Disease relevance of Gulo

• To identify the genetic basis for osteoporotic fractures, we used a mouse model that develops spontaneous fractures (sfx) at a very early age [1].
• The sfx/sfx mouse is characterized by a spontaneous femoral fracture seen around 6 weeks of age, which represents a new mouse model for bone fragility [2].
• This study was designed to determine the effects of vitamin C deficiency on the immune response to infection with influenza virus. l-Gulono-gamma-lactone oxidase gene-inactivated mice (gulo-/- mice) require vitamin C supplementation for survival [3].

High impact information on Gulo

• It was shown that nitrophenyl acetyl-poly-(L-glu56-L-lys35-L-phe9) (NP-GLO) could prime for NP responses only in strains of mice which are Ir gene responders to GLO [4].
• Hepatic URO accumulation was produced in AA-requiring Gulo(-/-) mice by treatment with 3,3',4,4',5-pentachlorbiphenyl, an inducer of CYP1A2, and 5-aminolevulinic acid [5].
• Fowl gamma-globulin, when chemically conjugated to GLO or GL, functions as a T-dependent immunogenic carrier and stimulates anti-GLO and anti-GL antibody production in nonresponder mice [6].
• CONCLUSION: The sfx is a mutation of the GULO gene, which leads to ascorbic acid deficiency, impaired osteoblast cell function, and fractures in affected mice [1].
• Spontaneous fractures in the mouse mutant sfx are caused by deletion of the gulonolactone oxidase gene, causing vitamin C deficiency [1].

Biological context of Gulo

• The Gulo gene is 22 kb long and contains 12 exons [7].
• Low rescue efficiency of Gulo-expressing adenoviral constructs and reduced viral growth in HEK293 cells were observed, suggesting that overexpression of Gulo may be inhibitory to cell growth [7].
• In the present study, we used Gulo-/- mutant mice, which are unable to synthesize ascorbic acid, to study the importance of dietary vitamin C (VC) on spermatogenesis [8].
• The sfx gene was fine mapped to a 2 MB region containing approximately 30 genes in chromosome 14 [1].
• Histomorphometric analyses of bones from sfx mice revealed that bone formation rate is reduced by >90% and is caused by impairment of differentiated functions of osteoblasts [1].

Anatomical context of Gulo

• Sarcocystis spp sporocysts were found in feces of 10.1% of 198 red foxes (Vulpes vulpes), in 3.2% of 61 bobcats (Lynx rufus), in 16.6% of 12 mountain lions (Felis concolor), in 16.6% of 6 fisher (Martes pennanti), and in none of 20 wolverines (Gulo gulo), 4 mink (Mustela vison), or 10 raccoons (Procyon lotor) [9].
• The last step in the pathway of vitamin C synthesis is the oxidation of l-gulonolactone to l-ascorbic acid by l-gulonolactone oxidase, an enzyme associated with the endoplasmic reticulum membrane and deficient in man, guinea pig and other species due to mutations in its gene [10].
• The present study utilized the glyoxalase I (GLO I) system as a new approach to lower in vitro the peritoneal fluid content of RCOs such as methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG) [11].
• The fact that genetically manipulated cells overexpressing GLO I activity have a similar effect suggests that maneuvers raising GLO I activity in peritoneal cells or in the peritoneal cavity might help prevent the deleterious effects of the peritoneal carbonyl stress in PD patients [11].
• The Chinese hamster genes ADK, NP, ESD, PGM2, PEPS, PEPB, GLO, and GSR, all of which are on Chinese hamster chromosome 1, were assigned to CHO-LA chromosomes by analysis of the segregation of CHO isozymes and chromosomes from interspecific somatic cell hybrids made with CHO cells and mouse C11D cells [12].

Associations of Gulo with chemical compounds

• Primates are absolutely dependent on exogenously supplied dietary vitamin C due to inactivation of the Gulo gene by mutation over 40 million years ago [7].
• Cells infected with Gulo-expressing vectors overexpressed an FAD-containing protein that corresponded in size to that predicted for recombinant GULO protein and expressed a functional enzyme as measured by the conversion of l-gulono-gamma-lactone to ascorbic acid in cell-free extracts [7].
• In the mouse, similar to most mammals but unlike humans who carry a mutant copy of this gene, Gulo produces ascorbic acid from glucose [13].
• By using various molecular genetic approaches, we identified that deletion of the gulonolactone oxidase (GULO) gene, which is involved in the synthesis of ascorbic acid, is responsible for the sfx phenotype [1].
• The tested compounds included aminoguanidine and glutathione (GSH), alone or together with GLO I [11].

Other interactions of Gulo

• MATERIALS AND METHODS: Skeletal phenotype of the sfx phenotype was evaluated by DXA using PIXImus instrumentation and by dynamic histomorphometry [1].

Analytical, diagnostic and therapeutic context of Gulo

• Northern blot analysis revealed high expression of Gulo transcript in the liver [7].
• The sfx gene was identified using various molecular genetic approaches, including fine mapping and sequencing of candidate genes, whole genome microarray, and PCR amplification of candidate genes using cDNA and genomic DNA as templates [1].
• With the hemolytic plaque assay, we have verified that GLO responder animals make both IgM and IgG responses, whereas nonresponder mice fail to make either IgM or IgG plaque-forming cells [6].

References