Non-pseudogene-derived complex acid beta-glucosidase mutations causing mild type 1 and severe type 2 gaucher disease

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• Gaucher disease is an inherited metabolic disorder caused by mutations in the GBA1 gene, leading to deficient acid beta-glucosidase activity.
• This deficiency results in the accumulation of glycosphingolipids within lysosomes, causing various clinical manifestations.
• Three main subtypes of Gaucher disease exist, distinguished by the severity of symptoms and age of onset, linked to different GBA1 mutations.

Observation:

• A severe neonatal Gaucher disease type 2 variant presented with collodion skin, ichthyosis, and rapid neurodegeneration.
• This patient harbored two novel GBA1 alleles: a complex maternal allele (E326K+L444P) and a paternal nonsense mutation (E233X).
• A mild type 1 patient with genotype D140H+E326K/K157Q carried a previously reported complex allele (D140H+E326K) also containing the E326K mutation.

Findings:

• Expression and characterization of the novel alleles revealed that E233X produced no enzyme activity, and K157Q had ~1% normal specific activity.
• The complex allele D140H+E326K in the type 1 patient encoded a neuroprotective enzyme with catalytic efficiency similar to the N370S variant.
• Conversely, the E326K+L444P allele lacked sufficient activity to prevent neurological damage, leading to the severe phenotype in the type 2 variant when combined with E233X.

Implications:

• Characterizing these novel Gaucher disease genotypes provides a molecular basis for the diverse clinical phenotypes observed.
• Understanding the functional impact of complex GBA1 mutations is crucial for predicting disease progression and developing targeted therapies.
• This study highlights the importance of detailed genotype-phenotype correlation in inherited metabolic disorders.