hpo 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.

N-Sulphoglucosamine Sulphohydrolase (SGSH) is an important member of the sulfatase family which is involved in the degradation of heparin sulfate. SGSH binds one calcium ion per subunit as a cofactor. SGSH catalyzes N-sulfo-D-glucosamine and H2O to D-glucosamine and sulfate. SGSH deficiency is result in mucopolysaccharidosis type 3A (MPS3A), a recessive lysosomal storage disease characterized by neurological dysfunction but relatively mild somatic manifestations.

Aldehyde reductase (AKR1A1) is a member of the aldo-keto reductase superfamily, which consists of more than 40 known enzymes and proteins that includes variety of monomeric NADPH-dependent oxidoreductases, such as aldehyde reductase. Aldehyde reductase has wide substrate specificities for carbonyl compounds. These enzymes are implicated in the development of diabetic complications by catalyzing the reduction of glucose to sorbitol. Aldehyde reductase possess a structure with a beta-alpha-beta fold which contains a novel NADP-binding motif. The binding site is located in a large, deep, elliptical pocket in the C-terminal end of the beta sheet, the substrate being bound in an extended conformation. This binding is more similar to FAD- than to NAD(P)-binding oxidoreductases. AKR1A1 is involved in the reduction of biogenic and xenobiotic aldehydes and is present in virtually every tissue.