Molecular defects in human carbamoy phosphate synthetase I: Mutational spectrum, diagnostic and protein structure considerations

Human Mutation

Volumn 32, Issue 6, 2011, Pages 579-589

  Häberle, Johannes ^a,b   Shchelochkov, Oleg A ^c   Wang, Jing ^d   Katsonis, Panagiotis ^d   Hall, Lynn ^e   Reiss, Sara ^e   Eeds, Angela ^e   Willis, Alecia ^d   Yadav, Meeta ^e   Summar, Samantha ^e   Lichtarge, Olivier ^d   Rubio, Vicente ^f   Wong, Lee Jun ^d   Summar, Marshall ^e,g  

^a UNIVERSITY CHILDREN S HOSPITAL   (Switzerland)

^b UNIVERSITY HOSPITAL MÜNSTER   (Germany)

^c UNIVERSITY OF IOWA HOSPITALS AND CLINICS   (United States)

^d BAYLOR COLLEGE OF MEDICINE   (United States)

^e VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^f INSTITUTO DE SALUD CARLOS III   (Spain)

^g CHILDREN'S NATIONAL MEDICAL CENTER   (United States)

Author keywords

CPS1; Evolutionary; Hyperammonemia; Structure; Urea cycle

Indexed keywords

CARBAMOYL PHOSPHATE SYNTHASE; DNA;

ALLOSTERISM; ARTICLE; CARBAMOYL PHOSPHATE SYNTHETASE I DEFICIENCY; CRYSTAL STRUCTURE; GENE DELETION; GENE INSERTION; GENE MUTATION; GENE SEQUENCE; HUMAN; HUMAN TISSUE; HYPERAMMONEMIA; MAJOR CLINICAL STUDY; MISSENSE MUTATION; MOLECULAR MODEL; NONSENSE MUTATION; PRIORITY JOURNAL; PROTEIN STRUCTURE; SKIN BIOPSY; SPLICING DEFECT;

CARBAMOYL-PHOSPHATE SYNTHASE (AMMONIA); CARBAMOYL-PHOSPHATE SYNTHASE I DEFICIENCY DISEASE; CODON, NONSENSE; DNA MUTATIONAL ANALYSIS; HUMANS; HYPERAMMONEMIA; INDEL MUTATION; MODELS, CHEMICAL; MUTATION, MISSENSE; PROTEIN CONFORMATION; PROTEIN ISOFORMS;

EID: 79957620774     PISSN: 10597794     EISSN: 10981004     Source Type: Journal    
DOI: 10.1002/humu.21406     Document Type: Article

References (72)

1. Ahuja V, Powers-Lee SG. 2008. Human carbamoyl-phosphate synthetase: insight into N-acetylglutamate interaction and the functional effects of a common single nucleotide polymorphism. J Inherit Metab Dis 31:481-491.
2. Alonso E, Cervera J, Garcia-Espana A, Bendala E, Rubio V. 1992. Oxidative inactivation of carbamoyl phosphate synthetase (ammonia). Mechanism and sites of oxidation, degradation of the oxidized enzyme, and inactivation by glycerol, EDTA, and thiol protecting agents. J Biol Chem 267:4524-4532.
3. Alonso E, Rubio V. 1995. Affinity cleavage of carbamoyl-phosphate synthetase I localizes regions of the enzyme interacting with the molecule of ATP that phosphorylates carbamate. Eur J Biochem 229:377-384.
4. Aoshima T, Kajita M, Sekido Y, Kikuchi S, Yasuda I, Saheki T, Watanabe K, Shimokata K, Niwa T. 2001a. Novel mutations (H337R and 238-362del) in the CPS1 gene cause carbamoyl phosphate synthetase I deficiency. Hum Hered 52:99-101.
5. Aoshima T, Kajita M, Sekido Y, Mimura S, Itakura A, Yasuda I, Saheki T, Watanabe K, Shimokata K, Niwa T. 2001b. Carbamoyl phosphate synthetase I deficiency: molecular genetic findings and prenatal diagnosis. Prenat Diagn 21:634-637.
6. Arnold K, Bordoli L, Kopp J, Schwede T. 2006. The SWISS-MODEL workspace: a Web-based environment for protein structure homology modelling. Bioinformatics 22:195-201.
7. Baameur F, Morgan DH, Yao H, Tran TM, Hammitt RA, Sabui S, McMurray JS, Lichtarge O, Clark RB. 2010. Role for the regulator of G-protein signaling homology domain of G protein-coupled receptor kinases 5 and 6 in beta 2-adrenergic receptor and rhodopsin phosphorylation. Mol Pharmacol 77:405-415.
8. Cervera J, Conejero-Lara F, Ruiz-Sanz J, Galisteo ML, Mateo PL, Lusty CJ, Rubio V. 1993. The influence of effectors and subunit interactions on Escherichia coli carbamoyl-phosphate synthetase studied by differential scanning calorimetry. J Biol Chem 268:12504-12511.
9. Chothia C, Lesk AM. 1986. The relation between the divergence of sequence and structure in proteins. EMBO J 5:823-826.
10. Edgar RC. 2004. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 32:1792-1797.
11. Eeds AM, Hall LD, Yadav M, Willis A, Summar S, Putnam A, Barr F, Summar ML. 2006. The frequent observation of evidence for nonsense-mediated decay in RNA from patients with carbamyl phosphate synthetase I deficiency. Mol Genet Metab 89:80-86.
12. Eeds AM, Mortlock D, Wade-Martins R, Summar ML. 2007. Assessing the functional characteristics of synonymous and nonsynonymous mutation candidates by use of large DNA constructs. Am J Hum Genet 80:740-750.
13. Falik-Zaccai TC, Kfir N, Frenkel P, Cohen C, Tanus M, Mandel H, Shihab S, Morkos S, Aaref S, Summar ML, Khayat M. 2008. Population screening in a Druze community: the challenge and the reward. Genet Med 10:903-909.
14. Finckh U, Kohlschütter A, Schafer H, Sperhake K, Colombo JP, Gal A. 1998. Prenatal diagnosis of carbamoyl phosphate synthetase I deficiency by identification of a missense mutation in CPS1. Hum Mutat 12:206-211.
15. Fresquet V, Mora P, Rochera L, Ramón-Maiques S, Rubio V, Cervera J. 2000. Site-directed mutagenesis of the regulatory domain of Escherichia coli carbamoyl phosphate synthetase identifies crucial residues for allosteric regulation and for transduction of the regulatory signals. J Mol Biol 299:979-991.
16. Funghini S, Donati MA, Pasquini E, Zammarchi E, Morrone A. 2003. Structural organization of the human carbamyl phosphate synthetase I gene (CPS1) and identification of two novel genetic lesions. Hum Mutat 22:340-341.
17. Häberle J, Schmidt E, Pauli S, Rapp B, Christensen E, Wermuth B, Koch HG. 2003. Gene structure of human carbamylphosphate synthetase 1 and novel mutations in patients with neonatal onset. Hum Mutat 21:444.
18. Haraguchi Y, Uchino T, Takiguchi M, Endo F, Mori M, Matsuda I. 1991. Cloning and sequence of a cDNA encoding human carbamyl phosphate synthetase I: molecular analysis of hyperammonemia. Gene 107:335-340.
19. Hart EJ, Powers-Lee SG. 2009. Role of Cys-1327 and Cys-1337 in redox sensitivity and allosteric monitoring in human carbamoyl phosphate synthetase. J Biol Chem 284:5977-5985.
20. Horwich AL, Kalousek F, Fenton WA, Pollock RA, Rosenberg LE. 1986. Targeting of pre-ornithine transcarbamylase to mitochondria: definition of critical regions and residues in the leader peptide. Cell 44:451-459.
21. Hoshide R, Matsuura T, Haraguchi Y, Endo F, Yoshinaga M, Matsuda I. 1993. Carbamyl phosphate synthetase I deficiency. One base substitution in an exon of the CPS I gene causes a 9-basepair deletion due to aberrant splicing. J Clin Invest 91:1884-1887.
22. Ihara K, Nakayama H, Hikino S, Hara T. 1999. Mutation in CPS1. Hum Genet 105:375.
23. Javid-Majd F, Stapleton MA, Harmon MF, Hanks BA, Mullins LS, Raushel FM. 1996. Comparison of the functional differences for the homologous residues within the carboxy phosphate and carbamate domains of carbamoyl phosphate synthetase. Biochemistry 35:14362-14369.
24. Kabsch W, Sander C. 1983. Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 22:2577-2637.
25. Khayat M. 2009. Novel human pathological mutations. Gene symbol: CPS1. Disease: carbamoyl phosphate synthetase I deficiency. Hum Genet 125:336.
26. Klaus V, Vermeulen T, Minassian B, Israelian N, Engel K, Lund AM, Roebrock K, Christensen E, Häberle J. 2009. Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family: an effect of allelic variation in gene expression? Clin Genet 76:263-269.
27. Krebs H, Henseleit K. 1932. Untersuchungen über die Harnstoffbildung im Tierkörper. Hoppe-Seyler's Zeitschrift für Physiologische Chemie 210:325-332.
28. Kurokawa K, Yorifuji T, Kawai M, Momoi T, Nagasaka H, Takayanagi M, Kobayashi K, Yoshino M, Kosho T, Adachi M, Otsuka H, Yamamoto S, Murata T, Suenaga A, Ishii T, Terada K, Shimura N, Kiwaki K, Shintaku H, Yamakawa M, Nakabayashi H, Wakutani Y, Nakahata T. 2007. Molecular and clinical analyses of Japanese patients with carbamoylphosphate synthetase 1 (CPS1) deficiency. J Hum Genet 52:349-354.
29. Laskowski RA, Hutchinson EG, Michie AD, Wallace AC, Jones ML, Thornton JM. 1997. PDBsum: a Web-based database of summaries and analyses of all PDB structures. Trends Biochem Sci 22:488-490.
30. Lichtarge O, Bourne HR, Cohen FE. 1996. An evolutionary trace method defines binding surfaces common to protein families. J Mol Biol 257:342-358.
31. Lichtarge O, Yamamoto KR, Cohen FE. 1997. Identification of functional surfaces of the zinc binding domains of intracellular receptors. J Mol Biol 274:325-337.
32. Loscalzo ML, Galczynski RL, Hamosh A, Summar M, Chinsky JM, Thomas GH. 2004. Interstitial deletion of chromosome 2q32-34 associated with multiple congenital anomalies and a urea cycle defect (CPS I deficiency). Am J Med Genet A 128A:311-315.
33. Meister A. 1989. Mechanism and regulation of the glutamine-dependent carbamyl phosphate synthetase of Escherichia coli. Adv Enzymol Relat Areas Mol Biol 62:315-374.
34. Mihalek I, Res I, Lichtarge O. 2004. A family of evolution-entropy hybrid methods for ranking protein residues by importance. J Mol Biol 336:1265-1282.
35. Mihalek I, Res I, Lichtarge O. 2006. Evolutionary trace report-maker: a new type of service for comparative analysis of proteins. Bioinformatics 22:1656-1657.
36. Mihalek I, Res I, Yao H, Lichtarge O. 2003. Combining inference from evolution and geometric probability in protein structure evaluation. J Mol Biol 331:263-279.
37. Mitchell S, Ellingson C, Coyne T, Hall L, Neill M, Christian N, Higham C, Dobrowolski SF, Tuchman M, Summar M. 2009. Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases. Hum Mutat 30:56-60.
38. Morgan DH, Kristensen DM, Mittelman D, Lichtarge O. 2006. ET viewer: an application for predicting and visualizing functional sites in protein structures. Bioinformatics 22:2049-2050.
39. Neill MA, Aschner J, Barr F, Summar ML. 2009. Quantitative RT-PCR comparison of the urea and nitric oxide cycle gene transcripts in adult human tissues. Mol Genet Metab 97:121-127.
40. Nyunoya H, Broglie KE, Widgren EE, Lusty CJ. 1985. Characterization and derivation of the gene coding for mitochondrial carbamyl phosphate synthetase I of rat. J Biol Chem 260:9346-9356.
41. Ono H, Suto T, Kinoshita Y, Sakano T, Furue T, Ohta T. 2009. A case of carbamoyl phosphate synthetase 1 deficiency presenting symptoms at one month of age. Brain Dev 31:779-781.
42. Oyanagi K, Nakamura K, Sogawa H, Tsukazaki H, Minami R, Nakao T. 1980. A study of urea-synthesizing enzymes in prenatal and postnatal human liver. Pediatr Res 14:236-241.
43. Pekkala S, Martinez AI, Barcelona B, Gallego J, Bendala E, Yefimenko I, Rubio V, Cervera J. 2009. Structural insight on the control of urea synthesis: identification of the binding site for N-acetyl-L-glutamate, the essential allosteric activator of mitochondrial carbamoyl phosphate synthetase. Biochem J 424:211-220.
44. Pekkala S, Martinez AI, Barcelona B, Yefimenko I, Finckh U, Rubio V, Cervera J. 2010. Understanding carbamoyl-phosphate synthetase I (CPS1) deficiency by using expression studies and structure-based analysis. Hum Mutat 31:801-808.
45. Pierrat OA, Raushel FM. 2002. A functional analysis of the allosteric nucleotide monophosphate binding site of carbamoyl phosphate synthetase. Arch Biochem Biophys 400:34-42.
46. Powers-Lee SG, Corina K. 1986. Domain structure of rat liver carbamoyl phosphate synthetase I. J Biol Chem 261:15349-15352.
47. Rapp B, Häberle J, Linnebank M, Wermuth B, Marquardt T, Harms E, Koch HG. 2001. Genetic analysis of carbamoylphosphate synthetase I and ornithine transcarbamylase deficiency using fibroblasts. Eur J Pediatr 160:283-287.
48. Ribes-Zamora A, Mihalek I, Lichtarge O, Bertuch AA. 2007. Distinct faces of the Ku heterodimer mediate DNA repair and telomeric functions. Nat Struct Mol Biol 14:301-307.
49. Rodriguez-Aparicio LB, Guadalajara AM, Rubio V. 1989. Physical location of the site for N-acetyl-L-glutamate, the allosteric activator of carbamoyl phosphate synthetase, in the 20-kilodalton COOH-terminal domain. Biochemistry 28:3070-3074.
50. Rubio V. 1993. Structure-function studies in carbamoyl phosphate synthetases. Biochem Soc Trans 21:198-202.
51. Rubio V, Cervera J. 1995. The carbamoyl-phosphate synthase family and carbamate kinase: structure-function studies. Biochem Soc Trans 23:879-883.
52. Rubio V, Grisolia S. 1981. Human carbamoylphosphate synthetase I. Enzyme 26:233-239.
53. Rubio V, Ramponi G, Grisolia S. 1981. Carbamoyl phosphate synthetase I of human liver. Purification, some properties and immunological cross-reactivity with the rat liver enzyme. Biochim Biophys Acta 659:150-160.
54. Ryall J, Nguyen M, Bendayan M, Shore GC. 1985. Expression of nuclear genes encoding the urea cycle enzymes, carbamoyl-phosphate synthetase I and ornithine carbamoyl transferase, in rat liver and intestinal mucosa. Eur J Biochem 152:287-292.
55. Saeed-Kothe A, Powers-Lee SG. 2003. Gain of glutaminase function in mutants of the ammonia-specific frog carbamoyl phosphate synthetase. J Biol Chem 278:26722-26726.
56. Schofield JP. 1993. Molecular studies on an ancient gene encoding for carbamoyl-phosphate synthetase. Clin Sci (Lond) 84:119-128.
57. Shambaugh 3rd GE. 1977. Urea biosynthesis I. The urea cycle and relationships to the citric acid cycle. Am J Clin Nutr 30:2083-2087.
58. Stapleton MA, Javid-Majd F, Harmon MF, Hanks BA, Grahmann JL, Mullins LS, Raushel FM. 1996. Role of conserved residues within the carboxy phosphate domain of carbamoyl phosphate synthetase. Biochemistry 35:14352-14361.
59. Summar ML. 1998. Molecular genetic research into carbamoyl-phosphate synthase I: molecular defects and linkage markers. J Inherit Metab Dis 21(Suppl 1):30-39.
60. Summar ML, Dobbelaere D, Brusilow S, Lee B. 2008. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr 97:1420-1425.
61. Summar ML, Hall L, Christman B, Barr F, Smith H, Kallianpur A, Brown N, Yadav M, Willis A, Eeds A, Cermak E, Summar S, Wilson A, Arvin M, Putnam A, Wills M, Cunningham G. 2004. Environmentally determined genetic expression: clinical correlates with molecular variants of carbamyl phosphate synthetase I. Mol Genet Metab 81(Suppl 1):S12-S19.
62. Summar ML, Hall LD, Eeds AM, Hutcheson HB, Kuo AN, Willis AS, Rubio V, Arvin MK, Schofield JP, Dawson EP. 2003. Characterization of genomic structure and polymorphisms in the human carbamyl phosphate synthetase I gene. Gene 311:51-57.
63. Thoden JB, Holden HM, Wesenberg G, Raushel FM, Rayment I. 1997. Structure of carbamoyl phosphate synthetase: a journey of 96 A from substrate to product. Biochemistry 36:6305-6316.
64. Thoden JB, Wesenberg G, Raushel FM, Holden HM. 1999. Carbamoyl phosphate synthetase: closure of the B-domain as a result of nucleotide binding. Biochemistry 38:2347-2357.
65. Tuchman M, Lee B, Lichter-Konecki U, Summar ML, Yudkoff M, Cederbaum SD, Kerr DS, Diaz GA, Seashore MR, Lee HS, McCarter RJ, Krischer JP, Batshaw ML; Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research Network. 2008. Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab 94:397-402.
66. Uchino T, Endo F, Matsuda I. 1998. Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan. J Inherit Metab Dis 21(Suppl 1):151-159.
67. Wakutani Y, Nakayasu H, Takeshima T, Mori N, Kobayashi K, Endo F, Nakashima K. 2001. A case of late-onset carbamoyl phosphate synthetase I deficiency, presenting periodic psychotic episodes coinciding with menstrual periods. Rinsho Shinkeigaku 41:780-785.
68. Wang Z, Moult J. 2001. SNPs, protein structure, and disease. Hum Mutat 17:263-270.
69. Windmueller HG, Spaeth AE. 1981. Source and fate of circulating citrulline. Am J Physiol 241:E473-E480.
70. Wong LJ, Craigen WJ, O'Brien WE. 1994. Postpartum coma and death due to carbamoyl-phosphate synthetase I deficiency. Ann Intern Med 120:216-217.
71. Yao H, Kristensen DM, Mihalek I, Sowa ME, Shaw C, Kimmel M, Kavraki L, Lichtarge O. 2003. An accurate, sensitive, and scalable method to identify functional sites in protein structures. J Mol Biol 326:255-261.
72. Yefimenko I, Fresquet V, Marco-Marin C, Rubio V, Cervera J. 2005. Understanding carbamoyl phosphate synthetase deficiency: impact of clinical mutations on enzyme functionality. J Mol Biol 349:127-141.