title: Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan.
abstract: Muscular dystrophies with reduced glycosylation of alpha-dystroglycan (alpha-DG), commonly referred to as dystroglycanopathies, are a heterogeneous group of autosomal recessive conditions which include a wide spectrum of clinical severity. Reported phenotypes range from severe congenital onset Walker-Warburg syndrome (WWS) with severe structural brain and eye involvement, to relatively mild adult onset limb girdle muscular dystrophy (LGMD). Specific clinical syndromes were originally described in association with mutations in any one of six demonstrated or putative glycosyltransferases. Work performed on patients with mutations in the FKRP gene has identified that the spectrum of phenotypes due to mutations in this gene is much wider than originally assumed. To further define the mutation frequency and phenotypes associated with mutations in the other five genes, we studied a large cohort of patients with evidence of a dystroglycanopathy. Exclusion of mutations in FKRP was a prerequisite for participation in this study. Ninety-two probands were screened for mutations in POMT1, POMT2, POMGnT1, fukutin and LARGE. Homozygous and compound heterozygous mutations were detected in a total of 31 probands (34 individuals from 31 families); 37 different mutations were identified, of which 32 were novel. Mutations in POMT2 were the most prevalent in our cohort with nine cases, followed by POMT1 with eight cases, POMGnT1 with seven cases, fukutin with six cases and LARGE with only a single case. All patients with POMT1 and POMT2 mutations had evidence of either structural or functional central nervous system involvement including four patients with mental retardation and a LGMD phenotype. In contrast mutations in fukutin and POMGnT1 were detected in four patients with LGMD and no evidence of brain involvement. The majority of patients (six out of nine) with mutations in POMT2 had a Muscle-Eye-Brain (MEB)-like condition. In addition we identified a mutation in the gene LARGE in a patient with WWS. Our data expands the clinical phenotypes associated with POMT1, POMT2, POMGnT1, fukutin and LARGE mutations. Mutations in these five glycosyltransferase genes were detected in 34% of patients indicating that, after the exclusion of FKRP, the majority of patients with a dystroglycanopathy harbour mutations in novel genes.
authors: Dubowitz Neuromuscular Unit, Hammersmith Hospital, Imperial College, London, UK.
authors: Caroline
authors: C
authors: Godfrey
authors: Emma
authors: E
authors: Clement
authors: Rachael
authors: R
authors: Mein
authors: Martin
authors: M
authors: Brockington
authors: Janine
authors: J
authors: Smith
authors: Beril
authors: B
authors: Talim
authors: Volker
authors: V
authors: Straub
authors: Stephanie
authors: S
authors: Robb
authors: Ros
authors: R
authors: Quinlivan
authors: Lucy
authors: L
authors: Feng
authors: Cecilia
authors: C
authors: Jimenez-Mallebrera
authors: Eugenio
authors: E
authors: Mercuri
authors: Adnan Y
authors: AY
authors: Manzur
authors: Maria
authors: M
authors: Kinali
authors: Silvia
authors: S
authors: Torelli
authors: Susan C
authors: SC
authors: Brown
authors: Caroline A
authors: CA
authors: Sewry
authors: Kate
authors: K
authors: Bushby
authors: Haluk
authors: H
authors: Topaloglu
authors: Kathryn
authors: K
authors: North
authors: Stephen
authors: S
authors: Abbs
authors: Francesco
authors: F
authors: Muntoni
mesh_terms: D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D049030:Dystroglycans / Q000235:genetics* / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007223:Infant; D008297:Male; D008364:Mannosyltransferases / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D010641:Phenotype
chemical_list: C483081:DAG1 protein, human; C113587:FKTN protein, human; D008565:Membrane Proteins; D049030:Dystroglycans; C117674:LARGE1 protein, human; D008364:Mannosyltransferases; D017351:N-Acetylglucosaminyltransferases; C082696:protein O-mannosyltransferase