Compound heterozygous p.L483P and p.S310G mutations in GBA1 cause type 1 adult Gaucher disease: A case report

Abstract

BACKGROUND Gaucher disease (GD) is caused by a GBA1 gene mutation that leads to decreased acid β-glucosidase activity [glucocerebrosidase (GCase)]. This study aimed to identify and characterise compound heterozygous mutations in GBA1 in a patient with type 1 GD. CASE SUMMARY Here, we report a rare adult-onset type 1 GD in a 46-year-old female patient with clinical manifestations of giant spleen, thrombocytopenia, and bone pain, diagnosed by enzymatic and genetic testing. Enzymology and whole exome sequencing revealed heterozygous missense mutations in exon 10 c.1448T>C (p.L483P) and exon 7 c.928A>G (p.S310G) of GBA1 . The latter was first reported in patients with GD. Structural modelling showed that p.S310G and p.L483P were distant from the GCase active site. The p.S310G mutation in domain 1 may decrease stability between the α2 and α3 helices of GBA1 . The p.L483P mutation in domain 2 reduced the van der Waals force of the side chain and disrupted the C-terminal β-sheet. The patient was treated with imiglucerase replacement therapy, and her condition was stable. CONCLUSION The p.L483P/p.S310G novel compound heterozygous mutation underlies type 1 GD and likely affects GCase protein function. This is the first description of p.S310G being associated with mild type 1 GD in the context of a coinherited p.L483P mutation.

Lysosomal storage disorders identified in adult population from India: Experience of a tertiary genetic centre and review of literature

“…Of note, this variant was seen in compound heterozygous state with another pathogenic variant on the other allele. Similar observation has been made in adult Gaucher patients where the authors propose that a milder phenotype of adult GD could be attributed to the presence of missense variant other than p.Leu483Pro on the second allele 41 . Surprisingly, variant Asn409Ser in the GBA1 gene has been the most common variant reported in ~80% of adult Gaucher patients 34 but was not observed in our study.…”

“…Similar observation has been made in adult Gaucher patients where the authors propose that a milder phenotype of adult GD could be attributed to the presence of missense variant other than p.Leu483Pro on the second allele. 41 Surprisingly, variant Asn409Ser in the GBA1 gene has been the most common variant reported in ~80% of adult Gaucher patients 34 but was not observed in our study. This suggests genetic heterogeneity in the Indian Gaucher patients.…”