GBA1 – Gaucher disease

Gaucher disease is a pan‐ethnic, autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in GBA1, which encodes acid β-glucosidase. Affected individuals present with hepatosplenomegaly, anemia, thrombocytopenia, bone pain and, in neuronopathic forms, neurologic involvement. Recognition of biallelic GBA1 variants enables definitive enzymatic and molecular diagnosis and informs treatment decisions including enzyme replacement and substrate reduction therapies.

Extensive genetic evidence supports a Definitive association between GBA1 and Gaucher disease. Over 56 distinct mutations were identified in 193 unrelated Spanish probands (PMID:17427031), and eight common alleles account for >75% of mutated chromosomes in non-Jewish patients (PMID:7627184). Segregation analysis in a Lebanese–Arab family spanning three generations with six affected homozygotes demonstrated full cosegregation of a private c.1240G>T (p.Val414Leu) variant (PMID:14994233). Additional segregation in consanguineous sibships further confirms recessive inheritance.

The variant spectrum is broad, encompassing missense (e.g., c.1226A>G (p.Asn409Ser) and c.1448T>C (p.Leu483Pro)), splice-site, small indels and complex recombinant alleles. N370S (c.1226A>G) and L444P (c.1448T>C) are the most frequent pathogenic variants in Ashkenazi and non-Jewish cohorts respectively. Both severe and mild alleles recur worldwide, enabling genotype-phenotype correlations and founder-effect analyses (PMID:1348297).

Functional studies demonstrate that many missense mutations markedly reduce enzyme activity and impair trafficking. Site-directed mutagenesis in Sf9 cells localized the catalytic acid/base to Glu235 and the nucleophile to Glu340, and showed that N370S retains 5–30% activity whereas L444P and D409H are largely inactive (PMID:8294487). Chemical chaperones such as N-nonyl-deoxynojirimycin increase residual activity of N370S and other variants, supporting haploinsufficiency as a mechanism (PMID:16298303). Expression of 13 alleles confirmed the pathogenicity of rare variants and defined E326K as a modifier (PMID:15146461).

No credible conflicting evidence has refuted this association. GBA1‐deficient mouse models recapitulate visceral and, in neuronopathic alleles, CNS pathology, and rescue experiments further support the causality of GBA1 variants.

Taken together, convergent genetic segregation, robust functional validation and successful therapeutic targeting underscore GBA1 as a Definitive disease gene for Gaucher disease. Molecular testing for GBA1 variants is clinically useful for early diagnosis, prognosis, and guiding enzyme replacement or chaperone therapy.

References

• Lancet (London, England) • 1992 • Genetic diagnosis of Gaucher's disease. PMID:1348297
• Human mutation • 1995 • Gaucher disease in Spanish patients: analysis of eight mutations. PMID:7627184
• American journal of medical genetics. Part A • 2004 • Novel mutation, L371V, causing multigenerational Gaucher disease in a Lebanese family. PMID:14994233
• The Journal of biological chemistry • 1994 • Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression. PMID:8294487
• Chemistry & biology • 2005 • Gaucher disease–associated glucocerebrosidases show mutation-dependent chemical chaperoning profiles. PMID:16298303
• Human mutation • 2004 • Functional analysis of 13 GBA mutant alleles identified in Gaucher disease patients: Pathogenic changes and "modifier" polymorphisms. PMID:15146461

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