Collagen type IV nephropathy: genetic heterogeneity examinations in affected Hungarian families.

The Col4A3, Col4A4 and Col4A5 collagen type IV genes are found to be mutated in Col IV nephropathy. In males with a mutation in the Col4A5 gene (X-linked Alport syndrome: XL-AS), progressive renal disease always develops. Female carriers with a mutation in the Col4A5 gene can develop thin basement membrane nephropathy (TBMN). Males and females who carry 1 Col4A3 or Col4A4 mutation usually manifest TBMN with nonprogressive hematuria. In the event of 2 Col4A3 or Col4A4 gene mutations, the autosomal recessive AS will develop. We examined the cosegregation pattern of hematuria in 20 families. The renal biopsies led to diagnoses of AS in 7 families, and of TBMN in 6 families. In 7 others, the diagnosis of familial hematuria (FHU) was based on the clinical symptoms. Markers of the ColA3/Col4A4 and Col4A5 loci (Col4A3: CA11 and D2S401; Col4A4: HaeIII/RFLP; and Col4A5: DXS456, 2B6 and 2B20) were used to assess their linkage to the clinical symptoms and morphological alterations. Maximum likelihood and the FASTLINK version of the linkage program were applied to compute logarithm of the odds (LOD) scores. A linkage to the Col4A3/Col4A4 genes was identified in 5 families (FHU in 3, AS in 2 families, 25%, LOD score range: 0.20-3.51). The XL-AS pattern of inheritance seemed likely with Col4A5 in 9 families (45%, LOD: 0.43-4.20); we found 4 disease-causative mutations by high-resolution melting curve analysis (LC480) and sequencing in this group. In 2 FHU families, the linkage to chromosomes 2 and X was precluded. Knowledge of the genetic background of Col IV nephropathy is essential to avoid the misdiagnosis of FHU and early AS. The allele frequencies, heterozygosity content and polymorphism information content of the applied STR markers on unrelated Hungarian normal and affected chromosomes 2 and X were also calculated.

Endreffy E ，Ondrik Z ，Iványi B ，Maróti Z ，Bereczki C ，Haszon I ，Györke Z ，Worum E ，Németh K ，Rikker C ，Ökrös Z ，Túri S ... -  《-》

[Collagen type IV nephropathy: from thin basement membrane nephropathy to Alport syndrome].

Endreffy E ，Ondrik Z ，Kemény E ，Vas Z ，Maróti Z ，Lencse G ，Bereczki C ，Haszon I ，Túri S ，Iványi B ... -  《ORVOSI HETILAP》

Alport syndrome and thin basement membrane nephropathy.

Both Alport syndrome and thin basement membrane nephropathy (TBMN) can be considered as genetic diseases of the GBM involving the alpha3/alpha4/alpha5 network of type IV collagen. Mutations in any of the COL4A3, COL4A4 or COL4A5 genes can lead to total or partial loss of this network. Males with mutations in the X-linked COL4A5 gene develop Alport syndrome with progressive renal disease and sometimes extra-renal disease. Females who are heterozygous for a COL4A5 mutation are considered to be carriers for X-linked Alport syndrome. Although their clinical course and GBM ultrastructural changes can sometimes mimic TBMN, more often it tends to be more progressive than usually seen in TBMN. Males or females who are heterozygous for COL4A3 or COL4A4 mutations usually manifest as TBMN, with nonprogressive hematuria, while those who are homozygous or combined heterozygotes develop autosomal-recessive Alport syndrome. Thus, individuals with TBMN can be considered to be carriers for autosomal-recessive Alport syndrome, but there remain some exceptions in which patients heterozygous for COL4A3 or COL4A4 mutations develop autosomal-dominant Alport syndrome. Distinguishing between all these groups of patients requires a combination of family history and a renal biopsy for electron microscopic examination of the GBM and immunohistochemical staining of the GBM for the alpha3, alpha4 and alpha5 chains of type IV collagen. Mutational analysis of the COL4A3, COL4A4, and COL4A5 genes, whenever it becomes available, will be a valuable adjunct to the diagnostic workup in these patients. Novel therapeutic approaches may one day provide a treatment or cure for these patients, avoiding the need for transplantation and dialysis.

Thorner PS 《-》

Alport syndrome. Molecular genetic aspects.

Hertz JM 《-》

Collagen type IV-related nephropathies in Portugal: pathogenic COL4A3 and COL4A4 mutations and clinical characterization of 25 families.

Pathogenic mutations in genes COL4A3/COL4A4 are responsible for autosomal Alport syndrome (AS) and thin basement membrane nephropathy (TBMN). We used Sanger sequencing to analyze all exons and splice site regions of COL4A3/COL4A4, in 40 unrelated Portuguese probands with clinical suspicion of AS/TBMN. To assess genotype-phenotype correlations, we compared clinically relevant phenotypes/outcomes between homozygous/compound heterozygous and apparently heterozygous patients. Seventeen novel and four reportedly pathogenic COL4A3/COL4A4 mutations were identified in 62.5% (25/40) of the probands. Regardless of the mutated gene, all patients with ARAS manifested chronic renal failure (CRF) and hearing loss, whereas a minority of the apparently heterozygous patients had CRF or extrarenal symptoms. CRF was diagnosed at a significantly younger age in patients with ARAS. In our families, the occurrence of COL4A3/COL4A4 mutations was higher, while the prevalence of XLAS was lower than expected. Overall, a pathogenic COL4A3/COL4A4/COL4A5 mutation was identified in >50% of patients with fewer than three of the standard diagnostic criteria of AS. With such a population background, simultaneous next-generation sequencing of all three genes may be recommended as the most expedite approach to diagnose collagen IV-related glomerular basement membrane nephropathies.

Nabais Sá MJ ，Storey H ，Flinter F ，Nagel M ，Sampaio S ，Castro R ，Araújo JA ，Gaspar MA ，Soares C ，Oliveira A ，Henriques AC ，da Costa AG ，Abreu CP ，Ponce P ，Alves R ，Pinho L ，Silva SE ，de Moura CP ，Mendonça L ，Carvalho F ，Pestana M ，Alves S ，Carvalho F ，Oliveira JP ... -  《-》