Identification of mutations in the α3(IV) and α4(IV) collagen genes in autosomal recessive Alport syndrome

Abstract

Alport syndrome (AS) is an hereditary disease of basement membranes characterized by progressive renal failure and deafness. Changes in the glomerular basement membrane (GBM) in AS suggest that the type IV collagen matrix, the major structural component of GBM, is disrupted. We recently isolated the genes for two type IV collagens, alpha 3(IV) and alpha 4(IV), that are encoded head-to-head on human chromosome 2. These chains are abundant in normal GBM but are sometimes absent in AS. We screened for mutations in families in which consanguinity suggested autosomal recessive inheritance. Homozygous mutations were found in alpha 3(IV) in two families and in alpha 4(IV) in two others, demonstrating that these chains are important in the structural integrity of the GBM and that there is an autosomal form of AS in addition to the previously-defined X-linked form.

Irradiation Prolongs Survival of Alport Mice

“…[1][2][3] Two major types exist in which an X-linked AS caused by mutations in COL4A5 includes Ͼ80% and an autosomal recessive form caused by mutations in COL4A3 or COL4A4 includes almost 15% in human. 2,3 Regarding the optimal treatment of this disease, there is no viable strategy except for renal transplantation at present. There are some reports in which conservative therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blocker effectively attenuated renal deterioration in the mouse.…”

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.…”

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

“…Passwell et al (1981) described an autosomal-recessive form of the disease in a 1-year-old girl who presented with failure to thrive, nephritis, and deafness and was born to first-cousin parents. Subsequently, Mochizuki et al (1994) reported four unrelated families with autosomal-recessive AS. In 1997, Colville et al and Rhys et al reported on the ocular manifestations of autosomal-recessive AS.…”

“…X-linked inheritance is observed in *85% of the cases, which is caused by mutations in COL4A5 (MIM 303630) coding the a5-chain of type IV collagen (Feingold et al, 1985;Barker et al, 1990). About 15% of the cases show autosomal-recessive inheritance and are caused by homozygous or compound heterozygous mutations in COL4A3 (MIM 120070) or COL4A4 (MIM 120131) Mochizuki et al, 1994). Autosomal-dominant inheritance is rare, and is usually caused by heterozygous COL4A3 or COL4A4 mutations ( Jefferson et al, 1997).…”