Scientists discovered a new mutation in the GLA gene that leads to the production of a shorter protein in a Chinese patient with Fabry disease, correlating with kidney symptoms associated with the disease, a study reports.
The study, “A novel α-galactosidase A splicing mutation predisposes to Fabry disease,” was published in Frontiers in Genetics.
Fabry disease is a rare genetic disorder caused by mutations in the GLA gene — located on the X chromosome — that provides instructions for the production of an enzyme called alpha-galactosidase A (alpha-GAL A). These mutations typically affect the function of alpha-GAL A, leading to the accumulation of a type of fat called globotriaosylceramide (Gb3) in several tissues and organs.
So far, hundreds of genetic mutations in GLA have been linked to Fabry disease, which can be found on the Human Gene Mutation Database and Fabry mutants list, including a series of missense and splicing mutations, such as p.P60L, p.E66Q, p.R118C, p.A143T and p.I198T.
Missense mutations are single nucleotide mutations that alter protein composition; splicing mutations are mutations that change the number of nucleotides — the building blocks of DNA — at splicing sites — regions of the gene that are prone to being removed or shifted to generate different proteins — leading to the production of abnormally long or short proteins.
In this study, a team of researchers from the Shanxi University in China identified a new splicing mutation in a patient with Fabry disease showing signs of kidney disease.
The study enrolled four patients from four unrelated Chinese families with a medical history of Fabry disease. While three of the patients carried missense mutations that had already been described in previous studies (c.119C>A, c.101A>G and c.680G>C), the fourth patient had a different splicing mutation.
The new mutation, which changed the first nucleotide of GLA intron 5 from a guanine to adenine (c.801+1G>A), caused alterations in GLA alternative splicing, leading to the production of a shorter protein lacking a total of 270 amino acids (the building blocks of proteins). For reference, there are four nucleotides in DNA: guanine, adenine, thymine, and cytosine.
An intron is the region of a gene that does not provide instructions for a protein; alternative splicing is the process of creating different proteins from the same gene.
Further analysis revealed this was triggered by a frameshift in the gene sequence, caused by an insertion of 36 nucleotides between GLA exons 5 and 6 that led to the premature termination of protein production. An exon is the coding sequence of a gene that provides instructions to make proteins.
Interestingly, when researchers forced lab-cultured cells to produce this mutant form of GLA, they observed that these cells aged faster and had lower activity of alpha-GAL A than those that had the normal version of the gene. In addition, they also found that alpha-GAL A had an abnormal localization inside cells that were carriers of the c.801+1G>A mutation.
“In summary, we report a novel intronic mutation c.801+1G>A causes a remarkable increase in the alternatively spliced GLA transcript and, consequently, results in the renal phenotype [symptoms shown] of FD [Fabry disease],” the researchers wrote.
“Our study confirms that c.801+1G>A is a Fabry-causative mutation and data in this study enrich Fabry mutation database and provide a FD causative mutation for accurate molecular diagnosis as well as scientific information,” they added.