TY - JOUR
T1 - Glycogen storage disease type II
T2 - Identification of four novel missense mutations (D645N, G648S, R672W, R672Q) and two insertions/deletions in the acid α-glucosidase locus of patients of differing phenotype
AU - Huie, M. L.
AU - Tsujino, S.
AU - Brooks, S. Sklower
AU - Engel, A.
AU - Elias, E.
AU - Bonthron, D. T.
AU - Bessley, C.
AU - Shanske, S.
AU - Dimauro, S.
AU - Goto, Y. I.
AU - Hirschhorn, R.
N1 - Funding Information:
This work was supported by a grant from the National Foundation, March of Dimes, and the Muscular Dystrophy Association. The authors are grateful to Dr. Harumi Goto (National Sanatorium Nishi-beppu Hospital), Dr. Toyojiro Matsuishi (Kurume University), Dr. Ikuya Nonaka (Musashi Hospital), and Dr. Yoshihiro Origuchi (National Sanatorium Nishibeppu Hospital) for clinical samples and information regarding the juvenile GSDII patient and sibling of Japanese descent (proband V) and to Dr. Kurt Hirschhorn for critical reading of the manuscript.
PY - 1998/3/27
Y1 - 1998/3/27
N2 - Glycogen storage disease type II (GSDII), an autosomal recessive myopathic disorder, results from deficiency of lysosomal acid α-glucosidase. We searched for mutations in an evolutionarily conserved region in 54 patients of differing phenotype. Four novel mutations (D645N, G448S, R672W, and R672Q) and a previously described mutation (C647W) were identified in five patients and their deleterious effect on enzyme expression demonstrated in vitro. Two novel frame-shifting insertions/deletions (Δnt766-785/insC and +insG@@@nt2243) were identified in two patients with exon 14 mutations. The remaining three patients were either homozygous for their mutations (D645N/D645 and C647W/C647W) or carried a previously described leaky splice site mutation (IVS1 -13T→G). For all patients 'in vivo' enzyme activity was consistent with clinical phenotype. Agreement of genotype with phenotype and in vitro versus in vivo enzyme was seen in three patients (two infantile patients carrying C647W/C647W and D645N/+insG@@@nt2243 and an adult patient heteroallelic for G648S/IVS1 -13T→G). Relative discordance was found in a juvenile patient homozygous for the non-expressing R672Q and an adult patient heterozygous for the minimally expressing R672W and Δnt766-785/+insC. Possible explanations include differences in in vitro assays vs in vivo enzyme activity, tissue specific expression with diminished enzyme expression/stability in fibroblasts vs muscle, somatic mosaicism, and modifying genes.
AB - Glycogen storage disease type II (GSDII), an autosomal recessive myopathic disorder, results from deficiency of lysosomal acid α-glucosidase. We searched for mutations in an evolutionarily conserved region in 54 patients of differing phenotype. Four novel mutations (D645N, G448S, R672W, and R672Q) and a previously described mutation (C647W) were identified in five patients and their deleterious effect on enzyme expression demonstrated in vitro. Two novel frame-shifting insertions/deletions (Δnt766-785/insC and +insG@@@nt2243) were identified in two patients with exon 14 mutations. The remaining three patients were either homozygous for their mutations (D645N/D645 and C647W/C647W) or carried a previously described leaky splice site mutation (IVS1 -13T→G). For all patients 'in vivo' enzyme activity was consistent with clinical phenotype. Agreement of genotype with phenotype and in vitro versus in vivo enzyme was seen in three patients (two infantile patients carrying C647W/C647W and D645N/+insG@@@nt2243 and an adult patient heteroallelic for G648S/IVS1 -13T→G). Relative discordance was found in a juvenile patient homozygous for the non-expressing R672Q and an adult patient heterozygous for the minimally expressing R672W and Δnt766-785/+insC. Possible explanations include differences in in vitro assays vs in vivo enzyme activity, tissue specific expression with diminished enzyme expression/stability in fibroblasts vs muscle, somatic mosaicism, and modifying genes.
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U2 - 10.1006/bbrc.1998.8255
DO - 10.1006/bbrc.1998.8255
M3 - Article
C2 - 9535769
AN - SCOPUS:0032571087
SN - 0006-291X
VL - 244
SP - 921
EP - 927
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -