Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035078 (renal failure)
 31,970 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the COL4A5 gene encoding the alpha 5 chain of type IV collagen have been found in linkage with X-chromosomal Alport syndrome (AS). To identify COL4A5 mutations in patients from Germany with clinically defined AS, DNA from 20 unrelated patients was analyzed by conventional Southern blotting. By using full length alpha 5(IV) cDNA probes, large COL4A5 deletions could be detected in two patients. In one case, a 34 kb deletion affecting the 14 most 3' exons of the gene was observed. The second patient harbored a complete COL4A5 deletion. In both cases, functional alpha 5(IV) mRNA was unlikely to be present. Clinically, both patients developed end-stage renal failure before age 30. Furthermore, they had characteristic retinal flecks, and sensorineural hearing loss with typical changes on the audiogram. The patient with the complete deletion of COL4A5 lost the renal allograft due to an anti-GBM mediated glomerulonephritis.
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PMID:Deletions of the COL4A5 gene in patients with Alport syndrome. 147 65

A single base mutation was identified in the type IV collagen alpha 5 chain gene (COL4A5) of a Danish kindred with Alport syndrome. The 27-year-old male proband developed hematuria in childhood and terminal renal failure at the age of 25 years. He has no hearing loss or ocular lesions. Electron microscopy demonstrated splitting of the lamina densa of the glomerular basement membrane. The proband's mother has had persistent microscopic hematuria since the age of 40 years, but no other manifestations. Southern analysis of MspI-digested genomic DNA from the proband showed the absence of 1.3-kb and 0.9-kb fragments present in control DNA but the presence of a 2.2-kb variant fragment, indicating the loss of an MspI restriction site in the 3' end of the gene. The mother had all three fragments, indicating heterozygosity. PCR amplification of exon 14 (counted from the 3' end) and subsequent denaturing gradient gel electrophoresis analysis suggested a sequence variant in the proband and his mother. This was confirmed by sequencing of the PCR-amplified exon 14 region of the hemizygous proband, which demonstrated the base change G----A abolishing an MspI restriction site. Hybridization analysis with allele-specific probes confirmed the inheritance of the mutation with the phenotype. The mutation changed the GGC codon for glycine-1143 to GAC for aspartate. Substitution of glycine-1143, located in the collagenous domain of the alpha 5(IV) chain, for any other amino acid can be expected to interfere with the maintenance of the triple-helical conformation of the collagen molecule. This could, in turn, weaken the glomerular-basement-membrane framework and lead to increased permeability.
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PMID:Mutation in the alpha 5(IV) collagen chain in juvenile-onset Alport syndrome without hearing loss or ocular lesions: detection by denaturing gradient gel electrophoresis of a PCR product. 159 9

Mutations in the COL4A5 collagen gene have been implicated as the primary defect in Alport syndrome, a heritable disorder characterized by sensorineural deafness and glomerulonephritis that progresses to end-stage renal failure. In the present study, the molecular nature of the defect in Alport glomerular basement membrane (GBM) was explored using anti-GBM alloantibodies (tissue-bound and circulating) produced in three Alport patients subsequent to renal transplantation. The alloantibodies bound to the alpha 3(IV)NC1 domain of type IV collagen and not to any other basement membrane component. In tissue sections, the alloantibodies bound specifically to peripheral GBM in normal kidney and the affected renal transplant but not to that of Alport kidney. These results establish that: the alpha 3 chain in type IV collagen molecules, the Goodpasture autoantigen, is the target alloantigen in post-transplant anti-GBM nephritis in patients with Alport syndrome, and that a molecular commonality exists in the pathogenesis of anti-GBM nephritis causing loss of renal allografts in patients with Alport syndrome and renal failure in patients with Goodpasture syndrome. These findings implicate: (1) defective assembly of type IV collagen molecules containing the alpha 3(IV) chain in Alport GBM; and (2) the existence of a mechanism linking the assembly of molecules containing the alpha 3(IV) chain with those containing the alpha 5(IV) chain.
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PMID:The pathogenesis of Alport syndrome involves type IV collagen molecules containing the alpha 3(IV) chain: evidence from anti-GBM nephritis after renal transplantation. 163 48

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

In a large Italian family with adult-onset Alport syndrome, molecular analysis of the COL4A5 gene, which encodes the alpha 5(IV)-chain of glomerular basement membrane collagen, revealed a GGC-->AGC change in exon 38, resulting in substitution of a serine for a glycine in position 1143 of the polypeptide chain, between interruptions 19 and 20 of the triple helical domain. The mutation leads to loss of a restriction site for the enzyme Msp I, and could thus be easily recognized in several female and male relatives. Among relatives of both sexes who carried the same mutation, the clinical phenotype of Alport syndrome was variable as for the onset of renal failure and the presence of associated ear and eye abnormalities.
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PMID:Variability of clinical phenotype in a large Alport family with Gly 1143 Ser change of collagen alpha 5(IV)-chain. 796 79

Small frameshift deletions within the COL4A5 gene were identified in three Alport syndrome Italian families by non-isotopic single-strand conformation polymorphism (SSCP) screening: in family RMA, a 7-bp deletion (GGGTGAA) in exon 39; in family DGR, a 4-bp deletion (TGGA) in exon 41; in family MIB, deletion of a G in exon 50. The phenotype was characterized by juvenile-onset renal failure with sensorineural hearing loss in males, and a milder clinical pattern in heterozygous females.
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PMID:Small frameshift deletions within the COL4A5 gene in juvenile-onset Alport syndrome. 822 25

Alport syndrome is a genetic disorder of basement membranes manifested clinically by a progressive nephropathy and, in many families, sensorineural hearing loss and ocular lesions. During the 1980s evidence was amassed indicating type IV (basement membrane) collagen as the defective protein in Alport This hypothesis was confirmed in 1990 by the cloning of the X-chromosomal gene COL4A5, which encodes the alpha 5 chain of type IV collagen, and the discovery of mutations in this gene in many Alport kindreds. The results of results of recent studies suggest that the alpha 5(IV) chain forms a distinct collagenous network with the alpha 3 and alpha 4 chains of type IV collagen and that mutations in alpha 5(IV) may prevent the normal incorporation of alpha 3(IV) and alpha 4(IV) into basement membranes. Renal biopsy remains an important modality for making the diagnosis of Alport syndrome, but may eventually be replaced by molecular genetic techniques. Posttransplant anti-glomerular basement membrane nephritis occurs rarely in Alport patients and may be restricted to a subgroup with particular COL4A5 mutations. It is not clear why COL4A5 mutations result in glomerulosclerosis and renal failure, or whether this process may be slowed through dietary or pharmacologic intervention.
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PMID:Alport syndrome: from bedside to genome to bedside. 823 7

Mutations affecting the COL4A5 gene encoding the alpha 5 chain of type IV collagen, are involved in the pathogenesis of X-linked Alport syndrome. We used denaturing gradient gel electrophoresis (DGGE) to screen PCR amplified exons of COL4A5 for point mutations in a set of 18 Alport patients previously characterized by Southern blotting. One sequence variant was identified in the exon 38 region of a male Alport patient. Sequence analysis revealed a G to C transversion in the 5' intron splice donor site downstream from exon 38 (GT to CT). To determine the effect of the mutation on mRNA splicing, alpha 5(IV) cDNA was generated from total RNA of peripheral blood lymphocytes. Subsequent cDNA PCR yielded a product 81 base pairs shorter in the affected Alport patient, compared to normal controls. The absence of exon 38 from the alpha 5(IV) cDNA was confirmed by sequence analysis. The results demonstrated that the mutation leads to skipping of exon 38 in the processing of alpha 5(IV) pre-mRNA. The shortened transcript lacked 27 codons encoding a Gly-X-Y-repeat sequence with a preserved reading frame, enabling the translation of codons further downstream. Clinically, the patient presented with juvenile onset Alport syndrome, end-stage renal failure, and deafness. He had no ocular lesions. Typical ultrastructural changes of the glomerular basement membrane (GBM) were shown on electron microscopy. The patient developed anti-GBM antibodies after renal transplantation, however, renal function deteriorated only moderately.
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PMID:COL4A5 splice site mutation and alpha 5(IV) collagen mRNA in Alport syndrome. 844 Dec 46

Mutations in the COL4A5 gene, which encodes the a5 chain of type IV collagen, are found in a large fraction of patients with X-linked Alport syndrome. The recently discovered COL4A6, tightly linked and highly homologous to COL4A5, represents a second candidate gene for Alport syndrome. We analyzed 177 Italian Alport syndrome families by Southern blotting using cDNA probes from both COL4A5 and COL4A6. Nine unrelated families, accounting for 5% of the cases, were found to have a rearrangement in COL4A5. No rearrangements were found in COL4A6, with the exception of a deletion encompassing the 5' ends of both COL4A5 and COL4A6 genes in a patient with Alport syndrome and leiomyomatosis. COL4A5 rearrangements were all intragenic and included 1 duplication and 7 deletions. Polymerase chain reaction (PCR) analysis was carried out to characterize deletion and duplication boundaries and to predict the resulting protein abnormality. The two smallest deletions involved a single exon (exons 17 and 40, respectively), while the largest ones spanned exons 1 to 36. The clinical phenotype of patients in whom a rearrangement in COL4A5 was detected was severe, with progression to end-stage renal failure in juvenile age and hypoacusis occurring in most cases. These data have some important implications in the diagnosis of patients with Alport syndrome.
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PMID:Major COL4A5 gene rearrangements in patients with juvenile type Alport syndrome. 859 66

Alport syndrome is an inherited disorder of collagen that affects the kidney, the eye, and the cochlea. The disease exhibits variability in its clinical and pathological manifestations, and is genetically heterogeneous. The X-linked dominant form of Alport syndrome arises from mutation in the COL4A5 gene, which encodes the alpha 5 chain of type IV collagen. The autosomal recessive form is caused by mutation in the COL4A3 gene, which encodes the alpha 3 chain of type IV collagen, or in the COL4A4 gene, which encodes the alpha 4 chain of type IV collagen. An autosomal dominant variety of Alport syndrome also exists, but mutations in this form of the disease have not yet been described. Cotransmission of X-linked dominant Alport syndrome and diffuse leiomyomatosis in some families results from deletions involving the COL4A5 gene and the contiguous COL4A6 gene. The clinical and pathologic features of Alport syndrome are attributable to abnormalities in the basement membrane collagen network composed of the alpha 3, alpha 4, and alpha 5 chains of type IV collagen, although the mechanism by which mutation in the gene encoding one of these chains effects the other two chains is not yet known. In addition, the processes that lead to progressive glomerular scarring and renal failure are incompletely understood. While diagnosis of Alport syndrome still rests on clinical and pathologic evaluation, immunohistochemical and molecular genetic tools can augment diagnostic precision.
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PMID:Clinical and molecular diagnosis of Alport syndrome. 860 15


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