alr-2

Alterations in GFER gene have been associated with progressive mitochondrial myopathy, congenital cataracts, hearing loss, developmental delay, lactic acidosis and respiratory chain deficiency in 3 siblings born to consanguineous Moroccan parents by homozygosity mapping and candidate gene approach. Using homozygosity mapping, we discovered that a mutation in the GFER gene causes an infantile mitochondrial disorder.

GFER is a hepatotrophic growth factor and flavin-linked sulfhydryl oxidase which belongs to the Erv1 ALR family of proteins. GFER is widely expressed in various human tissues. They are two isoforms of this protein. Isoform 1 could regenerate the redox-active disulfide bonds in CHCHD4 MIA40, a chaperone essential for disulfide bond formation and protein folding in the mitochondrial intermembrane space. The reduced form of CHCHD4 MIA40 forms a transient intermolecular disulfide bridge with GFER ERV1, resulting in regeneration of the essential disulfide bonds in CHCHD4 MIA40, while GFER ERV1 becomes re-oxidized by donating electrons to cytochrome c or molecular oxygen. Isoform 2 may act as an autocrine hepatotrophic growth factor promoting liver regeneration. GFER could also induce the expression of S-adenosylmethionine decarboxyl-ase and ornithine decarboxylases (ODC). S-adenosylmethionine decarboxyl-ase and ornithine decarboxylases play an important role in the synthesis of polyamines.

Aldose reductase (AKR1B1) belongs to the aldo keto reductase superfamily. AKR1B1 is a NADPH-dependent aldo-keto reductase best known as the rate-limiting enzyme of the polyol pathway. Expression of AKR1B1 was the highest in lens and retina. It is the first enzyme in the polyol pathway through which glucose is converted to sorbitol which is important for the function of various organs in the body, and has been implicated in the etiology of diabetic complications. AKR1B1 is quite abundant in the collecting tubule cells and thought to provide protection against hypertonic environment. Some human tissues contain AKR1B1 as well as AKR1B10, a closely related member of the aldo-keto reductase superfamily.