Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Alport Syndrome (ATS) [Q87.8]

OMIM numbers: 301050, 303630 (COL4A5), 203780, 104200, 120070 (COL4A3), 120131 (COL4A4)

PD Dr. med. Julia Höfele

Scientific Background

Alport syndrome (ATS) is a progressive hereditary nephropathy characterized by hematuria and proteinuria gradually progressing to end-stage renal disease (ESRD). Further symptoms include sensorineural hearing loss (60–80%) and ocular abnormalities (anterior lenticonus, 25–40%). Abnormalities in the type IV collagen which lead to structural defects of the glomerular basement membrane (GBM) are causal for the disease. Type IV collagen is composed of six homologous α-chains encoded by the genes COL4A1–COL4A6. Each α-chain contains a collagenous domain, a collagen tail and two non-collagenous domains.

Thus far 3 genes are known to be associated with ATS: COL4A3 and COL4A4 (autosomal dominant and autosomal recessive inheritance) and COL4A5 (X-linked). The frequency of all types is approx. 1:5,000; with 85% X-linked inheritance being the most frequent. Autosomal dominant inheritance is associated with a milder course of disease and later ESRD. Approximately 15% of all cases are caused by de novo mutations. Inframe or missense mutations are associated with a milder course of disease and late onset of ESRD. Frameshift and nonsense mutations as well as large gene rearrangements lead to a severe course of disease with early ESRD. Mutations in the triple helix of the collagen tail create a kink, an altered three-dimensional structure or shortened collagen chain.

The heterozygous frequency for the autosomal recessive inheritance is below 1:120. Familial benign hematuria (FBH) is phenotypically not distinguishable from heterozygous carriers of alport syndrome. Some patients with FBH bear a heterozygous mutation in COL4A3 or COL4A4. Children of parents bearing each a heterozygous mutation in COL4A3 or COL4A4 may develop ATS. Therefore, FBH is regarded as heterozygosity for the autosomal recessive type of ATS. Female carriers of X-linked Alport can develop hematuria, a slight proteinuria and, maybe later on, an ESRD.