GBA1 – Parkinson Disease

Heterozygous mutations in GBA1, encoding the lysosomal enzyme glucocerebrosidase, act as a significant genetic risk factor for Parkinson disease (PD) rather than a fully penetrant Mendelian cause. While biallelic GBA1 mutations cause Gaucher disease (an autosomal recessive lysosomal storage disorder), numerous case–control and family studies have demonstrated that carriers of a single pathogenic GBA1 allele have a 5–15-fold increased odds of PD compared to non-carriers (PMID:19846850).

Genetic epidemiology across diverse populations reveals that GBA1 variants are present in ~5–7% of non-Ashkenazi PD patients and up to 15% of Ashkenazi Jewish PD patients, versus ≤1% of controls (PMID:19846850). Familial segregation and penetrance studies in 525 familial PD probands identified 24 GBA1 carriers (4.6%) and 256 relatives, of whom 43 were affected and 26 carried mutations; PD penetrance estimates reached 29.7% by age 80 under a dominant model with reduced penetrance (PMID:22282650).

Segregation analyses further support a dominant inheritance with incomplete penetrance: among 256 at-risk relatives, 43 developed PD and 26 were confirmed GBA1 carriers, yielding robust age-specific risk estimates (PMID:22282650). Case–control meta-analyses of >5,600 PD patients and 4,900 controls demonstrated a consistent enrichment of GBA1 alleles (carrier frequency 3–4× higher in patients) with odds ratios around 5.4 across centers (PMID:19846850).

Biochemical and cellular studies elucidate a loss-of-function mechanism: patient fibroblasts and heterologous expression systems show that common variants (e.g., p.Asn409Ser) reduce glucocerebrosidase activity and impair trafficking out of the endoplasmic reticulum. Chemical chaperones such as N-nonyl-deoxynojirimycin partially restore enzyme activity in several GBA1 mutants, including N370S and G202R (PMID:16298303).

iPSC-derived dopaminergic neurons from PD patients carrying p.Asn409Ser exhibit markedly decreased GCase activity, reduced protein levels, and secondary alterations in lysosomal enzymes, mirroring PD-related lysosomal dysfunction in vitro (PMID:36901867). Functional brain imaging of GBA1 mutation carriers, both symptomatic and asymptomatic, reveals characteristic hypometabolism in the supplementary motor area and striatal dopaminergic deficits on FDG-PET and CFT/PET studies (PMID:20669267).

Together, genetic, family-based, and experimental data converge to a Strong level of clinical validity for GBA1 in PD. Heterozygous GBA1 variants confer a reproducible, population-scale risk and show concordant functional deficits. These findings support genetic testing for GBA1 in PD patients for risk stratification and have direct implications for genotype-driven trials of lysosomal and chaperone therapies.

References

• The New England Journal of Medicine • 2009 • Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease PMID:19846850
• Neurology • 2012 • Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers PMID:22282650
• Chemistry & Biology • 2005 • Gaucher disease-associated glucocerebrosidases show mutation-dependent chemical chaperoning profiles PMID:16298303
• International Journal of Molecular Sciences • 2023 • Biochemical Characteristics of iPSC-Derived Dopaminergic Neurons from N370S GBA Variant Carriers with and without Parkinson's Disease PMID:36901867
• Movement Disorders • 2010 • Functional brain imaging in glucocerebrosidase mutation carriers with and without parkinsonism PMID:20669267

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