A newly identified mutation in a region of the GBA gene that lacks information necessary to make the resulting beta-glucocerebrosidase (GCase) protein was found in a woman with Gaucher disease (GD) type 1.
That condition is described in the case report, “A novel mutation deep within intron 7 of the GBA gene causes Gaucher disease,” which was published in the journal Molecular Genetics and Genomic Medicine.
The GBA gene provides instructions for producing the enzyme GCase. In people with GD, this enzyme is made incorrectly, leading to the accumulation of a lipid (fat) called glucocerebroside in immune cells called macrophages, which then become Gaucher cells. More than 400 different mutations have been described in the GBA gene.
Each gene is composed of regions that contain the information to make proteins (called exons) and introns, which are regions that have no protein-coding information. Introns usually are “cut out” during protein production in a process called splicing. Mutations that alter this splicing usually insert a premature STOP sign in the RNA molecule (used as template to make proteins), which results in a protein shorter than normal. The GBA gene is composed of 11 exons and 10 introns.
A team from Cyprus reported a new GBA gene mutation in a woman with GD. The gene variant was found in intron 7 and caused a previously unknown splicing error.
At age 42, the patient presented with hepatosplenomegaly (enlarged liver and spleen), elevated blood levels of the enzyme acid phosphatase (a known alteration in people with GD), thrombocytopenia (low platelet levels), and hypergammaglobulinemia (elevated levels of immunoglobulin). A myelogram (an imaging test of the spinal canal) and a biopsy of the bone marrow confirmed the presence of Gaucher cells.
As characteristic in GD, she also showed low GCase activity in white blood cells. No neurological symptoms were found and she was diagnosed with type 1 GD.
From age 53, she started on two weekly doses of enzyme replacement therapy. After one year, treatment increased levels of hemoglobin and platelets, and reduced the size of the liver (30%) and spleen (40%).
The patient carried a mutation on the CHIT1 gene, causing a deficiency in an enzyme called chitotriosidase, which is a GD biomarker produced by activated macrophages.
DNA analysis did not find any of nine common mutations in the GBA gene. No changes were detected in this gene’s exons.
The researchers then investigated whether a splicing mutation was present. This revealed a mutation in both GBA gene copies that resulted in a premature STOP sign that may cause RNA degradation. Still, the patient showed normal RNA, which may explain her relatively mild complications and late onset of the disease, the scientists wrote.
“In the present study we have identified a novel mutation deep in intron 7 of the GBA gene in a Cypriot patient with type 1 GD. This is the first time that this type of mutation is described for GD,” they stated.
They also tested the patient’s family for GBA mutations. They discovered that her parents, one sister and her four children, all had this mutation in one of their GBA copies.
Overall, “this study expands the mutation spectrum of GD and highlights the importance of RNA sequencing for the molecular diagnosis of patients bearing mutations in nonexonic regions” [outside of exons], the team concluded.
