Mutations in the COL4A4 gene in thin basement membrane disease

Area of Science:

• Nephrology
• Genetics
• Molecular Biology

Background:

• Thin basement membrane disease (TBMD) often shows familial hematuria linked to COL4A3 and COL4A4 genes.
• These genes are also implicated in autosomal recessive Alport syndrome.
• Investigating COL4A4 mutations is crucial for understanding TBMD pathogenesis.

Purpose of the Study:

• To identify and characterize COL4A4 gene mutations in individuals diagnosed with TBMD.
• To determine the frequency of COL4A4 mutations in families with TBMD and hereditary hematuria.

Main Methods:

• Screened 47 coding exons of the COL4A4 gene in 48 unrelated TBMD patients using enzyme mismatch cleavage or SSCP analysis.
• Sequenced exons with electrophoretic abnormalities.
• Confirmed TBMD diagnosis via renal biopsy in 90% of cases or family history.

Main Results:

• Identified nine coding variants in COL4A4, including three pathogenic mutations (nonsense, frameshift, glycine substitution).
• Four pathogenic variants were identified, primarily those causing stop codons or absent in non-hematuric controls.
• Three of nine families (33%) with hematuria linked to COL4A3/COL4A4 locus showed pathogenic COL4A4 mutations.

Conclusions:

• Demonstrated pathogenic COL4A4 mutations in a significant subset of TBMD families with hereditary hematuria.
• Specific mutations (R1377X, 2788/91delG, G960R) caused hematuria in all tested family members.
• Identified S969X and R1377X mutations in TBMD, noting their presence in autosomal recessive Alport syndrome as well.