Alport syndrome and Alport kidney diseases - elucidating the disease spectrum

Abstract

Purpose of review: With the latest classification, variants in three collagen IV genes, COL4A3 , COL4A4 , and COL4A5 , represent the most prevalent genetic kidney disease in humans, exhibiting diverse, complex, and inconsistent clinical manifestations. This review breaks down the disease spectrum and genotype-phenotype correlations of kidney diseases linked to genetic variants in these genes and distinguishes "classic" Alport syndrome (AS) from the less severe nonsyndromic genetically related nephropathies that we suggest be called "Alport kidney diseases".

Recent findings: Several research studies have focused on the genotype-phenotype correlation under the latest classification scheme of AS. The historic diagnoses of "benign familial hematuria" and "thin basement membrane nephropathy" linked to heterozygous variants in COL4A3 or COL4A4 are suggested to be obsolete, but instead classified as autosomal AS by recent expert consensus due to a significant risk of disease progression.

Summary: The concept of Alport kidney disease extends beyond classic AS. Patients carrying pathogenic variants in any one of the COL4A3/A4/A5 genes can have variable phenotypes ranging from completely normal/clinically unrecognizable, hematuria without or with proteinuria, or progression to chronic kidney disease and kidney failure, depending on sex, genotype, and interplays of other genetic as well as environmental factors.

Box 1

no caption available

FIGURE 1

Schematic diagram of glomerular basement membrane (GBM) collagen IV in health and disease associated with different types of Alport gene variants. (a) The GBM is a network of extracellular matrix proteins flanked by endothelial cells and podocyte foot processes. (b) Normal GBM consists predominantly of a thick layer of collagen α3α4α5(IV) (blue) secreted by podocytes. Collagen α1α1α2(IV) (red), secreted by endothelial cells, appears as a thin layer at the endothelial aspect of the GBM. (c, d) In classic severe Alport syndrome (AS), (c) truncating variants result in no deposition of collagen α3α4α5(IV) in the GBM with a compensatory increase of collagen α1α1α2(IV), while (d) nontruncating variants result in deposition of defective collagen α3α4α5(IV) (yellow). (e, g) As for COL4A3 or A4 heterozygotes, (e) in cases of truncating variants, the wild-type allele contributes to expression of approximately 50% of intact collagen α3α4α5(IV) to the GBM, while (g) in cases of nontruncating variants, deposition of collagen α3α4α5(IV) derived from both alleles results in a mixture of 50% intact and 50% defective collagen α3α4α5(IV). (f) In digenic AS due to heterozygous variants in both COL4A3 and COL4A4, truncating variants in both genes result in a decrease in GBM deposition of intact collagen α3α4α5(IV) to 25% of normal, while (h) nontruncating variants in both genes result in a GBM network of 25% intact and 75% defective collagen α3α4α5(IV). Note that these percentages are only accurate if all nontruncated defective collagen IV trimers are secreted into the GBM, which is not always the case.

FIGURE 2

Schematic diagram of glomerular basement membrane (GBM) collagen IV in females with heterozygous X-linked Alport syndrome (AS). Unlike autosomal variants, heterozygous X-linked COL4A5 variants cause mosaic deposition of collagen α3α4α5(IV) in the GBM depending on which allele (wild-type or mutant) is active in the overlying podocytes after X inactivation. For truncating variants, the affected region of the GBM (covered by red podocytes) completely loses collagen α3α4α5(IV) with a compensatory increase of collagen α1α1α2(IV). For nontruncating variants, the affected region of the GBM (covered by yellow podocytes) can deposit only defective collagen α3α4α5(IV). The unaffected regions covered by podocytes with wild-type alleles show normal GBM collagen α3α4α5(IV). Transition zones are depicted where podocytes expressing the wild-type COL4A5 allele interdigitate with podocytes expressing a mutant allele.