title: Clinical and molecular characterization of patients with limb-girdle muscular dystrophy type 2I.
abstract: BACKGROUND
  Limb-girdle muscular dystrophy type 2I is caused by mutations in the fukutin-related protein gene (FKRP). FKRP encodes a putative glycosyltransferase protein that is involved in alpha-dystroglycan glycosylation.
  
  
  OBJECTIVE
  To identify patients with limb-girdle muscular dystrophy type 2I and to derive genotype-phenotype correlations.
  
  
  METHODS
  Two hundred fourteen patients who showed muscle histopathologic features consistent with muscular dystrophy or myopathy of unknown etiology were studied. The entire 1.5-kilobase FKRP coding sequence from patient DNA was analyzed using denaturing high-performance liquid chromatography of overlapping polymerase chain reaction products, followed by direct sequencing of heteroduplexes.
  
  
  RESULTS
  Thirteen patients with limb-girdle muscular dystrophy type 2I (6% of all patients tested) were identified by FKRP mutation analysis, and 7 additional patients were identified by family screening. Six missense mutations (1 novel) were identified. The 826C>A nucleotide change was a common mutation, present in 35% of the mutated chromosomes. Clinical presentations included asymptomatic hyperCKemia, severe early-onset muscular dystrophy, and mild late-onset muscular dystrophy. Dilated cardiomyopathy and ventilatory impairment were frequent features. Significant intrafamilial and interfamilial clinical variability was observed.
  
  
  CONCLUSIONS
  FKRP mutations are a frequent cause of limb-girdle muscular dystrophies. The degree of respiratory and cardiac insufficiency in patients did not correlate with the severity of muscle involvement. The finding of 2 asymptomatic patients with FKRP mutations suggests that modulating factors may ameliorate the clinical phenotype.
authors.affiliation: Department of Neurosciences, University of Padova, Italy.
authors.forename: Chiara A
authors.initials: CA
authors.lastname: Boito
authors.forename: Paola
authors.initials: P
authors.lastname: Melacini
authors.forename: Andrea
authors.initials: A
authors.lastname: Vianello
authors.forename: Paola
authors.initials: P
authors.lastname: Prandini
authors.forename: Bruno F
authors.initials: BF
authors.lastname: Gavassini
authors.forename: Alessia
authors.initials: A
authors.lastname: Bagattin
authors.forename: Gabriele
authors.initials: G
authors.lastname: Siciliano
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.forename: Elena
authors.initials: E
authors.lastname: Pegoraro
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000032:analysis / Q000235:genetics; D004252:DNA Mutational Analysis; D049030:Dystroglycans / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D049288:Muscular Dystrophies, Limb-Girdle / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense; D010430:Pentosyltransferases; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D012131:Respiratory Insufficiency / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
chemical_list: D011506:Proteins; D049030:Dystroglycans; D004247:DNA; C443107:FKRP protein, human; D010430:Pentosyltransferases