title: Mice with type 2 and 3 Gaucher disease point mutations generated by a single insertion mutagenesis procedure.
abstract: Gaucher disease is caused by mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GC). Three clinical types of Gaucher disease have been defined according to the presence (type 2 and 3) or absence (type 1) of central nervous system disease and severity of clinical manifestations. The clinical course of the disease correlates with the mutation carried by the GC gene. To produce mice with point mutations that correspond to the clinical types of Gaucher disease, we have devised a highly efficient one-step mutagenesis method-the single insertion mutagenesis procedure (SIMP)-to introduce human disease mutations into the mouse GC gene. By using SIMP, mice were generated carrying either the very severe RecNciI mutation that can cause type 2 disease or the less severe L444P mutation associated with type 3 disease. Mice homozygous for the RecNciI mutation had little GC enzyme activity and accumulated glucosylceramide in brain and liver. In contrast, the mice homozygous for the L444P mutation had higher levels of GC activity and no detectable accumulation of glucosylceramide in brain and liver. Surprisingly, both point mutation mice died within 48 hr of birth, apparently of a compromised epidermal permeability barrier caused by defective glucosylceramide metabolism in the epidermis.
authors.affiliation: Section on Biochemical Genetics, Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: J D
authors.initials: JD
authors.lastname: Reed
authors.forename: A
authors.initials: A
authors.lastname: Grinberg
authors.forename: H
authors.initials: H
authors.lastname: Westphal
authors.forename: A
authors.initials: A
authors.lastname: Hoffmann
authors.forename: T
authors.initials: T
authors.lastname: Döring
authors.forename: K
authors.initials: K
authors.lastname: Sandhoff
authors.forename: R L
authors.initials: RL
authors.lastname: Proia
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D005776:Gaucher Disease / Q000145:classification / Q000235:genetics* / Q000473:pathology; D005962:Glucosylceramidase / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D016254:Mutagenesis, Insertional; D017354:Point Mutation; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D015183:Restriction Mapping; D012867:Skin / Q000473:pathology; D013107:Sphingolipids / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D013107:Sphingolipids; D005962:Glucosylceramidase