McArdle disease: the mutation spectrum of PYGM in a large Italian cohort.
Deficiency of the muscle isozyme of glycogen phosphorylase is causative of McArdle disease or Glycogen storage disease type V (GSD-V), the most common autosomal recessive disorder of glycogen metabolism. The typical clinical presentation is characterized by exercise intolerance with cramps, and recurrent myoglobinuria. To date, 46 mutations in the PYGM gene have been detected in GSD-V patients. We report the mutational spectrum in 68 Italian patients. We identified 30 different mutations in the PYGM gene, including 19 mutations that have not been reported previously. The novel mutations include: eight missense mutations (c.475G>A, p.G159R; c.689C>G, p.P230R; c.1094C>T, p.A365E; c.1151C>A, p.A384D; c.1182C>T, p.R428C; c.1471C>T, p.R491C; c.2444A>C, p.D815A; c.2477G>C, p.W826S), two nonsense mutations (c.1475G>A, p.W492X; c.1627A>T, p.K543X), five splice site mutations (c.855 +1G>C; c.1092 +1G>A; c. 1093-1G>T; c.1239 +1G>A; c.2380 +1G>A), and four deletions (c.715_717delGTC, p.V239del; c.304delA, p.N102DfsX4; c.1970_2177del, p.V657_G726; c.2113_2114delGG, p.G705RfsX16). Whereas we confirmed lack of direct correlation between the clinical phenotype and the genotype, we also found that the so-called 'common mutation' (p.R50X) accounted for about 43% of alleles in our cohort and that no population-related mutations are clearly identified in Italian patients.
Bruno
Claudio
C
Neuromuscular Disease Unit, Department of Pediatrics, University of Genova, Giannina Gaslini Institute, Genova, Italy. claudiobruno@ospedale-gaslini.ge.it
Cassandrini
Denise
D
Martinuzzi
Andrea
A
Toscano
Antonio
A
Moggio
Maurizio
M
Morandi
Lucia
L
Servidei
Serena
S
Mongini
Tiziana
T
Angelini
Corrado
C
Musumeci
Olimpia
O
Comi
Giacomo P
GP
Lamperti
Costanza
C
Filosto
Massimiliano
M
Zara
Federico
F
Minetti
Carlo
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D024982:Glycogen Phosphorylase, Muscle Form / Q000235:genetics*; D006012:Glycogen Storage Disease Type V / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein
D024982:Glycogen Phosphorylase, Muscle Form