Alport syndrome: a unified classification of genetic disorders of collagen IV α345: a position paper of the Alport Syndrome Classification Working Group.

Mutations in the genes COL4A3, COL4A4, and COL4A5 affect the synthesis, assembly, deposition, or function of the collagen IV α345 molecule, the major collagenous constituent of the mature mammalian glomerular basement membrane. These mutations are associated with a spectrum of nephropathy, from microscopic hematuria to progressive renal disease leading to ESRD, and with extrarenal manifestations such as sensorineural deafness and ocular anomalies. The existing nomenclature for these conditions is confusing and can delay institution of appropriate nephroprotective therapy. Herein we propose a new classification of genetic disorders of the collagen IV α345 molecule with the goal of improving renal outcomes through regular monitoring and early treatment.

High mutation detection rate in the COL4A5 collagen gene in suspected Alport syndrome using PCR and direct DNA sequencing.

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. In the present work, the promoter sequence and previously unknown intron sequences flanking exons 2 and 37 of COL4A5 were determined. Furthermore, intron sequences flanking the other 49 exons were expanded from 35 to 190 to facilitate mutation analysis of the gene. Using this information, all 51 exons and the promoter region were PCR-amplified and sequenced from DNA of 50 randomly chosen patients with suspected Alport syndrome. Mutations were found in 41 patients, giving a mutation detection rate of 82%. Retrospective analysis of clinical data revealed that two of the cases might be autosomal. Although it could not be determined whether the remaining seven cases (14%) were autosomal or X chromosome-linked, it is likely that some of them were autosomal. It is concluded that PCR amplification and direct DNA sequencing of the promoter and exons is currently the best procedure to detect mutations in COL4A5 in Alport syndrome.

Major COL4A5 gene rearrangements in patients with juvenile type Alport syndrome.

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.

[Alport's syndrome: new findings]. / Síndrome de Alport: nuevos conocimientos.

The Alport's syndrome is a disease characterized by a symptomatic triad: nephropathy, hypoacusia and ocular alterations. This syndrome is genetically heterogeneous and results from numerous mutations in COL4A5 gene, whose locus resides on the long arm of the X chromosome (Xq22). This gene codifies for IV collagen alpha 5 chain, which is a fundamental constituent of the glomerular, lens and Corti's organ basal membranes. Present knowledge on molecular genetics and the characterization of the different mutations that affect the Alport's gene will lead to classification of this syndrome in subtypes, according to those mutations, and to its phenotypic expressions; in addition, some syndromes, phenotypically similar, will probably have to be distinguished from Alport's disease, in a future, if a genetic alteration is found in genes other than COL4A5.

[Hereditary nephropathies]. / Les néphropathies héréditaires.

Hereditary nephritis is usually accompanied by hematuria in childhood and, when associated with neurosensory deafness, is known as Alport's syndrome. In recent years, we have begun to understand that there are primary defects in glomerular basement membrane structure in hereditary nephritis. Increased knowledge concerning clinical and pathologic features has led to the identification of 4 types of hereditary nephritis. Herein, we review and update basic and clinical aspects of hereditary nephritis.

[Clinico-genetic characteristics of hereditary nephritis in different populations]. / Kliniko-geneticheskaia kharakteristika nasledstvennogo nefrita v raznykh populiatsiiakh.

Some data are presented on the clinical features of a course of hereditary nephritis in persons of 13 nationalities residing in the central zone of the RSFSR, in Central Asia and East Slovakia (the Czechoslovak Socialist Republic). At least 2 types of hereditary nephritis transmission (the dominant x-chromosome-linked one was more common than the autosomal-dominant one) not differing in their clinical course were revealed. Basing on a study of the clinical features of a course of disease in 123 autobred and 52 inbred families a more severe course of nephritis was observed in children from the inbred families.

Variants of Alport's syndrome.

Variants of Alport's syndrome include mainly those associated with hereditary macrothrombocytopenia (and occasionally leukocyte inclusions) or with esophageal, tracheobronchial and genital leiomyomatosis. Within Alport's syndrome there appears to be no justification for differentiating those with nephritis and deafness from those with nephritis alone. However, in indirect immunofluorescence studies using the mouse monoclonal antibody, MCA-P1, which recognizes the glomerular basement membrane (GBM), reduced or absent binding was found in 20 of 42 cases of hereditary nephritis. Most of these showed typical ultrastructural GMB changes. These results suggest that there is probably a subset of patients characterized by typical GBM lesions and an absence, inaccessibility or abnormality of the GBM antigen recognized by MCA-P1.

Basement membrane nephropathy: a new classification for Alport's syndrome and asymptomatic hematuria based on ultrastructural findings.

Renal biopsy specimens from 19 patients with asymptomatic hematuria, normal glomeruli on light microscopic examination, and negative immunofluorescence were studied to characterize the ultrastructural changes of the glomerular basement membrane. Three groups of patients were identified. Four patients (group 1) had type I basement membrane nephropathy, characterized by marked thickening and lamellation of the basement membrane in a pattern resembling that of Alport's syndrome. Seven patients (group 2) had type II basement membrane nephropathy, which was characterized by extensive attenuation of the basement membrane with only occasional small areas of lamellation or fragmentation. Eight patients (group 3) had moderate variability in basement membrane thickness with no other structural alterations. The authors propose that this pathologic classification be used in patients with asymptomatic hematuria as a basis for long-term clinical investigations, in hopes of distinguishing the natural history of each group.