location of the gene(s) involved in this association have not been elucidated. Southern blotting using cDNA probes spanning the whole COL4A5 and a 5' end COL4A5 genomic probe showed that three out of three patients with the DL-AS association had a deletion in the 5' part of the COL4A5 gene extending beyond its 5' end. This indicates that the same gene, COL4A5, is involved in classical AS and in DL-AS and that the transmission of DL-AS is X-linked dominant. These results also suggest that leiomyomatosis might be due to the alteration of a second gene involved in smooth muscle cell proliferation, which is located upstream of the COL4A5 gene, and that there might be a contiguous gene deletion syndrome, involving at least the genes coding for congenital cataract, DL and AS.
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PMID:Alport syndrome and diffuse leiomyomatosis: deletions in the 5' end of the COL4A5 collagen gene. 145 2

Alport syndrome is a hereditary glomerulonephritis in which progressive loss of kidney function is often accompanied by sensorineural deafness. Ultrastructural studies in glomerular basement membranes (GBM) of Alport syndrome patients implicate an altered GBM protein structure as the cause of nephritis. The product of COL4A5, the alpha 5 (IV) collagen chain, is a specific component of GBM of the kidney. Various mutations in the COL4A5 gene have been identified in X-linked dominant Alport syndrome, and these aberrations of the alpha 5 (IV) can account for at least a part of X-linked Alport syndrome.
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PMID:[Molecular genetics of Alport syndrome]. 149 54

Fourteen Italian patients affected with X-linked Alport syndrome were analyzed by Southern blotting, using cDNA probes of the COL4A5 gene. One proband was shown to carry a large deletion (greater than 38 kb) that included the 5' part of the gene.
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PMID:Alport syndrome caused by a 5' deletion within the COL4A5 gene. 157 59

X-linked Alport syndrome is a hereditary glomerulonephritis in which progressive loss of kidney function is often accompanied by progressive loss of hearing. Ultrastructural defects in glomerular basement membranes (GBM) of Alport syndrome patients implicate an altered structural protein as the cause of nephritis. The product of COL4A5, the alpha 5(IV) collagen chain, is a specific component of GBM within the kidney, and the gene maps to the same X chromosomal region as does Alport syndrome. 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.
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PMID:Identification of mutations in the COL4A5 collagen gene in Alport syndrome. 234 82

Alport syndrome is an inherited disorder characterized by progressive nephritis with ultrastructural basket-weave changes of the glomerular basement membrane and neurosensory deafness. Mutations in the COL4A5 gene encoding the Type IV collagen alpha 5 chain have been reported to occur in patients with X-linked Alport syndrome. A girl with hematuric nephritis, characteristic basket-weave glomerular basement membrane changes, and abnormal expression of the Type IV collagen alpha 5 chain immunohistochemically, but no family history of nephritis, was identified. Mutation detection enhancement gel electrophoresis of the polymerase chain reaction-amplified exons of COL4A5 from this patient revealed a sequence variant in the exon 50 region. Sequence analysis of her polymerase chain reaction product demonstrated a single-base (C; nucleotide 4728 from the 5' end) deletion in exon 50. This novel mutation alters the reading frame and introduces a translation stop codon that would be expected to result in a noncollagenous domain with only 209, instead of the normal 229, amino acid residues. Gene tracking with restriction enzyme AfIIII demonstrated that her mother was normal. These findings represent a new mutation of the X-linked Alport syndrome in this patient and demonstrate that a COL4A5 gene mutation causes the abnormal expression of Type IV collagen alpha 5 chain protein.
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PMID:Mutation in alpha 5(IV) collagen chain gene in nonfamilial hematuria. 757 94

The X-linked form of Alport disease, caused by mutations in the COL4A5 or the COL4A6 gene, usually leads to terminal renal failure in males, while affected females have a more variable and moderate phenotype. We detected in a female patient, with a severe Alport phenotype, two new missense mutations. One mutation (G289V) occurred in exon 15 and converted a glycine in a collagenous domain of COL4A5 to a valine. The second mutation, located in exon 46, substituted a cysteine proximal to the NC1 domain of COL4A5 for an arginine. In white blood cells and kidney both mutations were present on > 90% of the mRNA, while at the genomic level the patient was heterozygous for both mutations. The two mutations therefore occurred in the same COL4A5 allele. No mutation was found in the COL4A5 promoter region by sequencing nor was a major rearrangement of the normal allele detected. 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. 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.
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PMID:Severe alport phenotype in a woman with two missense mutations in the same COL4A5 gene and preponderant inactivation of the X chromosome carrying the normal allele. 770 90

Diffuse oesophageal leiomyomatosis (DL), an inherited smooth muscle proliferation process, has been reported to be associated with Alport syndrome (AS), a familial nephropathy, mainly dominant X-linked inherited, and characterized by ultrastructural changes of the glomerular basement membrane. The COL4A5 gene, encoding the alpha 5 chain of type IV collagen, has been identified as the site of mutations in families with X-linked AS. Recently, a novel alpha 6(IV) collagen chain encoding gene has been mapped closely upstream of COL4A5, and disruption of the 5' end of both genes has been reported in four patients with DL and AS (DL-AS). Here, we report a long-range restriction map around the COL4A6 locus, and show that the COL4A5/COL4A6 deletion observed in seven patients with DL-AS encompasses only the two first exons of COL4A6, with a breakpoint located in the second intron of COL4A6, whose size exceeds 65 kb. Furthermore, we demonstrate that three patients with AS without DL, known to have a deletion of the 5' part of the COL4A5 gene, display a larger deletion in COL4A6. Moreover, a COL4A6 mRNA product was detected by reverse-transcription-polymerase chain reaction in an oesophageal tumour sample of a patient with DL-AS. These results suggest that DL-AS could be caused by an abnormal truncated alpha 6(IV) chain.
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PMID:Deletions of both alpha 5(IV) and alpha 6(IV) collagen genes in Alport syndrome and in Alport syndrome associated with smooth muscle tumours. 771 41


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