Researchers Identify Two Gene Mutations That May Be Linked to Mild Form of Alport Syndrome

Researchers have identified two mutations of the COL4A3 gene that appear to be linked to the development of a mild form of autosomal recessive Alport syndrome, or ARAS.

The study, “A case of mild phenotype Alport syndrome caused by COL4A3 mutations,” was published in the journal CEN Case Reports.

Alport syndrome is caused by mutations of genes that encode a protein known as the type IV collagen α chain. The ARAS subtype of Alport syndrome is typically characterized by mutations of DNA sequences of genes that encode the type IV collagen α3 chain, or COL4A3, but that also encode the type IV collagen α4 chain, or COL4A4.

In the initial stages of ARAS, doctors commonly find blood in patients’ urine. As the disease progresses, protein levels in urine increase. The rapidly progressing kidney disease leads to kidney failure at a median age of 21.8 years.

A kidney biopsy is fundamental to diagnosing Alport syndrome, but levels of  type IV collagen also provide important information.

Researchers at Nagasaki University Hospital in Japan looked at the case of a 41-year-old patient with a history of slowly progressing kidney disease and hearing loss. A kidney biopsy revealed atypical type IV collagen associated with Alport syndrome.

The glomerular basement membrane supports kidney cells responsible for the kidneys’ filtering process. The Nagasaki researchers found normal α5 but relatively weak α2 Type IV collagen expression in the patient’s membrane. Expression is the process by which a gene produces a functional produce like a protein.

Both α chains showed normal expression in the Bowman’s capsules, a sac-like structure involved in the first step of filtration, the researchers discovered. This profile did not fit the standard ARAS Type IV chain expression profile.

Normally, researchers do not find expression of the α3, α4, and α5 chains in ARAS patients’ glomerular basement membrane, Bowman’s capsules, or other membranes.

The team discovered that the patient had two mutations of DNA sequencing in the COL4A3 gene. One was a deletion of 45 DNA letters that led to a break in part of the COL4A3 coding sequence.

Based on the atypical α chain expression in the glomerular basement membrane and the skipping mutation, the researchers hypothesized that a complex of α3, α4, and α5 chains had formed that led to  abnormal glomerular basement membrane functioning. “This mutation might be associated with mild renal dysfunction at the age of 41 years,” they wrote.

The second mutation was a deletion of eight DNA letters that led to a shorter form of the α3 chain. Based on a previous report of similar mutations, the researchers concluded that the truncated chain did not influence the patient’s kidney disease.

“These two gene mutations represented a new pattern of mutation” and suggested an association with “atypical a5 chain expression and mild phenotype [form of the disease],” they wrote. “Genetic testing may be useful for obtaining a definitive diagnosis” of Alport syndrome.