Three Novel Heterozygous COL4A4 Mutations Result in Three Different Collagen Type IV Kidney Disease Phenotypes

Cytogenet Genome Res. 2018;154(1):30-36. doi: 10.1159/000486979. Epub 2018 Feb 15.


Thin basement membrane nephropathy (TBMN), autosomal dominant Alport syndrome (ADAS), and focal segmental glomerulosclerosis (FSGS) are kidney diseases that differ in clinical diagnosis, treatment, and prognosis. Nevertheless, they may result from the same causative genes. Here, we report 3 COL4A4 heterozygous mutations (p.Gly208Arg, p.Ser513Glufs*2, and p.Met1617Cysfs*39) that lead to 3 different collagen type IV kidney disease phenotypes, manifesting as TBMN, ADAS, and FSGS. Using bioinformatics analyses and pedigree verification, we show that these novel variants are pathogenetic and cosegregate with TBMN, ADAS, and FSGS. Furthermore, we found that the collagen type IV-associated kidney disease phenotypes are heterogeneous, with overlapping pathology and genetic mutations. We propose that COL4A4-associated TBMN, ADAS, and FSGS should be considered as collagen type IV kidney disease subtypes that represent different phases of disease progression.

Keywords: COL4A4 mutations; Autosomal dominant Alport syndrome; Collagen type IV kidney disease; Focal segmental glomerulosclerosis; Thin basement membrane nephropathy.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Child
  • Collagen Type IV / genetics*
  • Collagen Type IV / metabolism
  • DNA Mutational Analysis
  • Glomerular Basement Membrane / metabolism
  • Glomerular Basement Membrane / pathology
  • Glomerular Basement Membrane / ultrastructure
  • Glomerulosclerosis, Focal Segmental / genetics*
  • Glomerulosclerosis, Focal Segmental / metabolism
  • Hematuria / genetics*
  • Hematuria / metabolism
  • Heterozygote
  • Humans
  • Male
  • Microscopy, Electron
  • Mutation*
  • Nephritis, Hereditary / genetics*
  • Nephritis, Hereditary / metabolism
  • Phenotype


  • COL4A4 protein, human
  • Collagen Type IV

Supplementary concepts

  • Hematuria, Benign Familial