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Molybdenum cofactor deficiency type B knock-in mouse models carrying patient-identical mutations and their rescue by singular AAV injections
No full textThe bicistronic MOCS1 gene has alternative start codons on two mutually exclusive exons
No full textThe bicistronic MOCS1 gene encodes two enzymatic activities that are necessary for the biosynthesis of the molybdenum cofactor (MoCo). Mutations in either of the two consecutive open reading frames are responsible for the majority of MoCo deficiency cases and result in a complementation group A phenotype. Two cDNA sequences have been described, which differ in the 5' sequence and encode for two forms of the protein MOCS1A with variable N-terminal sequences. We have reinvestigated the corresponding region by means of cDNA analysis and databank searches. This revealed three different splice variants, including two mutually exclusive first exons and a facultative intron. All three forms can be found in eight different human tissues in a constant ratio, which excludes tissue specificity of the different isoforms. (C) 2002 Elsevier Science (USA). All rights reserved
Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH
No full textMolybdenum cofactor deficiency in humans results in the loss of the activity of molybdoenzymes sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. The resultant severe phenotype, which includes progressive neurological damage leading in most cases to early childhood death, results primarily from the deficiency of sulfite oxidase. All forms of molybdenum cofactor deficiency are inherited as autosomal recessive traits. The cofactor is an unstable reduced pterin with a unique four-carbon side chain, synthesized by a complex pathway that requires the products of at least four different genes (MOCS1, MOCS2, MOCS3, and GEPH). Disease causing mutations have been identified in three of these genes: MOCS1, MOCS2, and GEPH. MOCS1 and MOCS2 have a bicistronic architecture; i.e., each gene encodes two proteins in different open reading frames. The protein products, MOCS1A and B and MOCS2A and B, are expressed either from different mRNAs generated by alternative splicing or by independent translation of a bicistronic mRNA. The gephyrin protein, encoded by a third locus, is required during cofactor assembly for insertion of molybdenum. A total of 32 different disease-causing mutations, including several common to more than one family, have been identified in molybdenum cofactor-deficient patients and their relatives. (C) 2003 Wiley-Liss, Inc.NIGMS NIH HHS [GM 44283
AAV-mediated gene therapy for metabolic diseases: dosage and reapplication studies in the molybdenum cofactor deficiency model.
No full textIn a mouse model for molybdenum cofactor deficiency as an example for an inherited metabolic disease we have determined the dosage of recombinant AAV necessary to rescue the lethal deficiency phenotype. We demonstrated long-term expression of different expression cassettes delivered in a chimeric AAV capsid of serotype 1/2 and compared different routes of application. We then studied the effect of double and triple injections at different time points after birth and found a short neonatal window for non-response of the immune system. Exposition with rAAV capsids within this window allows transgene expression after a second rAAV transduction later. However, exposition within this window does not trigger immunotolerance to the viral capsid, which limits rAAV-mediated refurbishment of the transgene to only one more application outside this permissive window
Long-Term Rescue of a Lethal Inherited Disease by Adeno-Associated Virus–Mediated Gene Transfer in a Mouse Model of Molybdenum-Cofactor Deficiency
No full textMolybdenum cofactor (MoCo) deficiency is a progressive neurological disorder that inevitably leads to early childhood death because of the lack of any effective therapy. In a mouse model of MoCo deficiency type A, the most frequent form of this autosomal recessively inherited disease, the affected animals show the biochemical characteristics of sulphite and xanthine intoxication and do not survive >2 wk after birth. We have constructed a recombinant-expression cassette for the gene MOCS1, which, via alternative splicing, facilitates the expression of the proteins MOCS1A and MOCS1B, both of which are necessary for the formation of a first intermediate, cyclic pyranopterin monophosphate (cPMP), within the biosynthetic pathway leading to active MoCo. A recombinant adeno-associated virus (AAV) vector was used to express the artificial MOCS1 minigene, in an attempt to cure the lethal MOCS1-deficient phenotype. The vector was used to transduce Mocs1-deficient mice at both 1 and 4 d after birth or, after a pretreatment with purified cPMP, at 40 d after birth. We report here that all Mocs1-deficient animals injected with a control AAV–enhanced green fluorescent protein vector died ∼8 d after birth or after withdrawal of cPMP supplementation, whereas AAV-MOCS1–transduced animals show significantly increased longevity. A single intrahepatic injection of AAV-MOCS1 resulted in fertile adult animals without any pathological phenotypes
Molybdenum cofactor deficiency: Mutations in GPHN, MOCS1, and MOCS2
No full textInternational audienceAll molybdenum-containing enzymes other than the bacterial nitrogenase share an identical molybdenum cofactor (MoCo), which is synthesized via a conserved pathway in all organisms and therefore also is called "universal molybdenum cofactor". In humans, four molybdoenzymes are known: aldehyde oxidase, mitochondrial amidoxime reducing component (mARC), xanthine oxidoreductase and sulfite oxidase. Mutations in the genes encoding the biosynthetic MoCo pathway enzymes abrogate the activities of all molybdoenzymes and result in the "combined" form of MoCo deficiency (OMIM # 252150), which is clinically very similar to isolated sulfite oxidase deficiency (OMIM # 606887), caused by mutations in the gene for the corresponding apoenzyme. Both deficiencies are inherited as an autosomal-recessive disease and result in progressive neurological damage and early childhood death in most cases. The majority of mutations leading to MoCo deficiency have been identified in the genes MOCS1 (type A deficiency) and MOCS2 (type B deficiency). For type A deficiency an effective substitution therapy has been described recently
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