Functional expression of human mutant phosphofructokinase in yeast: Genetic defects in French Canadian and Swiss patients with phosphofructokinase deficiency

N. Raben, R. Exelbert, R. Spiegel, J. B. Sherman, H. Nakajima, P. Plotz, J. Heinisch

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Human phosphofructokinase (PFK) is a tetrameric enzyme, encoded by muscle, liver, and platelet genes. Deficiency of muscle PFK (PFK-M), glycogenosis type VII (Tarui disease), is an autosomal recessive disorder characterized by an exertional myopathy and hemolytic syndrome. Several disease-causing mutations have been identified in the PFK-M gene in Japanese, Ashkenazi Jewish, and Italian patients. We describe the genetic defects in French Canadian and Swiss patients with the disease, and we use a genetically well- defined yeast system devoid of endogenous PFK for structure-function studies of the mutant PFKs. A G-to-A transition at codon 209-in exon 8 of the PFK-M gene, changing an encoded Gly to Asp, is responsible for the disease in a homozygous French Canadian patient. Gly-209-mutated protein is completely inactive in the yeast system. The Swiss patient is a genetic compound, carrying a G-to-A transition at codon 100 in exon 6 (Arg to Gln) and a G-to- A transition at codon 696 in exon 22 (Arg to His). The mutants expressed in yeast generate functional enzyme with modest changes in thermal stability. The advantages and limitations of the yeast system for expression of human mutant PFKs are discussed.

Original languageEnglish (US)
Pages (from-to)131-141
Number of pages11
JournalAmerican Journal of Human Genetics
Volume56
Issue number1
StatePublished - 1995
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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