Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT00572 (Asn)
 11,732 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperornithinemia, hyperammonemia and homocitrullinuria (HHH) syndrome presents with various neurological symptoms, including mental retardation, spastic paraparesis with pyramidal signs, cerebellar ataxia, and episodic disturbance of consciousness or coma caused by hyperammonemia. We report three novel mutations in the mitochondrial ornithine transporter gene (ORNT1) of Japanese patients with HHH syndrome: a nonsense mutation (R179X) associated with exon skipping and a frameshift, a missense mutation (G27E), and an insertion of AAC between codons 228 and 229, leading to an insertion of the amino acid Asn. The ORNT1 gene consists of at least six exons, and all exon-intron junction sequences conform to the GT/AG rule. All 3 patients were homozygous for their respective mutations. This study confirms that defects in the ORNT1 gene cause the HHH syndrome and that the genetic basis in Japanese patients is heterogeneous.
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PMID:Three novel mutations (G27E, insAAC, R179X) in the ORNT1 gene of Japanese patients with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. 1080 33

Mitochondrial ornithine transporter deficiency has been called HHH syndrome, because this disorder is characterized by three biochemical abnormalities; hyperornithinemia, hyperammonemia, and homocitrullinuria, and presents with various neurological symptoms; mental retardation, spastic paraparesis with pyramidal signs, cerebellar ataxia and episodic disturbance of consciousness or coma due to hyperammonemia. We identified four mutations in the mitochondrial ornithine transporter gene (ORNT1) of Japanese patients with HHH syndrome. These include a nonsense mutation (R179X), associated with exon skipping, missense mutations (G27E, P126R), and an insertion of AAC between codons 228 and 229, leading to an insertion of amino acid Asn. Especially, R179X was detected 4 of 7 Japanese patients (8 of 14 alleles), implying that this is a common mutation in Japanese population.
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PMID:[Molecular genetic studies of mitochondrial ornithine transporter deficiency (HHH syndrome)]. 1171 19

The P-type ATPase protein family includes, in addition to ion pumps such as Ca2+-ATPase and Na+,K+-ATPase, also phospholipid flippases that transfer phospholipids between membrane leaflets. P-type ATPase ion pumps translocate their substrates occluded between helices in the center of the transmembrane part of the protein. The large size of the lipid substrate has stimulated speculation that flippases use a different transport mechanism. Information on the functional importance of the most centrally located helices M5 and M6 in the transmembrane domain of flippases has, however, been sparse. Using mutagenesis, we examined the entire M5-M6 region of the mammalian flippase ATP8A2 to elucidate its possible function in the lipid transport mechanism. This mutational screen yielded an informative map assigning important roles in the interaction with the lipid substrate to only a few M5-M6 residues. The M6 asparagine Asn-905 stood out as being essential for the lipid substrate-induced dephosphorylation. The mutants N905A/D/E/H/L/Q/R all displayed very low activities and a dramatic insensitivity to the lipid substrate. Strikingly, Asn-905 aligns with key ion-binding residues of P-type ATPase ion pumps, and N905D was recently identified as one of the mutations causing the neurological disorder cerebellar ataxia, mental retardation, and disequilibrium (CAMRQ) syndrome. Moreover, the effects of substitutions to the adjacent residue Val-906 (i.e. V906A/E/F/L/Q/S) suggest that the lipid substrate approaches Val-906 during the translocation. These results favor a flippase mechanism with strong resemblance to the ion pumps, despite a location of the translocation pathway in the periphery of the transmembrane part of the flippase protein.
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PMID:Asparagine 905 of the mammalian phospholipid flippase ATP8A2 is essential for lipid substrate-induced activation of ATP8A2 dephosphorylation. 3076 May 26