Sixteen novel mutations identified in COL4A3, COL4A4, and COL4A5 genes in Slovenian families with Alport syndrome and benign familial hematuria

Abstract

Alport syndrome (ATS) and benign familial hematuria (BFH) are type IV collagen inherited disorders. Mutations in COL4A5 are generally believed to cause X-linked ATS, whereas mutations in COL4A3 and COL4A4 genes can be associated with the autosomal-recessive and -dominant type of ATS or BFH. In view of the wide spectrum of phenotypes, an exact diagnosis is sometimes difficult to achieve. This study involved screening each exon with boundary intronic sequences of COL4A3, COL4A4, and COL4A5 genes by optimized polymerase chain reaction-single-stranded conformational polymorphism analysis in 17 families with ATS and in 40 families diagnosed as having BFH. Twelve different mutations were found in the COL4A5 gene in ATS patients, comprising nine missense mutations, a splice site mutation, a mutation causing frameshift, and a nonsense mutation. One of the missense mutations (p.G624D) was present not only in one family with ATS but also in five families with suspected BFH. Three heterozygous mutations in the COL4A3 gene (two missense and one frameshift) and four heterozygous mutations in COL4A4 (two splice site, one in-frame deletion, and one missense) were identified in patients with BFH. Sixteen mutations are to the best of our knowledge new and private.

The Power of Molecular Genetics in Establishing the Diagnosis and Offering Prenatal Testing: The Case for Alport Syndrome

“…At the same time the EM studies do not show the classical thickening and lamellation of the usual X-linked Alport but extensive thinning of the GBM. Our findings agree with data presented in previous publications that identified this mutation in families from other populations [10][11][12][13] . However, the uncertainty and anxiety that accompany at-risk members belonging to families with conditions like this cannot always be dealt adequately clinically.…”

“…This sequencing revealed several polymorphic sites as well as a collagen mutation at position 624 that resulted in substitution of glycine by aspartic acid, G624D 10 . This mutation had been previously reported by three other groups and it was known to be associated with a milder Alport Syndrome phenotype, something that supported the mild presentation in our family [11][12][13] . Further molecular analysis for this mutation by polymerase chain reaction and restriction enzyme digestion showed that the two brothers II-1 and II-3 share this identical mutation which they have both inherited from their mother, individual I-2 in the pedigree ( Figure 2).…”

Familial C3 Glomerulopathy Associated with CFHR5 Mutations

“…Until recently, the causes of familial hematuric nephropathies were restricted mostly to mutations in the type IV collagen genes, responsible for the X-linked or autosomal recessive Alport syndrome (3)(4)(5)(6). Heterozygous mutations in COL4A3/ COL4A4 genes are responsible for up to 40% of families with thin basement membrane disease (7)(8)(9). Familial IgA nephropathy may also account for a small number of families with hereditary hematuria (10).…”

A NovelCOL4A3Mutation Causes Autosomal-Recessive Alport Syndrome in a Large Turkish Family

“…To date, 71 COL4A3 variants that include mis-sense, nonsense, deletion, insertion, and splice-site changes have been determined, 52 of which are related with autosomal-recessive or autosomaldominant AS. The other COL4A3 mutations have been found to be related with hematuria, focal segmental glomerulosclerosis, microhematuria, and proteinuria, and one mutation has been found to be related with chronic obstructive pulmonary disease Ding et al, 1995;Knebelmann et al, 1995;Van Der Loop et al, 2000;Heidet et al, 2001;Badenas et al, 2002;Longo et al, 2002;Tazon et al, 2003;Pescucci et al, 2004;Wang et al, 2004;Nagel et al, 2005;Longo et al, 2006;Hou et al, 2007;Slajpah et al, 2007;Voskarides et al, 2007;Hou et al, 2008;Kim et al, 2008, Hoefele et al, 2010Zhang et al, 2011).…”