Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene

Yong Bao, Priya Kishnani, Jer Yuarn Wu, Yuan Tsong Chen

Research output: Contribution to journalArticle

124 Citations (Scopus)

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 languageEnglish
Pages (from-to)941-948
Number of pages8
JournalJournal of Clinical Investigation
Volume97
Issue number4
StatePublished - Feb 15 1996
Externally publishedYes

Fingerprint

Glycogen Storage Disease Type IV
1,4-alpha-Glucan Branching Enzyme
Mutation
Liver
Genes
Alleles
Point Mutation
Neuromuscular Diseases
Liver Failure
Genetic Association Studies
Liver Cirrhosis
Liver Transplantation
Liver Diseases

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 journalArticle

@article{15b051b845634964b86142f863716dd1,
title = "Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene",
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.",
keywords = "human glycogen-branching enzyme, inborn error of metabolism, mutation analysis, type IV glycogen storage disease",
author = "Yong Bao and Priya Kishnani and Wu, {Jer Yuarn} and Chen, {Yuan Tsong}",
year = "1996",
month = "2",
day = "15",
language = "English",
volume = "97",
pages = "941--948",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "4",

}

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

C2 - 8613547

AN - SCOPUS:0030032758

VL - 97

SP - 941

EP - 948

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 4

ER -