Mutation analysis in myophosphorylase deficiency (McArdle's disease)

Abstract

Inherited deficiency of myophosphorylase leads to glycogen storage disease type V (McArdle's disease). We performed mutation analysis in 9 patients of eight unrelated families from Germany with typical clinical presentation of myophosphorylase deficiency. Beside previously described mutations we identified four novel mutations in the myophosphorylase gene. Four patients were homozygous for a nonsense mutation Arg49Stop that has been reported to be the most common mutation in white patients. Two affected siblings were compound heterozygotes for a novel missense mutation Gly685Arg and the nonsense mutation Arg49Stop. One patient carried a novel nonsense mutation Arg575Stop and a previously identified missense mutation Gly204Ser. In another patient, we identified a novel missense mutation Gln665Glu and a single-base deletion delA in Lys753. One patient of Turkish ancestry carried a newly identified homozygous A-to-G transition (ATG to GTG) abolishing the translation initiation codon of the myophosphorylase gene. These results suggest that Arg49Stop also is the most common genetic error associated with myophosphorylase deficiency in the German population. Our findings further demonstrate molecular heterogeneity of myophosphorylase deficiency among the clinically homogeneous patients we studied.

A proposed molecular diagnostic flowchart for myophosphorylase deficiency (McArdle disease) in blood samples from Spanish patients

“…The mutation c.1768 +1G>A has been reported in patients from different ethnic background (Martin et al 2001b, Tsujino et al 1994b. In this regard, the mutations p.R94W and p.R576X identified in two patients, were previously described in McArdle disease patients of German origin (Deschauer et al 2003, Vorgerd et al 1998 suggesting that these mutations are not private, and might be found in individuals from other ethnic backgrounds. The p.K754NfsX49, p.A660D, p.R602W, p.A704V, c.1827G>A and p.L5VfsX22 mutations have already been reported in Spanish patients with McArdle disease (Fernandez-Cadenas et al 2003, Martin et al 2001a, Martin et al 2001b, Rubio et al 2006.…”

“…Eighteen additional mutations were identified. Of them, nine were reported elsewhere: c.13_14del, p.L5VfsX22; (Rubio et al 2006, in press); c.280C>T, p.R94W (Deschauer et al 2001); c.1726C>T, p.R576X (Vorgerd et al 1998); c.1768 +1G>A (Tsujino et al 1994b); c.1804C>T, p.R602W (Martin et al 2001a); c.1827G>A (Fernandez-Cadenas et al 2003); c.1979C>A, p.A660D ); c.2111C>T, p.A704V (Martin et al 2001a); and c.2262del, p.K754NfsX49 , Martin et al 2001b.…”

“…Aerobic and anaerobic exercise forearm tests display no increase in lactate values (lactate flat response) (Kazemi-Stephani et al 2002). Molecular heterogeneity has been demonstrated by the identification of various different mutations in the coding regions or splice sites of the gene , Bartram et al 1993, Bruno et al 1999a, Bruno et al 1999b, Bruno et al 2006, Deschauer et al 2003, Fernandez-Cadenas et al 2003, Martin et al 2001a, Martin et al 2001b, Quintans et al 2004, Tsujino et al 1994a, Tsujino et al 1993, Tsujino et al 1994b, Vorgerd et al 1998. The most common among European and American patients is a nonsense mutation at codon 50 in exon 1 (p.R50X) (Andreu et al 1998, Bartram et al 1993, Bruno et al 2006, el-Schahawi et al 1996, Martin et al 2001a, Martinuzzi et al 1996, Tsujino et al 1993, Tsujino et al 1995, Vorgerd et al 1998.…”

GTG Mutation in the Start Codon of the Androgen Receptor Gene in a Family of Horses with 64,XY Disorder of Sex Development

“…A GUG start codon identified in the CYP2C19 gene in a poor metabolizer patient was not translated in an in vitro mutagenesis test [Ferguson et al, 1998]. Similarly, in a clinical case of McArdle's disease with a GTG start codon in the myophosphorilase gene, the enzyme could not be detected by muscular staining, suggesting a loss of expression [Vorgerd et al, 1998]. These examples are congruent with the most accepted model of eukaryotic translation initiation where the canonical start site is only the first AUG [Kozak, 2002].…”

Muscle glycogenosis with low phosphorylase kinase activity: mutations in PHKA1, PHKG1 or six other candidate genes explain only a minority of cases

“…The PYGM gene (20 exons) was amplified from genomic DNA (patients 2 -4) in 14 segments with intronic primers, and sequences of exons and flanking intron regions were compared with the revised genomic sequence of PYGM. 34,35 The 13 exons and their flanking intron sequences of the PRKAG3 gene (NT_005289) were amplified in eight intervals from genomic DNA of patients 2 -6.…”