Loading Pathway...
Error: Pathway image not found.
Hide
Pathway Description
Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH-syndrome)
Homo sapiens
Disease Pathway
Created: 2013-08-29
Last Updated: 2022-11-03
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder of the urea cycle caused by a defective SLC25A15 gene. SLC25A15 codes for the mitochondrial ornithine carrier (ORC1) which transports ornithine between the cytoplasm and the mitochondrial matrix. This disease is characterized by a large accumulation of homocitrulline in the urine. Symptoms of the disease include mental retardation, spastic paraparesis, and myoclonic seizures associated with hyperornithinemia, hyperammonemia, and homocitrullinemia. Ornithine supplementation and restricted protein intake appear to be useful in the treatment of HHH syndrome.
References
Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH-syndrome) References
[Metagen: HYPERORNITHINEMIA-HYPERAMMONEMIA-HOMOCITRULLINURIA [HHH-SYNDROME]](http://metagene.de/program/d.prg?id_d=215)
[OMIM: 238970](http://omim.org/entry/238970})
Camacho JA, Obie C, Biery B, Goodman BK, Hu CA, Almashanu S, Steel G, Casey R, Lambert M, Mitchell GA, Valle D: Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat Genet. 1999 Jun;22(2):151-8. doi: 10.1038/9658.
Pubmed: 10369256
Camacho J, Rioseco-Camacho N: Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome
Pubmed: 22649802
Arginine and Proline Metabolism References
Lehninger, A.L. Lehninger principles of biochemistry (4th ed.) (2005). New York: W.H Freeman.
Salway, J.G. Metabolism at a glance (3rd ed.) (2004). Alden, Mass.: Blackwell Pub.
Wu G, Bazer FW, Davis TA, Kim SW, Li P, Marc Rhoads J, Carey Satterfield M, Smith SB, Spencer TE, Yin Y: Arginine metabolism and nutrition in growth, health and disease. Amino Acids. 2009 May;37(1):153-68. doi: 10.1007/s00726-008-0210-y. Epub 2008 Nov 23.
Pubmed: 19030957
Wu G, Morris SM Jr: Arginine metabolism: nitric oxide and beyond. Biochem J. 1998 Nov 15;336 ( Pt 1):1-17. doi: 10.1042/bj3360001.
Pubmed: 9806879
Bock HG, Su TS, O'Brien WE, Beaudet AL: Sequence for human argininosuccinate synthetase cDNA. Nucleic Acids Res. 1983 Sep 24;11(18):6505-12. doi: 10.1093/nar/11.18.6505.
Pubmed: 6194510
Freytag SO, Bock HG, Beaudet AL, O'Brien WE: Molecular structures of human argininosuccinate synthetase pseudogenes. Evolutionary and mechanistic implications. J Biol Chem. 1984 Mar 10;259(5):3160-6.
Pubmed: 6321498
Haberle J, Pauli S, Linnebank M, Kleijer WJ, Bakker HD, Wanders RJ, Harms E, Koch HG: Structure of the human argininosuccinate synthetase gene and an improved system for molecular diagnostics in patients with classical and mild citrullinemia. Hum Genet. 2002 Apr;110(4):327-33. doi: 10.1007/s00439-002-0686-6. Epub 2002 Mar 1.
Pubmed: 11941481
Matuo S, Tatsuno M, Kobayashi K, Saheki T, Miyata T, Iwanaga S, Amaya Y, Mori M: Isolation of cDNA clones of human argininosuccinate lyase and corrected amino acid sequence. FEBS Lett. 1988 Jul 18;234(2):395-9. doi: 10.1016/0014-5793(88)80124-8.
Pubmed: 3391281
O'Brien WE, McInnes R, Kalumuck K, Adcock M: Cloning and sequence analysis of cDNA for human argininosuccinate lyase. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7211-5. doi: 10.1073/pnas.83.19.7211.
Pubmed: 3463959
Todd S, McGill JR, McCombs JL, Moore CM, Weider I, Naylor SL: cDNA sequence, interspecies comparison, and gene mapping analysis of argininosuccinate lyase. Genomics. 1989 Jan;4(1):53-9.
Pubmed: 2644168
Finckh U, Kohlschutter A, Schafer H, Sperhake K, Colombo JP, Gal A: Prenatal diagnosis of carbamoyl phosphate synthetase I deficiency by identification of a missense mutation in CPS1. Hum Mutat. 1998;12(3):206-11. doi: 10.1002/(SICI)1098-1004(1998)12:3<206::AID-HUMU8>3.0.CO;2-E.
Pubmed: 9711878
Funghini S, Donati MA, Pasquini E, Zammarchi E, Morrone A: Structural organization of the human carbamyl phosphate synthetase I gene (CPS1) and identification of two novel genetic lesions. Hum Mutat. 2003 Oct;22(4):340-1. doi: 10.1002/humu.9184.
Pubmed: 12955727
Aoshima T, Kajita M, Sekido Y, Kikuchi S, Yasuda I, Saheki T, Watanabe K, Shimokata K, Niwa T: Novel mutations (H337R and 238-362del) in the CPS1 gene cause carbamoyl phosphate synthetase I deficiency. Hum Hered. 2001;52(2):99-101. doi: 10.1159/000053360.
Pubmed: 11474210
Nakatani Y, Banner C, von Herrath M, Schneider ME, Smith HH, Freese E: Comparison of human brain and liver glutamate dehydrogenase cDNAS. Biochem Biophys Res Commun. 1987 Dec 16;149(2):405-10. doi: 10.1016/0006-291x(87)90381-0.
Pubmed: 3426581
Amuro N, Yamaura M, Goto Y, Okazaki T: Molecular cloning and nucleotide sequence of the cDNA for human liver glutamate dehydrogenase precursor. Biochem Biophys Res Commun. 1988 May 16;152(3):1395-400. doi: 10.1016/s0006-291x(88)80440-6.
Pubmed: 3377777
Nakatani Y, Schneider M, Banner C, Freese E: Complete nucleotide sequence of human glutamate dehydrogenase cDNA. Nucleic Acids Res. 1988 Jul 11;16(13):6237. doi: 10.1093/nar/16.13.6237.
Pubmed: 3399399
Inana G, Totsuka S, Redmond M, Dougherty T, Nagle J, Shiono T, Ohura T, Kominami E, Katunuma N: Molecular cloning of human ornithine aminotransferase mRNA. Proc Natl Acad Sci U S A. 1986 Mar;83(5):1203-7. doi: 10.1073/pnas.83.5.1203.
Pubmed: 3456579
Ramesh V, Shaffer MM, Allaire JM, Shih VE, Gusella JF: Investigation of gyrate atrophy using a cDNA clone for human ornithine aminotransferase. DNA. 1986 Dec;5(6):493-501.
Pubmed: 3816496
Kobayashi T, Nishii M, Takagi Y, Titani K, Matsuzawa T: Molecular cloning and nucleotide sequence analysis of mRNA for human kidney ornithine aminotransferase. An examination of ornithine aminotransferase isozymes between liver and kidney. FEBS Lett. 1989 Sep 25;255(2):300-4. doi: 10.1016/0014-5793(89)81110-x.
Pubmed: 2507357
Hu CA, Lin WW, Valle D: Cloning, characterization, and expression of cDNAs encoding human delta 1-pyrroline-5-carboxylate dehydrogenase. J Biol Chem. 1996 Apr 19;271(16):9795-800. doi: 10.1074/jbc.271.16.9795.
Pubmed: 8621661
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Gregory SG, Barlow KF, McLay KE, Kaul R, Swarbreck D, Dunham A, Scott CE, Howe KL, Woodfine K, Spencer CC, Jones MC, Gillson C, Searle S, Zhou Y, Kokocinski F, McDonald L, Evans R, Phillips K, Atkinson A, Cooper R, Jones C, Hall RE, Andrews TD, Lloyd C, Ainscough R, Almeida JP, Ambrose KD, Anderson F, Andrew RW, Ashwell RI, Aubin K, Babbage AK, Bagguley CL, Bailey J, Beasley H, Bethel G, Bird CP, Bray-Allen S, Brown JY, Brown AJ, Buckley D, Burton J, Bye J, Carder C, Chapman JC, Clark SY, Clarke G, Clee C, Cobley V, Collier RE, Corby N, Coville GJ, Davies J, Deadman R, Dunn M, Earthrowl M, Ellington AG, Errington H, Frankish A, Frankland J, French L, Garner P, Garnett J, Gay L, Ghori MR, Gibson R, Gilby LM, Gillett W, Glithero RJ, Grafham DV, Griffiths C, Griffiths-Jones S, Grocock R, Hammond S, Harrison ES, Hart E, Haugen E, Heath PD, Holmes S, Holt K, Howden PJ, Hunt AR, Hunt SE, Hunter G, Isherwood J, James R, Johnson C, Johnson D, Joy A, Kay M, Kershaw JK, Kibukawa M, Kimberley AM, King A, Knights AJ, Lad H, Laird G, Lawlor S, Leongamornlert DA, Lloyd DM, Loveland J, Lovell J, Lush MJ, Lyne R, Martin S, Mashreghi-Mohammadi M, Matthews L, Matthews NS, McLaren S, Milne S, Mistry S, Moore MJ, Nickerson T, O'Dell CN, Oliver K, Palmeiri A, Palmer SA, Parker A, Patel D, Pearce AV, Peck AI, Pelan S, Phelps K, Phillimore BJ, Plumb R, Rajan J, Raymond C, Rouse G, Saenphimmachak C, Sehra HK, Sheridan E, Shownkeen R, Sims S, Skuce CD, Smith M, Steward C, Subramanian S, Sycamore N, Tracey A, Tromans A, Van Helmond Z, Wall M, Wallis JM, White S, Whitehead SL, Wilkinson JE, Willey DL, Williams H, Wilming L, Wray PW, Wu Z, Coulson A, Vaudin M, Sulston JE, Durbin R, Hubbard T, Wooster R, Dunham I, Carter NP, McVean G, Ross MT, Harrow J, Olson MV, Beck S, Rogers J, Bentley DR, Banerjee R, Bryant SP, Burford DC, Burrill WD, Clegg SM, Dhami P, Dovey O, Faulkner LM, Gribble SM, Langford CF, Pandian RD, Porter KM, Prigmore E: The DNA sequence and biological annotation of human chromosome 1. Nature. 2006 May 18;441(7091):315-21. doi: 10.1038/nature04727.
Pubmed: 16710414
Bender HU, Almashanu S, Steel G, Hu CA, Lin WW, Willis A, Pulver A, Valle D: Functional consequences of PRODH missense mutations. Am J Hum Genet. 2005 Mar;76(3):409-20. doi: 10.1086/428142. Epub 2005 Jan 20.
Pubmed: 15662599
Liu H, Heath SC, Sobin C, Roos JL, Galke BL, Blundell ML, Lenane M, Robertson B, Wijsman EM, Rapoport JL, Gogos JA, Karayiorgou M: Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3717-22. doi: 10.1073/pnas.042700699. Epub 2002 Mar 12.
Pubmed: 11891283
Campbell HD, Webb GC, Young IG: A human homologue of the Drosophila melanogaster sluggish-A (proline oxidase) gene maps to 22q11.2, and is a candidate gene for type-I hyperprolinaemia. Hum Genet. 1997 Nov;101(1):69-74. doi: 10.1007/s004390050589.
Pubmed: 9385373
Nakayama T, Al-Maawali A, El-Quessny M, Rajab A, Khalil S, Stoler JM, Tan WH, Nasir R, Schmitz-Abe K, Hill RS, Partlow JN, Al-Saffar M, Servattalab S, LaCoursiere CM, Tambunan DE, Coulter ME, Elhosary PC, Gorski G, Barkovich AJ, Markianos K, Poduri A, Mochida GH: Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination. Am J Hum Genet. 2015 May 7;96(5):709-19. doi: 10.1016/j.ajhg.2015.03.003. Epub 2015 Apr 9.
Pubmed: 25865492
Highlighted elements will appear in red.
Highlight Compounds
Highlight Proteins
Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.
Visualize Compound Data
Visualize Protein Data
Downloads
Settings