New Mutation in the COL4A5 Gene of X-linked Alport Syndrome Found, Case Study Reports

A new mutation in the COL4A5 gene — the gene involved in X-linked Alport syndrome — was found in a Japanese mother and daughter who had hematuria (blood in the urine), but no other kidney problems or the often observed hearing and vision symptoms, a case report shows.

Based on these findings, the researchers suggest that Alport syndrome should be considered in patients with hematuria, regardless of family history of the disease, or hearing or vision problems.

The case report, “A family case of X-linked Alport syndrome patients with a novel variant in COL4A5,” was published in the journal Clinical and Experimental Nephrology Case Reports.

Alport syndrome is caused by defects in a major structural protein called type 4 collagen, which acts like a barrier between tissue compartments and is essential for the normal functioning of the kidney, inner ear, and eye.

All Alport patients will have symptoms of kidney problems, often in the form of hematuria and proteinuria (proteins in the urine). Hearing loss is also often the first symptom in these patients, and some of them develop vision problems.

About 80 percent of patients with Alport syndrome have the X-linked form of the disease, meaning they inherited it from a mutation in the COL4A5 gene located on the X chromosome — one of the two sex chromosomes — of one of their parents. To date, more than 900 COL4A5 mutations have been reported.

Due to the existence of only one X chromosome in men, X-linked Alport syndrome is more severe in men than in women, who have two X chromosomes.

The less severe form of the disease in women can make its diagnosis difficult and/or delayed, often not even being considered as a possibility.

Researchers at Tokyo Medical University have now identified a new COL4A5 mutation in two Japanese women: a mother and a daughter.

The 16-year-old daughter was 3 years old when she was referred to the hospital due to microscopic hematuria (blood in the urine that is only visible under a microscope), without proteinuria, kidney dysfunction, hearing loss, or eye abnormalities.

When she was 13, the doctors conducted a kidney biopsy due to a suspicion of IgA nephropathy (Berger’s disease), a leading cause of kidney failure. The biopsy showed it was not IgA nephropathy, but Alport syndrome was not considered at that time.

Alport syndrome was only suspected three years later, when her mother, at 40 years old, was found to have asymptomatic hematuria, proteinuria, and other features of kidney dysfunction. She had also no clinically detectable hearing loss or vision problems.

At that point, doctors re-analyzed the preserved tissue of the daughter’s previous kidney biopsy for the presence of changes in type 4 collagen and found features consistent with Alport syndrome.

A genetic analysis of the DNA of the daughter, mother, and father showed that the mother and daughter had a specific mutation in the COL4A5 gene (c.C3769T: p.Q1257X), which resulted in a shorter unfinished protein and an abnormal structure of type 4 collagen.

The researchers noted that while microscopic hematuria was detected when the girl was 3 years old, a diagnosis of X-linked Alport syndrome was only made 13 years later, suggesting that this condition should be considered “in all patients with hematuria despite absent/present of family history, hearing loss, and ocular abnormality.”

They believe that if the kidney biopsy was evaluated adequately, a diagnosis of Alport syndrome could have been suggested earlier, and that data obtained with electron microscopy — a technique that enables researchers to acquire images of a tissue sample at a greater resolution than with a light microscope — is very important for its diagnosis.