Mutations in the type IV collagen α3 (COL4A3) gene in autosomal recessive Alport syndrome

Abstract

A group of 22 unrelated patients with sporadic or non-X-linked Alport syndrome were screened for mutations in the non-collagenous domain of the type IV collagen alpha 3 (COL4A3) chain gene. The five 3'-exons of this gene, located on chromosome 2qter, were tested by single strand conformation polymorphism analysis and direct sequencing. One patient was heterozygous and another homozygous (Mochizuki et al., Nature Genetics, in press) for a deletion of five nucleotides. A third patient appeared to be a compound heterozygote for two different nonsense mutations. In two patients and the father of a deceased patient we found a heterozygous substitution of an evolutionary conserved leucine by proline. However, segregation data of the mutation and a COL4A3/COL4A4 CA-repeat marker in their families argued against a causative role of the missense mutation. Even drastic changes of strongly conserved amino acids, as in the Leu36Pro case, may not be significant. Autosomal recessive inheritance due to pathogenic COL4A3 mutations accounts for at least 13% of Alport syndrome cases in this sample. It is concluded that COL4A3 is a major gene in the genetically and clinically heterogeneous Alport syndrome.

Determinants of Vascular Permeability in the Kidney Glomerulus

“…These molecules assemble in an ordered fashion to provide a highly cross-linked insoluble compact structure with a net negative charge contributed predominantly by the proteoglycan moieties within the GBM (20). The importance of GBM was further validated when the human mutations in type IV collagen were identified as responsible for chronic renal injury associated with microhematuria and glomerular vascular leak (GVL) or proteinuria (21)(22)(23).…”

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

“…In 1994, Mochizuki et al identified a homozygous deletion of five nucleotides in exon 5 of COL4A3, resulting in a truncated protein. Subsequently, Lemmink et al (1994) identified compound heterozygous mutations in COL4A3 in a patient with autosomal-recessive AS. 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.…”

Expression studies of osteoglycin/mimecan (OGN) in the cochlea and auditory phenotype of Ogn-deficient mice

“…Various types of collagen are needed to maintain the precise structures of the cochlea. The fundamental importance of these collagens is demonstrated by the impressive number of hearing disorders caused by their mutation: COL4A5, COL4A3, COL4A4 in Alport Syndrome; COL2A1, COL11A1, COL11A2, COL9A1 in Stickler syndrome; and COL11A2 in DFNA13 (Vikkula et al, 1995;McGuirt et al, 1999;Renieri et al, 1992a;Renieri et al, 1992b;Smeets et al, 1992;Lemmink et al, 1994b;Lemmink et al, 1994a;Mochizuki et al, 1994;Ahmad et al, 1991;Van Camp et al, 2006). If osteoglycin participates in the proper development of these proteins, it is reasonable to hypothesize that a deficiency of OGN would potentially lead to disruption of the structural integrity of the inner ear and, thereby, affect normal hearing.…”

“…Mutations in COL1A1 and COL1A2 are responsible for osteogenesis imperfecta (Pope et al, 1985;Pihlajaniemi et al, 1984) and COL1A2 is also one of the most highly expressed in the Morton cochlear cDNA library (Skvorak et al, 1999;Resendes et al, 2002). COL4A3 and COL4A5 mutations are associated with Alport syndrome (Lemmink et al, 1994b;Barker et al, 1990), while disruption of COL11A1 and COL11A2 causes Stickler syndrome (Richards et al, 1996;Vikkula et al, 1995). Several modifiers of extracellular matrix, including matrix metallopeptidase 2 (Mmp2), Mmp14 and Mmp15 also share a similar expression pattern.…”