Compound heterozygous p.L483P and p.S310G mutations in GBA1 cause type 1 adult Gaucher disease: case report with a novel mutation

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Abstract Background Gaucher disease (GD) is a rare autosomal recessive hereditary lysosomal storage disease. It is caused by glucocerebrosidase (GBA1) gene mutation that leads to decreased activity of acid β-glucosidase (glucocerebrosidase [GCase]). GD genotype-phenotype correlation is not fully understood. The aim of the current study was to identify and characterize compound heterozygous mutations of GBA1 in a type 1 adult GD patient. Results Using enzymological studies and whole exome sequencing, the patient with type 1 GD was found to becompound heterozygous for GBA1 missense mutations in exon 10 c.1448T > C (p.L483P) and exon 7 c.928A > G (p.S310G). The patient's mother who had Parkinson disease history was heterozygous for p.S310G mutation. The asymptomatic father was heterozygous for p.L483P mutation. The sister did not carry either mutation. Structural modeling showed both p.S310G and p.L483P are far away from the GCase active site. The p.S310G mutation in domain 1 could cause decreased stability between the α2 and α3 helices of GBA1. The p.L483P mutation in domain 2 could reduce the van der Waals force of the side chain and disrupt the C-terminal -sheet. Conclusions The p.L483P/p.S310G novel compound heterozygous mutation underlies type 1 GD and likely impacts GCase protein function. This is the first description of p.S310G associated with mild type 1 GD in the context of coinherited p.L483P mutation.

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