Single-point Mutation in Critical Gene Seen to Cause Key Alport Symptoms

A single-point mutation in a critical gene, AMMECR1, is responsible for the physical expression of the main symptoms associated with Alport syndrome, researchers report.

This finding is detailed in the study “AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis.” It was published in the Journal of Medical Genetics in November but recently released online for a wider audience to access.

The physical manifestations of the gene deletions found in Alport patients include intellectual disabilities, incomplete structural development of facial tissue and bones — or midface hypoplasia — and abnormally shaped red-blood cells, a condition known as elliptocytosis.  

Researchers think the symptoms are associated with a missense mutation in the genetic code. The term refers to an amino acid being in a location other than the one specified in the genetic map that DNA reads to make protein.

To understand the abnormal genetic components, such as the missense mutation, that are the theoretical cause of the disease, investigators analyzed the gene features of two half-brothers. Both had nephrocalcinosis, a kidney ailment; delayed early speech and language; and midface hypoplasia, including a submucous cleft palate and bifid uvula.

The reason for examining the brothers was to pinpoint the exact location on the gene where the mutational displacement occurred.

Researchers used whole exome sequencing to map the brothers’ entire genome.  The patient-specific mutations that were found were then introduced to another cell line through a process called transfection. The goal was to understand the mutation process from start to finish under a microscope to pinpoint where the mutation begins and ends.

A genetic sequence analysis of each boy showed there was a single-point mutation — or place within the gene where only one base pair was altered — that caused the physical expression of symptoms associated with Alport. That place was in the X-linked gene from the mother’s side.

”Our study narrows the AMME locus to a single point mutation in AMMECR1 that appears critical in the pathogenesis of midface hypoplasia and elliptocytosis, and contributes to early speech and language delay, hypotonia and hearing loss, and may, in addition, play a role in dysmorphism, nephrocalcinosis and submucous cleft palate,” the researchers wrote.

The findings add a significant component to the gene map that scientists are using to better understand Alport syndrome in hopes of finding a way to prevent and possibly cure it.