GBA1 – Gaucher disease type III

GBA1 (HGNC:4177) is definitively associated with Gaucher disease type III, a subacute neuronopathic form of Gaucher disease. This autosomal recessive disorder arises from biallelic loss-of-function variants in GBA1 leading to glucocerebrosidase deficiency and lysosomal glucosylceramide accumulation. Patients typically present in early childhood with visceral involvement and progressive neurological features, including oculomotor apraxia, splenomegaly, and hepatosplenomegaly.

Genetic evidence includes 37 probands with confirmed type III phenotypes: 26 patients from the Gaucher Outcome Survey ([PMID:29326879]), eight Japanese cases with p.Phe252Ile ([PMID:1840477]), and three single-patient reports ([PMID:10714667], [PMID:39201895], [PMID:39544691]). Although formal segregation data are limited, recurrent identification of homozygous or compound heterozygous variants across unrelated families supports autosomal recessive inheritance.

The variant spectrum is dominated by missense changes, with c.1448T>C (p.Leu483Pro) recurrent in 16 of 23 genotyped GD3 patients ([PMID:29326879]). Other pathogenic alleles include c.754T>A (p.Phe252Ile) ([PMID:1840477]) and c.1342G>C (p.Asp448His) associated with type 3c cardiac-predominant phenotypes ([PMID:39544691]). No founder-specific structural variants have been described beyond pseudogene-derived recombinant alleles.

Functional studies demonstrate that pathogenic GBA1 alleles severely reduce glucocerebrosidase catalytic activity and stability. In vitro expression of p.Phe252Ile results in deficient enzyme activity ([PMID:1840477]), while broader mutational analyses show misfolded enzymes with <1% residual activity for many variants ([PMID:8294487]). Chemical chaperones partially rescue the activity of select variants, confirming misfolding and endoplasmic reticulum retention as key pathogenic mechanisms.

Some alleles, notably E326K, behave as modifier variants rather than primary causative mutations, given their occurrence in healthy controls and co-segregation with severe mutations ([PMID:11903352]). Careful interpretation via haplotype and functional assays is therefore essential.

Collectively, the extensive case series, recurrent variant findings, and concordant functional data fulfill definitive ClinGen criteria for the GBA1–Gaucher disease type III relationship. This robust evidence base underpins clinical genetic testing, prognostic counseling, and the development of targeted chaperone-based therapies. Key take-home: Biallelic missense mutations in GBA1 cause type III Gaucher disease, and functional assays can clarify variant pathogenicity to guide diagnosis and management.

References

• Molecular genetics and metabolism reports • 2018 • Characteristics of 26 patients with type 3 Gaucher disease: A descriptive analysis from the Gaucher Outcome Survey [PMID:29326879]
• American journal of human genetics • 1991 • A new glucocerebrosidase-gene missense mutation responsible for neuronopathic Gaucher disease in Japanese patients [PMID:1840477]
• Archives of neurology • 2000 • Myoclonus from selective dentate nucleus degeneration in type 3 Gaucher disease [PMID:10714667]
• Children (Basel, Switzerland) • 2024 • Pediatric Gaucher Disease Type 3 Presenting with Oculomotor Apraxia: A Case Report [PMID:39201895]
• JIMD reports • 2024 • Gaucher disease type 3c: Expanding the clinical spectrum of an ultra-rare disease [PMID:39544691]
• The Journal of biological chemistry • 1994 • Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression [PMID:8294487]
• Clinical genetics • 2002 • The E326K mutation and Gaucher disease: mutation or polymorphism? [PMID:11903352]

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