5m6r

Structural highlights

Disease

[HEM3_HUMAN] Defects in HMBS are the cause of acute intermittent porphyria (AIP) [MIM:176000]. AIP is a form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. AIP is an autosomal dominant form of hepatic porphyria characterized by acute attacks of neurological dysfunctions with abdominal pain, hypertension, tachycardia, and peripheral neuropathy. Most attacks are precipitated by drugs, alcohol, caloric deprivation, infections, or endocrine factors.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27]} [:]^{[28] [29] [30] [31] [32] [33]}

Function

[HEM3_HUMAN] Tetrapolymerization of the monopyrrole PBG into the hydroxymethylbilane pre-uroporphyrinogen in several discrete steps.

References

1. ↑ Delfau MH, Picat C, de Rooij FW, Hamer K, Bogard M, Wilson JH, Deybach JC, Nordmann Y, Grandchamp B. Two different point G to A mutations in exon 10 of the porphobilinogen deaminase gene are responsible for acute intermittent porphyria. J Clin Invest. 1990 Nov;86(5):1511-6. PMID:2243128 doi:http://dx.doi.org/10.1172/JCI114869
2. ↑ Delfau MH, Picat C, De Rooij F, Voortman G, Deybach JC, Nordmann Y, Grandchamp B. Molecular heterogeneity of acute intermittent porphyria: identification of four additional mutations resulting in the CRIM-negative subtype of the disease. Am J Hum Genet. 1991 Aug;49(2):421-8. PMID:1714233
3. ↑ Gu XF, de Rooij F, Voortman G, Te Velde K, Nordmann Y, Grandchamp B. High frequency of mutations in exon 10 of the porphobilinogen deaminase gene in patients with a CRIM-positive subtype of acute intermittent porphyria. Am J Hum Genet. 1992 Sep;51(3):660-5. PMID:1496994
4. ↑ Mgone CS, Lanyon WG, Moore MR, Connor JM. Detection of seven point mutations in the porphobilinogen deaminase gene in patients with acute intermittent porphyria, by direct sequencing of in vitro amplified cDNA. Hum Genet. 1992 Sep-Oct;90(1-2):12-6. PMID:1427766
5. ↑ Kauppinen R, Peltonen L, Pihlaja H, Mustajoki P. CRIM-positive mutations of acute intermittent porphyria in Finland. Hum Mutat. 1992;1(5):392-6. PMID:1301948 doi:http://dx.doi.org/10.1002/humu.1380010508
6. ↑ Mgone CS, Lanyon WG, Moore MR, Louie GV, Connor JM. Detection of a high mutation frequency in exon 12 of the porphobilinogen deaminase gene in patients with acute intermittent porphyria. Hum Genet. 1993 Dec;92(6):619-22. PMID:8262523
7. ↑ Llewellyn DH, Whatley S, Elder GH. Acute intermittent porphyria caused by an arginine to histidine substitution (R26H) in the cofactor-binding cleft of porphobilinogen deaminase. Hum Mol Genet. 1993 Aug;2(8):1315-6. PMID:8401516
8. ↑ Gu XF, de Rooij F, de Baar E, Bruyland M, Lissens W, Nordmann Y, Grandchamp B. Two novel mutations of the porphobilinogen deaminase gene in acute intermittent porphyria. Hum Mol Genet. 1993 Oct;2(10):1735-6. PMID:8268934
9. ↑ Gu XF, de Rooij F, Voortman G, Te Velde K, Deybach JC, Nordmann Y, Grandchamp B. Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis. Hum Genet. 1994 Jan;93(1):47-52. PMID:8270254
10. ↑ Lundin G, Wedell A, Thunell S, Anvret M. Two new mutations in the porphobilinogen deaminase gene and a screening method using PCR amplification of specific alleles. Hum Genet. 1994 Jan;93(1):59-62. PMID:8270256
11. ↑ Mgone CS, Lanyon WG, Moore MR, Louie GV, Connor JM. Identification of five novel mutations in the porphobilinogen deaminase gene. Hum Mol Genet. 1994 May;3(5):809-11. PMID:8081367
12. ↑ Chen CH, Astrin KH, Lee G, Anderson KE, Desnick RJ. Acute intermittent porphyria: identification and expression of exonic mutations in the hydroxymethylbilane synthase gene. An initiation codon missense mutation in the housekeeping transcript causes "variant acute intermittent porphyria" with normal expression of the erythroid-specific enzyme. J Clin Invest. 1994 Nov;94(5):1927-37. PMID:7962538 doi:http://dx.doi.org/10.1172/JCI117543
13. ↑ Kauppinen R, Mustajoki S, Pihlaja H, Peltonen L, Mustajoki P. Acute intermittent porphyria in Finland: 19 mutations in the porphobilinogen deaminase gene. Hum Mol Genet. 1995 Feb;4(2):215-22. PMID:7757070
14. ↑ Lundin G, Hashemi J, Floderus Y, Thunell S, Sagen E, Laegreid A, Wassif W, Peters T, Anvret M. Four mutations in the porphobilinogen deaminase gene in patients with acute intermittent porphyria. J Med Genet. 1995 Dec;32(12):979-81. PMID:8825929
15. ↑ Puy H, Deybach JC, Lamoril J, Robreau AM, Da Silva V, Gouya L, Grandchamp B, Nordmann Y. Molecular epidemiology and diagnosis of PBG deaminase gene defects in acute intermittent porphyria. Am J Hum Genet. 1997 Jun;60(6):1373-83. PMID:9199558 doi:S0002-9297(07)64229-3
16. ↑ Lundin G, Lee JS, Thunell S, Anvret M. Genetic investigation of the porphobilinogen deaminase gene in Swedish acute intermittent porphyria families. Hum Genet. 1997 Jul;100(1):63-6. PMID:9225970
17. ↑ Mustajoki S, Pihlaja H, Ahola H, Petersen NE, Mustajoki P, Kauppinen R. Three splicing defects, an insertion, and two missense mutations responsible for acute intermittent porphyria. Hum Genet. 1998 May;102(5):541-8. PMID:9654202
18. ↑ Ong PM, Lanyon WG, Hift RJ, Halkett J, Cramp CE, Moore MR, Connor JM. Identification of two novel mutations in the hydroxymethylbilane synthase gene in three patients from two unrelated families with acute intermittent porphyria. Hum Hered. 1998 Jan-Feb;48(1):24-9. PMID:9463797
19. ↑ De Siervi A, Rossetti MV, Parera VE, Astrin KH, Aizencang GI, Glass IA, Batlle AM, Desnick RJ. Identification and characterization of hydroxymethylbilane synthase mutations causing acute intermittent porphyria: evidence for an ancestral founder of the common G111R mutation. Am J Med Genet. 1999 Oct 8;86(4):366-75. PMID:10494093
20. ↑ Whatley SD, Woolf JR, Elder GH. Comparison of complementary and genomic DNA sequencing for the detection of mutations in the HMBS gene in British patients with acute intermittent porphyria: identification of 25 novel mutations. Hum Genet. 1999 Jun;104(6):505-10. PMID:10453740
21. ↑ De Siervi A, Mendez M, Parera VE, Varela L, Batlle AM, Rossetti MV. Acute intermittent porphyria: characterization of two novel mutations in the porphobilinogen deaminase gene, one amino acid deletion (453-455delAGC) and one splicing aceptor site mutation (IVS8-1G>T). Hum Mutat. 1999 Oct;14(4):355. PMID:10502788 doi:<355::AID-HUMU19>3.0.CO;2-T 10.1002/(SICI)1098-1004(199910)14:4<355::AID-HUMU19>3.0.CO;2-T
22. ↑ Gross U, Puy H, Doss M, Robreau AM, Nordmann Y, Doss MO, Deybach JC. New mutations of the hydroxymethylbilane synthase gene in German patients with acute intermittent porphyria. Mol Cell Probes. 1999 Dec;13(6):443-7. PMID:10657149 doi:10.1006/mcpr.1999.0276
23. ↑ Solis C, Lopez-Echaniz I, Sefarty-Graneda D, Astrin KH, Desnick RJ. Identification and expression of mutations in the hydroxymethylbilane synthase gene causing acute intermittent porphyria (AIP). Mol Med. 1999 Oct;5(10):664-71. PMID:10602775
24. ↑ Ramdall RB, Cunha L, Astrin KH, Katz DR, Anderson KE, Glucksman M, Bottomley SS, Desnick RJ. Acute intermittent porphyria: novel missense mutations in the human hydroxymethylbilane synthase gene. Genet Med. 2000 Sep-Oct;2(5):290-5. PMID:11399210 doi:10.109700125817-200009000-00004
25. ↑ Robreau-Fraolini AM, Puy H, Aquaron C, Bogard C, Traore M, Nordmann Y, Aquaron R, Deybach JC. Porphobilinogen deaminase gene in African and Afro-Caribbean ethnic groups: mutations causing acute intermittent porphyria and specific intragenic polymorphisms. Hum Genet. 2000 Aug;107(2):150-9. PMID:11030413
26. ↑ Schneider-Yin X, Bogard C, Rufenacht UB, Puy H, Nordmann Y, Minder EI, Deybach J. Identification of a prevalent nonsense mutation (W283X) and two novel mutations in the porphobilinogen deaminase gene of Swiss patients with acute intermittent porphyria. Hum Hered. 2000 Jul-Aug;50(4):247-50. PMID:10782018 doi:22924
27. ↑ De Siervi A, Weiss Cadiz DE, Parera VE, del C Batlle AM, Rossetti MV. Identification and characterization of two novel mutations that produce acute intermittent porphyria: A 3-base deletion (841-843delGGA) and a missense mutation (T35M). Hum Mutat. 2000 Oct;16(4):373. PMID:11013452 doi:<373::AID-HUMU14>3.0.CO;2-A 10.1002/1098-1004(200010)16:4<373::AID-HUMU14>3.0.CO;2-A
28. ↑ Kauppinen R, von und zu Fraunberg M. Molecular and biochemical studies of acute intermittent porphyria in 196 patients and their families. Clin Chem. 2002 Nov;48(11):1891-900. PMID:12406973
29. ↑ Floderus Y, Shoolingin-Jordan PM, Harper P. Acute intermittent porphyria in Sweden. Molecular, functional and clinical consequences of some new mutations found in the porphobilinogen deaminase gene. Clin Genet. 2002 Oct;62(4):288-97. PMID:12372055
30. ↑ Gregor A, Schneider-Yin X, Szlendak U, Wettstein A, Lipniacka A, Rufenacht UB, Minder EI. Molecular study of the hydroxymethylbilane synthase gene (HMBS) among Polish patients with acute intermittent porphyria. Hum Mutat. 2002 Mar;19(3):310. PMID:11857754 doi:10.1002/humu.9020
31. ↑ Gouya L, Puy H, Robreau AM, Lyoumi S, Lamoril J, Da Silva V, Grandchamp B, Deybach JC. Modulation of penetrance by the wild-type allele in dominantly inherited erythropoietic protoporphyria and acute hepatic porphyrias. Hum Genet. 2004 Feb;114(3):256-62. Epub 2003 Dec 11. PMID:14669009 doi:10.1007/s00439-003-1059-5
32. ↑ Hessels J, Voortman G, van der Wagen A, van der Elzen C, Scheffer H, Zuijderhoudt FM. Homozygous acute intermittent porphyria in a 7-year-old boy with massive excretions of porphyrins and porphyrin precursors. J Inherit Metab Dis. 2004;27(1):19-27. PMID:14970743 doi:10.1023/B:BOLI.0000016613.75677.05
33. ↑ Schneider-Yin X, Hergersberg M, Schuurmans MM, Gregor A, Minder EI. Mutation hotspots in the human porphobilinogen deaminase gene: recurrent mutations G111R and R173Q occurring at CpG motifs. J Inherit Metab Dis. 2004;27(5):625-31. PMID:15669678