Abstract
Glycogen storage disease type IV (GSD-IV) is an autosomal recessive disease resulting from deficient glycogen-branching enzyme (GBE) activity. The classic and most common form is progressive liver cirrhosis and failure leading to either liver transplantation or death by 5 yr of age. However, the liver disease is not always progressive. In addition, a neuromuscular type of the disease has been reported. The molecular basis of GSD-IV is not known, nor is there a known reason for the clinical variability. We studied the GBE gene in patients with various presentations of GSD-IV. Three point mutations in the GBE gene were found in two patients with the classical presentation: R515C, F257L, and R524X. Transient expression experiments showed that these mutations inactivated GBE activity. Two point mutations, L224P and Y329S, were detected in two separate alleles of a patient with the nonprogressive hepatic form. The L224P resulted in complete loss of GBE activity, whereas the Y329S resulted in loss of ~ 50% of GBE activity. The Y329S allele was also detected in another patient with the nonprogressive form of GSD-IV but not in 35 unrelated controls or in patients with the more severe forms of GSD-IV. A 210-bp deletion from nucleotide 873 to 1082 of the GBE cDNA was detected in a patient with the fatal neonatal neuromuscular presentation. This deletion, representing the loss of one full exon, was caused by a 3' acceptor splicing site mutation (ag to aa). The deletion abolished GBE activity. Our studies indicate that the three different forms of GSD-IV were caused by mutations in the same GBE gene. The data also suggest that the significant retention of GBE activity in the Y329S allele may be a reason for the mild disease. Further study of genotype/phenotype correlations may yield useful information in predicting the clinical outcomes.
| Original language | English |
|---|---|
| Pages (from-to) | 941-948 |
| Number of pages | 8 |
| Journal | Journal of Clinical Investigation |
| Volume | 97 |
| Issue number | 4 |
| State | Published - Feb 15 1996 |
| Externally published | Yes |
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Keywords
- human glycogen-branching enzyme
- inborn error of metabolism
- mutation analysis
- type IV glycogen storage disease
ASJC Scopus subject areas
- Medicine(all)
Cite this
Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene. / Bao, Yong; Kishnani, Priya; Wu, Jer Yuarn; Chen, Yuan Tsong.
In: Journal of Clinical Investigation, Vol. 97, No. 4, 15.02.1996, p. 941-948.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene
AU - Bao, Yong
AU - Kishnani, Priya
AU - Wu, Jer Yuarn
AU - Chen, Yuan Tsong
PY - 1996/2/15
Y1 - 1996/2/15
N2 - Glycogen storage disease type IV (GSD-IV) is an autosomal recessive disease resulting from deficient glycogen-branching enzyme (GBE) activity. The classic and most common form is progressive liver cirrhosis and failure leading to either liver transplantation or death by 5 yr of age. However, the liver disease is not always progressive. In addition, a neuromuscular type of the disease has been reported. The molecular basis of GSD-IV is not known, nor is there a known reason for the clinical variability. We studied the GBE gene in patients with various presentations of GSD-IV. Three point mutations in the GBE gene were found in two patients with the classical presentation: R515C, F257L, and R524X. Transient expression experiments showed that these mutations inactivated GBE activity. Two point mutations, L224P and Y329S, were detected in two separate alleles of a patient with the nonprogressive hepatic form. The L224P resulted in complete loss of GBE activity, whereas the Y329S resulted in loss of ~ 50% of GBE activity. The Y329S allele was also detected in another patient with the nonprogressive form of GSD-IV but not in 35 unrelated controls or in patients with the more severe forms of GSD-IV. A 210-bp deletion from nucleotide 873 to 1082 of the GBE cDNA was detected in a patient with the fatal neonatal neuromuscular presentation. This deletion, representing the loss of one full exon, was caused by a 3' acceptor splicing site mutation (ag to aa). The deletion abolished GBE activity. Our studies indicate that the three different forms of GSD-IV were caused by mutations in the same GBE gene. The data also suggest that the significant retention of GBE activity in the Y329S allele may be a reason for the mild disease. Further study of genotype/phenotype correlations may yield useful information in predicting the clinical outcomes.
AB - Glycogen storage disease type IV (GSD-IV) is an autosomal recessive disease resulting from deficient glycogen-branching enzyme (GBE) activity. The classic and most common form is progressive liver cirrhosis and failure leading to either liver transplantation or death by 5 yr of age. However, the liver disease is not always progressive. In addition, a neuromuscular type of the disease has been reported. The molecular basis of GSD-IV is not known, nor is there a known reason for the clinical variability. We studied the GBE gene in patients with various presentations of GSD-IV. Three point mutations in the GBE gene were found in two patients with the classical presentation: R515C, F257L, and R524X. Transient expression experiments showed that these mutations inactivated GBE activity. Two point mutations, L224P and Y329S, were detected in two separate alleles of a patient with the nonprogressive hepatic form. The L224P resulted in complete loss of GBE activity, whereas the Y329S resulted in loss of ~ 50% of GBE activity. The Y329S allele was also detected in another patient with the nonprogressive form of GSD-IV but not in 35 unrelated controls or in patients with the more severe forms of GSD-IV. A 210-bp deletion from nucleotide 873 to 1082 of the GBE cDNA was detected in a patient with the fatal neonatal neuromuscular presentation. This deletion, representing the loss of one full exon, was caused by a 3' acceptor splicing site mutation (ag to aa). The deletion abolished GBE activity. Our studies indicate that the three different forms of GSD-IV were caused by mutations in the same GBE gene. The data also suggest that the significant retention of GBE activity in the Y329S allele may be a reason for the mild disease. Further study of genotype/phenotype correlations may yield useful information in predicting the clinical outcomes.
KW - human glycogen-branching enzyme
KW - inborn error of metabolism
KW - mutation analysis
KW - type IV glycogen storage disease
UR - http://www.scopus.com/inward/record.url?scp=0030032758&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030032758&partnerID=8YFLogxK
M3 - Article
VL - 97
SP - 941
EP - 948
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 4
ER -