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تسجيل

Gaucher Disease: Genetics and Biochemistry

المؤلف:  Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.

المصدر:  Hematology : Basic Principles and Practice

الجزء والصفحة:  8th E , P775-776

2026-08-16

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 Glucocerebrosidase is encoded by the GBA1 gene, located on chromosome 1q21, close to a pseudogene, GBA1P, which shares 96% identity with the GBA1 active gene. The consequent occurrence (fortunately rare) of complex gene/pseudogene rearrangements may create pitfalls in molecular diagnosis, particularly when performed by next-generation sequencing (NGS) analysis. More than 860 different mutations have been identified in the GBA1 gene, including exonic missense, splice-junction, complex/recombinant alleles, deletions, insertions, and termination mutations. These explain, in part, the great phenotypic heterogeneity which is a hallmark of GD. A mild mutation on one of the alleles (such as N370S; according to the new nomenclature it would be termed: c.1226 A>G p.Asn409Ser, but we keep the traditional or “legendary” one throughout the chapter) will ensure GD1, which will be milder when the second allele also has a mild mutation. The combination of two severe mutations (any mutation that has been detected in a patient with nGD) will cause GD3 or GD2; two null alleles are incompatible with life. These basic genotype-phenotype correlations are important for genetic counseling and management.

In addition to the GC storage in macrophages, there are many other pathophysiological processes (partially delineated in the first part of this chapter) including inflammation, complement activation, protein misfolding, impaired autophagy, and other processes leading to lysosomal dysfunction and together25 contributing to the diversity of disease manifestations.