title: Correlation of enzyme activity and clinical phenotype in POMT1-associated dystroglycanopathies.
abstract: BACKGROUND
  Mutations in protein O-mannosyltransferases (POMTs) cause a heterogeneous group of muscular dystrophies with abnormal glycosylation of alpha-dystroglycan (dystroglycanopathies). The wide spectrum of clinical severities ranges from Walker-Warburg syndrome (WWS), associated with brain and eye abnormalities, to mild forms of limb girdle muscular dystrophy (LGMD).
  
  
  OBJECTIVE
  The aim of this study was to elucidate the impact of mutations in POMT1 on the clinical phenotype.
  
  
  METHODS
  We examined 2 patients with POMT1-associated alpha-dystroglycanopathy, 1 displaying a LGMD2K and 1 with a WWS phenotype. Using dermal fibroblasts, we analyzed the influence of the POMT1 mutations on the glycosylation status of alpha-dystroglycan, protein O-mannosyltransferase activity, and the stability of the mutant POMT1 protein.
  
  
  RESULTS
  We report on novel compound heterozygous mutations in POMT1 (p.L171A and p.A589VfsX38) that result in LGMD2K. We further demonstrate that a homozygous splice site mutation of a recently identified WWS patient results in POMT1 p.del77-93. Using dermal fibroblasts, we show that mannosyltransferase activity is reduced in the patients and that stability of POMT1 mutant proteins p.A589VfsX38 and p.del77-93 is significantly decreased.
  
  
  CONCLUSIONS
  Our results suggest that dermal fibroblasts can be applied to facilitate the diagnostic analysis of dystroglycanopathy patients as well as to study the pathogenic mechanism of POMT mutations. Characterization of the POMT1 substrate protein alpha-dystroglycan and POMT in vitro mannosyltransferase activity shows that the severity of the clinical phenotype of the patients analyzed is inversely correlated with POMT activity.
authors.affiliation: Heidelberg Institute for Plant Sciences, Dept. V Cell Chemistry, University of Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Lommel
authors.forename: S
authors.initials: S
authors.lastname: Cirak
authors.forename: T
authors.initials: T
authors.lastname: Willer
authors.forename: R
authors.initials: R
authors.lastname: Hermann
authors.forename: G
authors.initials: G
authors.lastname: Uyanik
authors.forename: H
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: C
authors.initials: C
authors.lastname: Körner
authors.forename: T
authors.initials: T
authors.lastname: Voit
authors.forename: I
authors.initials: I
authors.lastname: Barić
authors.forename: U
authors.initials: U
authors.lastname: Hehr
authors.forename: S
authors.initials: S
authors.lastname: Strahl
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002648:Child; D004252:DNA Mutational Analysis; D015536:Down-Regulation / Q000235:genetics; D049030:Dystroglycans / Q000378:metabolism; D005347:Fibroblasts; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D008364:Mannosyltransferases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D049288:Muscular Dystrophies, Limb-Girdle / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics; D011817:Rabbits
chemical_list: C483081:DAG1 protein, human; D005819:Genetic Markers; D022821:RNA Splice Sites; D049030:Dystroglycans; D008364:Mannosyltransferases; C082696:protein O-mannosyltransferase