Nine novel COL4A3 and COL4A4 mutations and polymorphisms identified in inherited membrane diseases

Abstract

Both thin basement membrane nephropathy (TBMN) and autosomal recessive Alport syndrome result from mutations in the COL4A3 and COL4A4 genes, and this study documents further mutations and polymorphisms in these genes. Thirteen unrelated children with TBMN and five individuals with autosomal recessive Alport syndrome were examined for mutations in the 52 exons of COL4A3 and the 47 coding exons of COL4A4 using single-stranded conformation polymorphism (SSCP) analysis. Amplicons producing different electrophoretic patterns were sequenced, and mutations were defined as variants that changed an amino acid but were not present in 50 non-hematuric normals. Three further novel mutations were identified. These were IVS 22-5 T>A in the COL4A3 gene in a consanguineous family with autosomal recessive Alport syndrome, and R1677C and R1682Q in the COL4A4 gene. In addition, six novel polymorphisms (G455G, I462I, G736G and IVS 38-8 G>A in COL4A3, and L658L and A1577A in COL4A4) were demonstrated.Many different COL4A3 and COL4A4 mutations cause TBMN and autosomal recessive Alport syndrome. The identification of polymorphisms in these genes is particularly important to enable diagnostic laboratories to distinguish mutations from uncommon normal variants.

COL4A3/COL4A4 Mutations and Features in Individuals with Autosomal Recessive Alport Syndrome

“…Ten mutations that had been described previously in Alport syndrome or TBMN were present in 22 of the patients (Leiden Open Variation Database, https://grenada.lumc.nl/LOVD2/ COL4A/home.php?action=switch_db). [7][8][9]11,15,18,19,27 Nine mutations were found more than once. The most common variant, p.(Ser969*), was detected 12 times in nine individuals (23% of patients) and represented 13% (9 of 68) of all mutations in this cohort.…”

“…The previously in both autosomal recessive Alport syndrome and TBMN. 9,11,18,19 Of the 68 pathogenic mutations detected, 25 (37%) resulted in a missense change, 24 (35%) were frameshift mutations, 12 (18%) were nonsense mutations, 4 (6%) were small deletions/ duplications, and 3 (4%) were splicing mutations (Table 1). Of the 24 frameshift mutations, 17 affected COL4A3 and 7 affected COL4A4; of the 12 nonsense mutations, 1 affected COL4A3 and 11 were found in COL4A4, 9 of which were the same c.2906C.G change ( Table 2).…”

A case of mild phenotype Alport syndrome caused by COL4A3 mutations

“…X-linked AS (XLAS) is caused by genetic anomalies in the type IV collagen a5 chain (COL4A5). In contrast, autosomal recessive AS (ARAS) occurs due to a homozygous or compound heterozygous mutations, and autosomal dominant AS occurs due to heterozygous mutations in the type IV collagen a3 chain (COL4A3) or type IV collagen a4 chain [4]. Microscopic hematuria is observed during initial stages, and proteinuria develops with disease progression.…”

Association of COL4A3 (rs55703767), MMP-9 (rs17576)and TIMP-1 (rs6609533) gene polymorphisms with susceptibility to type 2 diabetes

“…Alterations in connective tissue metabolism may associate with the development of diabetic complications, such as neuropathy, nephropathy and retinopathy (12). Rana et al (31) proposed that thin BM nephropathy (TBMN) results from mutations in COL4A3. Numerous different COL4A3 mutations cause TBMN and the identification of polymorphisms in this gene is particularly important (31).…”