title: A mutation in SCARB2 is a modifier in Gaucher disease.
abstract: Lysosomal integral membrane protein type 2 (LIMP-2) is responsible for proper sorting and lysosomal targeting of glucocerebrosidase, the enzyme deficient in Gaucher disease (GD). Mutations in the gene for LIMP-2, SCARB2, are implicated in inherited forms of myoclonic epilepsy, and myoclonic epilepsy is part of the phenotypic spectrum associated with GD. We investigated whether SCARB2 mutations impact the Gaucher phenotype focusing on patients with myoclonic epilepsy, including a pair of siblings with GD who were discordant for myoclonic seizures. Sequencing of SCARB2 genomic and cDNA identified a heterozygous, maternally inherited novel mutation, c.1412A>G (p.Glu471Gly), in the brother with GD and myoclonic epilepsy, absent from his sibling and controls. Glucocerebrosidase activity, Western blots, real-time PCR, and immunofluorescence studies demonstrated markedly decreased LIMP-2 and glucocerebrosidase in cells from the sibling with (p.Glu471Gly) LIMP-2, and diminished glucocerebrosidase in lysosomes. The cells secreted highly glycosylated enzyme and showed mistrafficking of glucocerebrosidase. Sequencing of SCARB2 in 13 other subjects with GD and myoclonic epilepsy and 40 controls failed to identify additional mutations. The study provides further evidence for the association of LIMP-2 and myoclonic epilepsy, explains the drastically different phenotypes encountered in the siblings, and demonstrates that LIMP-2 can serve as a modifier in GD.
authors.affiliation: Section on Molecular Neurogenetics, Medical Genetics Branch, NHGRI, National Institutes of Health, Bethesda, Maryland 20892-3708, USA.
authors.forename: Arash
authors.initials: A
authors.lastname: Velayati
authors.forename: John
authors.initials: J
authors.lastname: DePaolo
authors.forename: Nidhi
authors.initials: N
authors.lastname: Gupta
authors.forename: Jae H
authors.initials: JH
authors.lastname: Choi
authors.forename: Nima
authors.initials: N
authors.lastname: Moaven
authors.forename: Wendy
authors.initials: W
authors.lastname: Westbroek
authors.forename: Ozlem
authors.initials: O
authors.lastname: Goker-Alpan
authors.forename: Ehud
authors.initials: E
authors.lastname: Goldin
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Stubblefield
authors.forename: Edwin
authors.initials: E
authors.lastname: Kolodny
authors.forename: Nahid
authors.initials: N
authors.lastname: Tayebi
authors.forename: Ellen
authors.initials: E
authors.lastname: Sidransky
mesh_terms: D000328:Adult; D004831:Epilepsies, Myoclonic / Q000235:genetics; D005260:Female; D005776:Gaucher Disease / Q000235:genetics*; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D051116:Receptors, Scavenger / Q000235:genetics*
chemical_list: D051907:Lysosomal Membrane Proteins; D051116:Receptors, Scavenger; C074299:SCARB2 protein, human