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, located at Xq22, cause Alport syndrome (AS), a nephritis characterized by progressive deterioration of the glomerular basement membrane and usually associated with progressive hearing loss. We have identified a novel mutation, L1649R, present in 9 of 121 independently ascertained families. Affected males shared the same haplotype of eight polymorphic markers tightly linked to COL4A5, indicating common ancestry. Genealogical studies place the birth of this ancestor >200 years ago. The L1649R mutation is a relatively common cause of Alport syndrome in the western United States, in part because of the rapid growth and migratory expansion of mid-nineteenth-century pioneer populations carrying the gene. L1649R affects a highly conserved residue in the NC1 domain, which is involved in key inter- and intramolecular interactions, but results in a relatively mild disease phenotype. Renal failure in an L1649R male typically occurs in the 4th or 5th decade and precedes the onset of significant hearing loss by approximately 10 years.
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PMID:A mutation causing Alport syndrome with tardive hearing loss is common in the western United States. 865 Dec 92

Conditions for polymerase chain-reaction amplification of ten exon regions (Exons 3, 7, 11 through 13, and 15 through 19) of the collagen COL4A5 gene and four exon regions (Exons 2, and 12 through 14) of the COL4A6 gene were sequenced and established in this study. These Type IV collagen genes contain 51 and 48 exons, respectively. The sequences of these exons were determined in the two genes in 250 male patients with hematuria and suspected Alport syndrome. Seventeen mutations were found in nine of the ten exons studied in the COL4A5 gene in 17 patients, whereas no mutations were identified in COL4A6. One mutation was identical in two patients known to be unrelated. The results indicate that mutations in COL4A5 that leading to renal failure are more frequent than those involved in classic Alport syndrome, and also that mutations in COL4A6 are not likely to cause this disease. Furthermore, mutations in COL4A5 are distributed quite randomly and no "hot spots" were found.
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PMID:Identification of 17 mutations in ten exons in the COL4A5 collagen gene, but no mutations found in four exons in COL4A6: a study of 250 patients with hematuria and suspected of having Alport syndrome. 873 5

Alport syndrome is a mainly X-linked hereditary disease of basement membranes that is characterized by progressive renal failure, deafness, and ocular lesions. It is associated with mutations of the COL4A5 gene located at Xq22 and encoding the alpha5 chain of type IV collagen. We have screened 48 of the 51 exons of the COL4A5 gene by SSCP analysis and have identified 64 mutations and 10 sequence variants among 131 unrelated Alport syndrome patients. This represents a mutation-detection rate of 50%. There were no hot-spot mutations and no recurrent mutations in our population. The identified mutations were 6 nonsense mutations, 12 frameshift mutations, 17 splice-site mutations, and 29 missense mutations, 27 of the latter being glycine substitutions in the collagenous domain. Two of these occurred on the same allele in one patient and segregated with the disease in the family. We showed that some of the glycine substitutions could be associated with the lack of immunological expression of the alpha3(IV)-alpha5(IV) collagen chains in the glomerular basement membrane.
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PMID:Spectrum of mutations in the COL4A5 collagen gene in X-linked Alport syndrome. 894 Feb 67

Clinical manifestations of type IV collagen mutations can vary from the severe, clinically and genetically heterogeneous renal disorder, Alport syndrome, to autosomal dominant familial benign hematuria. The predominant form of Alport syndrome is X-linked; more than 160 different mutations have yet been identified in the type IV collagen alpha 5 chain (COL4A5) gene, located at Xq22-24 head to head to the COL4A6 gene. The autosomal recessive form of Alport syndrome is caused by mutations in the COL4A3 and COL4A4 genes, located at 2q35-37. Recently, the first mutation in the COL4A4 gene was identified in familial benign hematuria. This paper presents an overview of type IV collagen mutations, including eight novel COL4A5 mutations from our own group in patients with Alport syndrome. The spectrum of mutations is broad and provides insight into the clinical heterogeneity of Alport syndrome with respect to age at renal failure and accompanying features such as deafness, leiomyomatosis, and anti-GBM nephritis.
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PMID:The clinical spectrum of type IV collagen mutations. 919 22

Ocular abnormalities are common in X-linked Alport syndrome, but they have not been studied in patients with the rarer autosomal recessive disease. We have examined the eyes of a family with autosomal recessive Alport syndrome. Four of the eight offspring of a consanguineous marriage had renal failure and deafness by the age of 20 years. The diagnosis of Alport syndrome was confirmed on the ultrastructural demonstration of a lamellated glomerular basement membrane (GBM) in one affected family member. Autosomal recessive inheritance was suggested by the lack of linkage to the COL4A5/COL4A6 locus, and by linkage to the COL4A3/COL4A4 locus. All four affected family members had anterior lenticonus (or had had a lens replacement for this) and the three who were examined had a dot-and-fleck retinopathy. Neither of the two unaffected offspring who were examined nor the father had these abnormalities. The ocular manifestations of autosomal recessive Alport syndrome are probably identical to those for the X-linked form. Although the mutations in these diseases affect genes for different type IV collagen chains, these chains occur together in the basement membranes of the kidney, eye and ear, and abnormalities in any one may result in the same clinical phenotype.
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PMID:Ocular manifestations of autosomal recessive Alport syndrome. 936 9

Alport syndrome has a prevalence of 1/5000, and 85% of patients have the X-linked form, where affected males develop renal failure and usually have a high-tone sensorineural deafness by the age of 20. The typical ocular associations are a dot-and-fleck retinopathy which occurs in about 85% of affected adult males, anterior lenticonus which occurs in about 25%, and the rare posterior polymorphous corneal dystrophy. The retinopathy and anterior lenticonus are not usually demonstrated in childhood but worsen with time so that the retinal lesion is often present at the onset of renal failure, and the anterior lenticonus, later. The demonstration of a dot-and-fleck retinopathy in any individual with a family history of Alport syndrome or with end-stage renal disease is diagnostic of Alport syndrome. The presence of anterior lenticonus or posterior polymorphous corneal dystrophy in any individual is highly suggestive of the diagnosis of Alport syndrome. Additional ocular features described in X-linked Alport syndrome include other corneal dystrophies, microcornea, arcus, iris atrophy, cataracts, spontaneous lens rupture, spherophakia, posterior lenticonus, a poor macular reflex, fluorescein angiogram hyperfluorescence, electrooculogram and electroretinogram abnormalities, and retinal pigmentation. All mutations demonstrated to date in X-linked Alport syndrome have affected the COL4A5 gene which encodes the alpha 5 chain of type IV collagen. This protein is probably common to the basement membranes of the glomerulus, cochlea, retina, lens capsule, and cornea. However, the alpha 3(IV) and 4(IV) as well as the alpha 5(IV) collagen chains are usually absent from the affected basement membranes, because the abnormal alpha 5(IV) molecule interferes with the stability of all three. The loss of these collagen molecules from the affected basement membranes results in an abnormal ultrastructural appearance. The ocular and other clinical features of autosomal recessive Alport syndrome are identical to those seen in X-linked disease, while retinopathy and cataracts are the only ocular abnormalities described in the rare autosomal dominant form of Alport syndrome. There are no ocular associations of thin basement membrane disease which is a common disease that probably represents the heterozygous expression of X-linked or autosomal recessive Alport syndrome.
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PMID:Alport syndrome. A review of the ocular manifestations. 945 47

Alport syndrome (AS) is a type IV collagen hereditary disease characterized by the association of progressive hematuric nephritis, hearing loss, and, frequently, ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease. Considerable allelic heterogeneity has been observed. A "European Community Alport Syndrome Concerted Action" has been established to delineate accurately the AS phenotype and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of the 401 male patients belonging to the 195 families with COL4A5 mutation are presented. All male patients were hematuric, and the rate of progression to end-stage renal failure and deafness was mutation-dependent. Large deletions, non-sense mutations, or small mutations changing the reading frame conferred to affected male patients a 90% probability of developing end-stage renal failure before 30 yr of age, whereas the same risk was of 50 and 70%, respectively, in patients with missense or splice site mutation. The risk of developing hearing loss before 30 yr of age was approximately 60% in patients with missense mutations, contrary to 90% for the other types of mutations. The natural history of X-linked AS and correlations with COL4A5 mutations have been established in a large cohort of male patients. These data could be used for further evaluation of therapeutic approaches.
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PMID:X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males. 1075 24

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

Alport syndrome is a human hereditary glomerulonephritis which results in end-stage renal failure (ESRF) in most cases. It is caused by mutations in any one of the collagen alpha3(IV), alpha4(IV), or alpha5(IV) chain genes (COL4A3-COL4A5). Patients carrying identical mutations can exhibit very different disease courses, suggesting that other genes or the environment influence disease progression. We previously generated a knockout mouse model of Alport syndrome by mutating Col4a3. Here, we show that genetic background strongly influences the timing of onset of disease and rate of progression to ESRF in these mice. On the 129X1/SvJ background, Col4a3 -/- mice reached ESRF at approximately 66 days of age, while on the C57BL/6J background, the mean age at ESRF was 194 days of age. This suggests the existence of modifier genes that influence disease progression. A detailed histopathological analysis revealed that glomerular basement membrane lesions typical of Alport syndrome were significantly more frequent in homozygotes on the 129X1/SvJ background than on the C57BL/6J background as early as two weeks of age, suggesting that modifier genes act by influencing glomerular basement membrane structure. Additional data indicated that differential physiological responses to basement membrane splitting also underlie the differences in disease progression. We attempted to map the modifier genes as quantitative trait loci (QTLs) using age at ESRF as the quantitative trait. Genome scans were performed on mice at the two extremes in a cohort of mutant F1 x C57BL/6J backcross mice. Analysis with Map Manager QT revealed QTLs linked to markers on chromosomes 9 and 16. A more detailed understanding of how these QTLs act could lead to new approaches for therapy in diverse renal diseases.
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PMID:Quantitative trait loci influence renal disease progression in a mouse model of Alport syndrome. 1183 93

Alport syndrome (AS) is a hereditary nephropathy with hematuria progressing to end-stage renal failure (ESRF), sensorineural deafness, and specific eye signs (lenticonus, macular flecks, and congenital cataracts). Inheritance is X-linked in about 85% of the cases, caused by different mutations in the COL4A5 gene. Rarely AS is seen in combination with diffuse leiomyomatosis (DL). DL is a tumorous process involving smooth muscle cells, mostly of the esophagus, but also of the tracheobronchial tree and the female genital tract. Characteristically, the patients have deletions of the 5'-end of both the COL4A5 and the COL4A6 genes, respectively. We here present a 9-year-old boy who was admitted because of a newly diagnosed sensorineural deafness. He was born with cataracts and presented symptoms of dysphagia and bronchial irritation in the first year of life. Macroscopic hematuria was first noticed at 2 years during a febrile infection. Since early childhood the boy suffered from severe constipation. Taking together these symptoms, the diagnosis of Alport syndrome with diffuse leiomyomatosis (AS-DL) has to be considered. Genetic analysis demonstrated the predicted deletion of the COL4A5/COL4A6 genes.
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PMID:Alport syndrome with diffuse leiomyomatosis. 1278 10


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