Identification of genotype–biochemical phenotype correlations associated with fructose 1,6-bisphosphatase deficiency

Author:

Sakuma Ikki,Nagano Hidekazu,Hashimoto Naoko,Fujimoto Masanori,Nakayama Akitoshi,Fuchigami Takahiro,Taki Yuki,Matsuda Tatsuma,Akamine Hiroyuki,Kono Satomi,Kono Takashi,Yokoyama Masataka,Nishimura Motoi,Yokote Koutaro,Ogasawara Tatsuki,Fujii Yoichi,Ogawa Seishi,Lee Eunyoung,Miki Takashi,Tanaka TomoakiORCID

Abstract

AbstractFructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessive disorder characterized by hypoglycemic lactic acidosis. Due to the rarity of FBPase deficiency, the mechanism by which the mutations cause enzyme activity loss still remains unclear. Here we identify compound heterozygous missense mutations of FBP1, c.491G>A (p.G164D) and c.581T>C (p.F194S), in an adult patient with hypoglycemic lactic acidosis. The G164D and F194S FBP1 mutants exhibit decreased FBP1 protein expression and a loss of FBPase enzyme activity. The biochemical phenotypes of all previously reported FBP1 missense mutations in addition to G164D and F194S are classified into three functional categories. Type 1 mutations are located at pivotal residues in enzyme activity motifs and have no effects on protein expression. Type 2 mutations structurally cluster around the substrate binding pocket and are associated with decreased protein expression due to protein misfolding. Type 3 mutations are likely nonpathogenic. These findings demonstrate a key role of protein misfolding in mediating the pathogenesis of FBPase deficiency, particularly for Type 2 mutations. This study provides important insights that certain patients with Type 2 mutations may respond to chaperone molecules.

Funder

Grants-in-Aid for Scientific Research

Publisher

Springer Science and Business Media LLC

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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