title: Mutations at the lysosomal acid cholesteryl ester hydrolase gene locus in Wolman disease.
abstract: The genomic sequences encoding the human lysosomal acid lipase/cholesteryl esterase (sterol esterase; EC 3.1.1.13) have been isolated and sequenced, and the information has been used to identify mutations in both alleles of the gene from a patient with Wolman disease, an autosomal recessive lysosomal lipid storage disorder. The genomic locus consists of 10 exons spread over 36 kb. The 5' flanking region is G+C-rich and has characteristics of a "housekeeping" gene promoter. One of the identified mutations involves the insertion of a T residue after position 634, resulting in the appearance of an in-frame translation stop signal 13 codons downstream. The second mutation is a T-to-C transition at nucleotide 638. This results in a leucine-to-proline substitution at amino acid 179 and is predicted to lead to the disruption of the alpha-helical structure in a highly conserved region of the protein. These mutations are each capable of completely disrupting the catalytic function of the lysosomal acid cholesteryl ester hydrolase; their presence can account for the extreme phenotype of the lysosomal lipid storage disorder manifested in members of this patient's family.
authors.affiliation: Department of Internal Medicine, Wake Forest University Medical Center, Winston-Salem, NC 27157.
authors.forename: R A
authors.initials: RA
authors.lastname: Anderson
authors.forename: R S
authors.initials: RS
authors.lastname: Byrum
authors.forename: P M
authors.initials: PM
authors.lastname: Coates
authors.forename: G N
authors.initials: GN
authors.lastname: Sando
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D005091:Exons / Q000235:genetics; D005333:Fetus / Q000002:abnormalities*; D005796:Genes / Q000235:genetics; D015894:Genome, Human; D015698:Genomic Library; D006801:Humans; D008247:Lysosomes / Q000201:enzymology*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D002787:Sterol Esterase / Q000172:deficiency / Q000235:genetics*; D014158:Transcription, Genetic; D015223:Wolman Disease / Q000201:enzymology / Q000235:genetics*
chemical_list: D002787:Sterol Esterase