The COL4A3 and COL4A4 genes have both arisen from the COL4A1 gene and are located head-to-head on chromosome 2. Mutations in both genes have similar clinical consequences and cause the same diseases. The COL4A3, COL4A4 and the COL4A5 (affected in XL Alport syndrome) genes code for the collagen IV alpha 3, alpha 4 and alpha 5 chains respectively and form a heterotrimer (collagen IV alpha3alpha4alpha5) and the collagen IV network found in the basement membranes in the kidney, ear and eye.
A single mutation in the COL4A3 or COL4A4 gene (heterozygous or monoallelic) results most often in autosomal dominant (AD) Alport syndrome. This is characterised by haematuria, and sometimes proteinuria and impaired kidney function. There is usually no hearing loss or ocular abnormalities. AD Alport syndrome affects about one in 100 people.
However two pathogenic variants affecting COL4A3 or COL4A4 on different chromosomes result in autosomal recessive (AR) Alport syndrome. The clinical features in AR Alport syndrome resemble those found in males with XL Alport syndrome with haematuria, proteinuria, kidney failure, hearing loss, and eye abnormalities (lenticonus and central and peripheral fleck retinopathy). However this differs from XL disease in that males and females are affected equally often, and equally severely, and the disease appears to be sporadic, occurring in only a single generation. AR Alport syndrome is also suspected when the parents are consanguineous or a young girl develops kidney failure, with a hearing loss or anterior lenticonus. AR Alport syndrome is rare occurring in fewer than one in 10,000 people.
COL4A4