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) is a hereditary disorder of progressive nephritis. Most cases are X-linked, but autosomal forms have been reported. The X-linked form is associated with mutations in the COL4A5 gene that encodes the alpha 5 chain of type IV collagen. More than 200 mutations have been reported in X-linked AS. We report a novel 1616 G > A mutation resulting in glycine substitution to arginine at position 472 in a Turkish family with a severely affected man and several variably affected women. This is the first Turkish family in whom the molecular basis of the disease has been reported.
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PMID:A novel G472R mutation in a Turkish family with X-linked Alport syndrome. 1087 88

Alport syndrome (AS) is a genetic disorder of basement membranes caused by mutations in type IV collagen genes that is characterized by chronic hematuria and progressive nephropathy leading to renal failure. The main extrarenal features include sensorineural hearing loss and ocular lesions. The mode of inheritance is X-linked dominant in about 80%-85% of the affected families, whereas autosomal transmission is rarely encountered. We report a male patient originating from a healthy consanguineous Lebanese family who presented with an unusual association of obstructive uropathy and AS. Hematuria and proteinuria were initially attributed to a suspected poststreptococcal glomerulonephritis (GN) and high-grade subpelvic ureteral stenosis. Persistence of symptoms after medical treatment of poststreptococcal GN and surgical correction of obstructive uropathy finally led to renal biopsy. The observed ultrastructural changes of the glomerular basement membrane were typical for AS. Molecular genetic studies revealed a previously undescribed de novo mutation in the COL4A5 gene, excluding maternal heterozygotic carrier status. This case report emphasizes the importance of hereditary nephritis in the differential diagnosis of chronic hematuria, and demonstrates the value of molecular studies for genetic counselling in AS.
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PMID:Sporadic case of X-chromosomal Alport syndrome in a consanguineous family. 1095 21

Tissue-specific expression patterns of the paired type IV collagen genes COL4A5 and COL4A6 form the basis for organ involvement in X-linked Alport syndrome, a disorder in which these genes are mutated. We investigated the proximal promoter region of COL4A5 and COL4A6 using glomerular visceral epithelial cells, in which COL4A5 alone is transcribed; keratinocytes, in which the genes are co-transcribed; and additional model cell lines. By RNase protection assays, the intergenic region is 292 base pairs. Transcription start sites for two 5' splice variants of COL4A6 are 1 kilobase apart. Transient transfections with reporter gene constructs revealed that the minimal promoters for COL4A5 and COL4A6 are within 100 base pairs of their respective transcription start sites and are functionally distinct. In further transfection, gel shift and footprinting assays, we defined a bidirectional positive regulatory element, which functions in several cell types, but not in glomerular visceral epithelial cells selectively transcribing COL4A5. The existence of separate promoters for COL4A5 and COL4A6 permits fine control over their expression. Activation through the bidirectional element can bring about co-expression of the genes, exploiting their paired arrangement. Features of the proximal promoter region frame its roles in a hierarchy regulating type IV collagen gene expression.
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PMID:Regulation of the paired type IV collagen genes COL4A5 and COL4A6. Role of the proximal promoter region. 1109 82

Alport syndrome is a progressive renal disease leading to chronic renal failure, which often is accompanied by sensorineural deafness and ophthalmological signs in the form of anterior lenticonus. The X-linked form of the disease is caused by mutations in the COL4A5 gene encoding the alpha5-chain of type IV-collagen. We performed mutation analysis of the COL4A5 gene by PCR-SSCP analysis of each of the 51 exons with flanking intronic sequences in 81 patients suspected of X-linked Alport syndrome including 29 clear X-linked cases, 37 cases from families with a pedigree compatible with X-linked inheritance, and 15 isolated cases. We found a mutation detection rate of 52% (42/81) (58% in males and 21% in females), and 69% (20/29) in families who clearly demonstrated X-linked inheritance. Thirty-six different mutations were found in 42 patients comprising 16 missense mutations, seven frameshifts, three in-frame deletions, four nonsense mutations, and six splice site mutations. Twenty-two of the mutations have not previously been reported. Furthermore, we found one non-pathogenic amino acid substitution, one rare variant in a non-coding region, and one polymorphism with a heterozygosity of 28%. Three de novo mutations were found, two of which were paternal and one of maternal origin.
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PMID:Detection of mutations in the COL4A5 gene by SSCP in X-linked Alport syndrome. 1146 38

Alport syndrome is an inherited disorder of type IV collagen with progressive nephropathy, ocular abnormalities, and high-tone sensorineural deafness. In X-linked Alport syndrome, mutations in the COL4A5 gene encoding the alpha5 chain of type IV collagen lead to loss of the alpha3/alpha4/alpha5 network and increased susceptibility of the glomerular basement membrane to long-term damage. The molecular defects that underlie the otopathology in this disease remain poorly understood. We used a canine model of X-linked Alport syndrome to determine the expression of type IV collagen alpha-chains in the inner ear. By 1 month in normal adult dogs, the alpha3, alpha4, and alpha5 chains were co-expressed in a thin continuous line extending along the basilar membrane and the internal and external sulci, with the strongest expression along the lateral aspect of the spiral ligament in the basal turn of the cochlea. Affected dogs showed complete absence of the alpha3/alpha4/alpha5 network. The lateral aspect of the spiral ligament is populated by tension fibroblasts that express alpha-smooth muscle actin and nonmuscle myosin and are postulated to generate radial tension on the basilar membrane via the extracellular matrix for reception of high frequency sound. We propose that in Alport syndrome, the loss of the alpha3/alpha4/alpha5 network eventually weakens the interaction of these cells with their extracellular matrix, resulting in reduced tension on the basilar membrane and the inability to respond to high frequency sounds.
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PMID:The inner ear of dogs with X-linked nephritis provides clues to the pathogenesis of hearing loss in X-linked Alport syndrome. 1154 2

Genes of most of the hereditary renal diseases progressing to renal insufficiency are now identified. In the first part of this paper we describe their multi-faceted genetics. Genetic heterogeneity has been demonstrated in many of these diseases, such as Alport's syndrome and nephronophtisis. In some of them an allelic heterogeneity is present as in the X-linked form of Alport's syndrome (more than 300 different mutations have been described along the COL4A5 gene). Besides these classical mendelian diseases, mendelian subentities have been isolated within common diseases such as cortico-resistant nephrosis. Many diseases also demonstrate a variability of their phenotype resulting from allelic and/or genetic heterogeneity, or from modifier genes. In the second part of the paper we discuss the consequences of this explosion of knowledge with respect to epidemiology, genetic diagnosis, prenatal diagnosis and treatment.
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PMID:[Contribution of genetics to knowledge and management of hereditary kidney diseases progressing to renal failure]. 1168 2

Recent genetic studies indicate that Alport syndrome and thin glomerular basement membrane disease (TMD) may both be due to COL4A3, COL4A4, and COL4A5 mutations, but there is continuing uncertainty concerning the diagnosis and management of patients without classic family history and symptoms. We examined kidney pathology and collagen alpha 3 to alpha 5(IV) expression in a series of 16 patients who presented with overlapping signs between TMD and Alport nephritis. All patients presented with hematuria, and 11 also had proteinuria, of whom 5 had nephrotic range proteinuria. Only 9 had family history of hematuria. In 9 of 16 (60%) we found premature glomerulosclerosis in the renal biopsies. Three of 16 had predominantly wide, lamellated glomerullar basement membranes (GBM), and in these, alpha 3 to alpha 5(IV) was absent in glomeruli or skin, diagnostic of Alport nephritis. One patient (12) had a very wide GBM with intramembranous lucencies but no lamellation. Skin biopsy was collagen alpha 5(IV) positive. Nine of 16 patients had predominantly thin GBM by electron microscopy, and 3 had thin and slightly lamellated GBM. Collagen alpha 3 to alpha 5(IV) expression in the kidney or skin biopsy was present in all of the latter 12 patients. Three patients had end-stage renal disease, 7 patients had hypertension, and 1 patient had chronic renal failure. We found that of the 16 patients with presumed TMD, 3 had X-linked Alport nephritis, 2 appeared to have autosomal recessive Alport nephritis, and the remaining patients had either an Alport or a TMD variant. The latter had histologic and/or clinical evidence of progressive renal disease, including premature glomerulosclerosis, hypertension, sustained proteinuria, and either thin or slight GBM lamellation focally, and preserved alpha 3 to alpha 5(IV) expression. These patients have a TMD variant, but an Alport variant with a potentially transmissible severe defect different from benign hematuria cannot be excluded.
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PMID:Histopathology, ultrastructure, and clinical phenotypes in thin glomerular basement membrane disease variants. 1220 17

The X-linked form of Alport syndrome is caused by mutations in the COL4A5 gene in Xq22. This large multiexonic gene has, in the past, been difficult to screen, with several studies detecting only about 50% of mutations. We report three novel intronic mutations that may, in part, explain this poor success rate and demonstrate that single base changes deep within introns can, and do, cause disease: one mutation creates a new donor splice site within an intron resulting in the inclusion of a novel in-frame cryptic exon; a second mutation results in a new exon splice enhancer sequence (ESE) that promotes splicing of a cryptic exon containing a stop codon; a third patient exhibits exon skipping as a result of a base substitution within the polypyrimidine tract that precedes the acceptor splice site. All three cases would have been missed using an exon-by-exon DNA screening approach.
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PMID:Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome. 1243 46

Chinese Alport syndrome (AS) was analyzed in 44 unrelated patients who were screened for mutations in the COL4A5 gene by polymerase chain reaction (PCR)-single-strand conformation polymorphism analysis or PCR direct sequencing in 30 of the 44 patients. The clinical data showed that all patients had hematuria; 25 of 29 male patients (86%) and 9 of 15 female patients (60%) had proteinuria; 11 of 29 male patients (38%) and 1 of 15 female patients (7%) had nephrotic-level proteinuria; 10 of 21 male patients examined (48%) and 1 of 12 female patients examined (8%) had hearing abnormalities. Renal function remained normal despite hearing abnormalities, and ocular lesions occurred in 10%. Among 30 of 44 patients who had a family history of end-stage renal disease (ESRD), 80% (24/30) belonged to X-linked juvenile kindreds, and 20% (6/30) patients to adult kindreds. Of the 44 patients, 14 did not have a family history of ESRD, while 11 of 14 patients diagnosed with X-linked AS did. DNA analysis revealed four missense mutations, two silent mutations, one substitution, and one in-frame deletion. PCR along with Southern hybridization analysis revealed a large deletion of the paired COL4A5 and COL4A6 genes. Chinese AS patients were characterized clinically with hematuria, heavy proteinuria, and more juvenile forms. Mutations in these patients were usually small mutations, while a large deletion involving the 5' part of both COL4A5 and COL4A6 genes was identified.
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PMID:Phenotypic and genotypic features of Alport syndrome in Chinese children. 1247 50

X-linked Alport syndrome is a progressive renal disease caused by mutations in the COL4A5 gene, which encodes the alpha 5(IV) collagen chain. As an initial step toward gene therapy for Alport syndrome, we report on the expression of recombinant alpha 5(IV) collagen in vitro and in vivo. A full-length cDNA-encoding canine alpha 5(IV) collagen was cloned and expressed in vitro by transfection of HEK293 cells that synthesize the alpha1(IV) and alpha2(IV), but not the alpha 3(IV) to alpha 6(IV) collagen chains. By Northern blotting, an alpha 5(IV) mRNA transcript of 5.2 kb was expressed and the recombinant protein was detected by immunocytochemistry. The chain was secreted into the medium as a 190-kd monomer; no triple helical species were detected. Transfected cells synthesized an extracellular matrix containing the alpha1(IV) and alpha2(IV) chains but the recombinant alpha 5(IV) chain was not incorporated. These findings are consistent with the concept that the alpha 5(IV) chain requires one or more of the alpha 3(IV), alpha 4(IV), or alpha 6(IV) chains for triple helical assembly. In vivo studies were performed in dogs with X-linked Alport syndrome. An adenoviral vector containing the alpha 5(IV) transgene was injected into bladder smooth muscle that lacks both the alpha 5(IV) and alpha 6(IV) chains in these animals. At 5 weeks after injection, there was expression of both the alpha 5(IV) and alpha 6(IV) chains by smooth muscle cells at the injection site in a basement membrane distribution. Thus, this recombinant alpha 5(IV) chain is capable of restoring expression of a second alpha(IV) chain that requires the presence of the alpha 5(IV) chain for incorporation into collagen trimers. This vector will serve as a useful tool to further explore gene therapy for Alport syndrome.
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PMID:Transfer of the alpha 5(IV) collagen chain gene to smooth muscle restores in vivo expression of the alpha 6(IV) collagen chain in a canine model of Alport syndrome. 1259 21


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