New COL4A3 Gene Mutation Linked to Alport Syndrome Identified in Spanish Family

A new genetic mutation in the COL4A3 gene was identified in a Spanish family and linked to the development of Alport syndrome.

According to findings reported in the study, “Phenotype variability in a large Spanish family with Alport syndrome associated with novel mutations in COL4A3 gene,” which appeared in the journal BMC Nephrology, when combined with other COL4A3 mutations this new variant leads to early-onset Alport syndrome with more severe symptoms.

Alport syndrome is a genetic disorder characterized by renal dysfunction, but it can also affect the eyes and ears. Several genetic mutations have been associated with this disease, all affecting genes that encode type IV collagen protein.

About 1-5% of Alport syndrome patients have a specific subtype of the disease called autosomal dominant AS, or ADAS. This condition is associated with genetic mutations on COL4A3 or COL4A4 genes that encode the type IV collagen α3 and α4 chains, respectively.

ADAS affects both men and women and presents high clinical variability. Because of this, and given that many of its symptoms may wrongly point toward other medical conditions such as benign familial hematuria, it is essential to perform detailed genetic and molecular analysis of affected patients and their direct family members. This is not only important to reach a diagnosis but also to allow suitable care and counseling.

A research team led by Elena Domínguez-Garrido, PhD, director of the Molecular Diagnostics Unit at Center for Biomedical Research (CIBIR), in Spain, analyzed the case of a patient who presented signs of renal deficiency. Further evaluation of renal morphology confirmed changed renal basement membrane structures, probably due to abnormal collagen production.

Genetic analysis of the genes responsible for collagen production revealed the presence of a new mutation, identified as G333E, in the COL4A3 gene. No alterations were found in the COL4A4 gene.

Analysis of the genetics of direct family members showed that 12 — nine males and three females — had the G333E mutation. Two additional mutations in COL4A3 (P1461L and S1492C) were detected in some family members, but the role they played in the development of Alport syndrome was unclear. No other potentially disease-associated mutations in the COL4A3 gene were detected in the family.

Evaluation of the clinical features presented by each family member showed that carriers of the G333E mutation all had renal dysfunction with blood present in the urine (hematuria), and 61.5% had increased levels of protein in the urine (proteinuria). Additionally, 46.1% had hearing loss. None of the individuals had ocular abnormalities.

Those with G333E plus P1461L or G333E plus S1492C experienced more severe symptoms and early onset of the disease. In contrast, the individuals with P1461L or S1492C alone did not show any signs of the disease.

Based on these findings, researchers speculated that the mutations could cooperate to promote disease progression, which could help explain the different clinical features of various members of the family.

“A correct diagnosis and prognosis should be based on a combination of a comprehensive clinical investigation of all family members, including examination of renal and extra-renal signs of AS [Alport syndrome], associated with a broadly formal molecular genetic analysis of the pedigree,” the authors wrote.