title: Morphological and biochemical studies of human beta-mannosidosis: identification of a novel beta-mannosidase gene mutation.
abstract: BACKGROUND
  There are seven well-known lysosomal storage diseases that produce angiokeratoma corporis diffusum clinically. beta-Mannosidosis (MANB1; OMIM248510), first reported in humans in 1986, is a rare hereditary lysosomal storage disease caused by a deficiency of the enzyme beta-mannosidase. Since then, 13 cases of beta-mannosidase deficiency in ten families have been described. A human beta-mannosidase mutation has been reported only by Alkhayat et al. in 1998.
  
  
  OBJECTIVE
  To clarify its pathogenesis we did electron microscopic, biochemical and molecular biological investigations of a Japanese patient with beta-mannosidosis.
  
  
  METHODS
  Ultrastructural analyses, enzyme assays, cell culture and mRNA and genomic DNA were sequenced to find mutations in the beta-mannosidase gene.
  
  
  RESULTS
  Electron microscopy of skin biopsy specimens from the patient showed cytoplasmic vacuolation of lysosomes in blood and lymph vessels, endothelial cells, fibroblasts, secretory portions of eccrine sweat glands, neural cells and basal keratinocytes in the epidermis. This vacuolation was also observed in cultured keratinocytes and fibroblasts. Assays of seven enzyme activities in plasma and cultured skin fibroblasts showed a marked decrease of beta-mannosidase activity. Sequencing the beta-mannosidase cDNA revealed a four-base (ATAA) insertion between exons 7 and 8, resulting in a frameshift at codon 321 and termination at codon 325. Analysis of the patient's genomic DNA revealed a novel homozygous A(+1)-->G splice site mutation in intron 7.
  
  
  CONCLUSIONS
  To our knowledge, this is the first case of beta-mannosidosis reported in Japan and the second report in which a gene mutation is identified. The biological importance of beta-mannose moieties in glycoproteins in basal keratinocytes is suggested.
authors.affiliation: Department of Dermatology, Kagoshima University Faculty of Medicine, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Uchino
authors.forename: T
authors.initials: T
authors.lastname: Fukushige
authors.forename: S
authors.initials: S
authors.lastname: Yotsumoto
authors.forename: T
authors.initials: T
authors.lastname: Hashiguchi
authors.forename: H
authors.initials: H
authors.lastname: Taguchi
authors.forename: N
authors.initials: N
authors.lastname: Suzuki
authors.forename: I
authors.initials: I
authors.lastname: Konohana
authors.forename: T
authors.initials: T
authors.lastname: Kanzaki
mesh_terms: D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D006801:Humans; D007642:Keratosis / Q000235:genetics / Q000473:pathology; D008297:Male; D008361:Mannosidases / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D008854:Microscopy, Electron; D008875:Middle Aged; D017354:Point Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000648:ultrastructure; D008363:alpha-Mannosidosis / Q000235:genetics* / Q000473:pathology; D044902:beta-Mannosidase
chemical_list: D018076:DNA, Complementary; D008361:Mannosidases; D044902:beta-Mannosidase