Hematologically Important Mutations: Acute Intermittent Porphyria

Cappellini, Maria Domenica; Montemuros, Franco Martinez di; Pierro, Elena Di; Fiorelli, G.

doi:10.1006/bcmd.2001.0478

Cited by 9 publications

(4 citation statements)

References 56 publications

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“…There are those that lead to a truncated protein, such as W198X, a mutation exceptionally common in Sweden [7]. There are a number of mutations in the hydrophobic core of the enzyme that are likely to compromise normal protein folding or that result in an unstable protein [8]. Some mutations, like R149Q [9] and R173Q [10], are thought to result in apoproteins.…”

Section: Scheme 2 the Catalytic Cycle Of Porphobilingen Deaminasementioning

confidence: 99%

Human porphobilinogen deaminase mutations in the investigation of the mechanism of dipyrromethane cofactor assembly and tetrapyrrole formation

Shoolingin‐Jordan

Al-Dbass

McNeill

et al. 2003

Biochemical Society Transactions

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Porphobilinogen deaminase mutants that cause acute intermittent porphyria have been investigated as recombinant proteins expressed in Escherichia coli, yielding important insight into the mechanism of dipyrromethane cofactor assembly and tetrapyrrole chain polymerization. A mutation that affects a key catalytic residue, D99G, results in an inactive holo -protein that exists as a complex with two substrate molecules covalently bound to the dipyrromethane cofactor arising from the reaction between the apo -protein and pre-uroporphyrinogen. The R149Q mutant is also devoid of catalytic activity but the mutant protein is unable to assemble the dipyrromethane cofactor from pre-uroporphyrinogen and persists as an unstable, heat-labile apo -protein. The mutant, R173Q, has very low activity and, like R149Q, also exhibits largely as an apo -protein. The inability to reconstitute either R149Q or R173Q with exogenous pre-uroporphyrinogen confirms the importance of these two arginine residues for dipyrromethane cofactor assembly. In contrast, the mutant R167Q exists as a holo -enzyme but the catalytic cycle is severely compromised, leading to the accumulation of stable enzyme-substrate intermediates from the catalytic cycle.

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Section: Scheme 2 the Catalytic Cycle Of Porphobilingen Deaminasementioning

confidence: 99%

Human porphobilinogen deaminase mutations in the investigation of the mechanism of dipyrromethane cofactor assembly and tetrapyrrole formation

Shoolingin‐Jordan

Al-Dbass

McNeill

et al. 2003

Biochemical Society Transactions

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“…The first mutation in the PBGD gene, associated with AIP, was reported in 1989 (11) and these have grown in number to 210 mutations currently known (12). In Sweden, 39 mutations have now been described in the PBGD gene and they are summarized in the present article.…”

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confidence: 99%

Acute intermittent porphyria in Sweden. Molecular, functional and clinical consequences of some new mutations found in the porphobilinogen deaminase gene

2002

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Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by a partial deficit of porphobilinogen deaminase (PBGD), the third of eight enzymes in the haem biosynthetic pathway. The overt disease is characterized by neuropsychiatric symptoms that are often triggered by exogenous factors such as certain drugs, stress, and alcohol. The aim of this work has been to identify the underlying genetic defect in each AIP-affected family in order to provide early counselling to assist in the avoidance of precipitating factors. The prevalence of AIP in Sweden is in the order of 1:10 000. The major mutation in Sweden, W198X, is due to a founder effect in the northern part of the country. This mutation, together with a further 11 mutations, have been reported previously. The present communication encompasses the great majority of AIP kindreds in Sweden and includes a further 27 mutations within the PBGD gene. This includes 14 completely new mutations, as well as 11 known mutations detected for the first time in Sweden. The majority of the mutations are located in exons 10 and 12 with fewer in exon 7. The clinical and biochemical outcomes in some patients are described. We also use the three-dimensional structure of the porphobilinogen deaminase enzyme to predict the possible molecular and functional consequences of the new Swedish missense and nonsense mutations.

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“…Nevertheless it still remains difficult due to the high number and the high variability in type of possible gene mutations; [in AIP, for example, to date, over 200 mutations including deletions, insertions, missense, nonsense, and splicing mutations have been identified, and most of these mutations resulted from family-specific analysis] and need to be undertaken by expert laboratories (cfr. http://www.porphyria-europe.com) [40]. To date, the exact locations for all genes responsible for the acute porphyrias have been identified, and a rapid growing knowledge in this area is expected [39].…”

Section: Diagnosismentioning

confidence: 99%

The acute porphyrias: a diagnostic and therapeutic challenge in internal and emergency medicine

2009

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The porphyrias are a heterogeneous group of metabolic diseases resulting from a variable catalytic defect of one of the eight enzymes involved in the heme biosynthesis pathway; they are mostly inherited diseases, but in some circumstances the metabolic disturbance may be acquired. The specific patterns of tissue overproduction (and hence accumulation and excretion) of toxic heme precursors, associated with each enzymatic deficiency, are responsible for the characteristic biochemical and clinical features of each of these diseases. Moreover, even in the presence of a specific inherited enzymatic defect, many different environmental factors (such as drugs, calorie restriction, hormones, sunlight exposition, infections, etc.) often play a key role in triggering the clinical expression of the various forms of porphyrias. The porphyrias are often misdiagnosed diseases, due their multiform clinical manifestations, able to mimic many other more common diseases. For this reason, many different specialists, such as surgeons, psychiatrists, gastroenterologists, neurologists, emergency physicians and dermatologists may be variably involved in the diagnostic process, especially for the forms presenting with acute and life-threatening clinical features. According to the clinical features, the porphyrias can be classified into neuropsychiatric (characterized by neurovisceral crises involving autonomic and central nervous system but also the liver and the kidney with possible consequences in terms of neurological, psychic, cardiac, respiratory, liver and kidney functions), dermatological (mostly presenting with cutaneous lesions due to photosensitivity), and mixed forms. From a strictly clinical point of view, porphyrias presenting with neurovisceral attacks are also referred as acute porphyrias: they are the object of the present review. An accurate diagnosis of acute porphyria requires knowledge and the use of correct diagnostic tools, and it is mandatory to provide a more appropriate therapeutic approach and prevent the use of potentially unsafe drugs, able to severely precipitate these diseases, especially in the presence of life-threatening symptoms. To date, availability of a relatively stable haem preparation (haem arginate) has significantly improved the treatment outcome of acute porphyric attacks, so the knowledge about the diagnosis and the management of these diseases may be relevant for physicians working in internal medicine, neurology and emergency units.

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Hematologically Important Mutations: Acute Intermittent Porphyria

Cited by 9 publications

References 56 publications

Human porphobilinogen deaminase mutations in the investigation of the mechanism of dipyrromethane cofactor assembly and tetrapyrrole formation

Human porphobilinogen deaminase mutations in the investigation of the mechanism of dipyrromethane cofactor assembly and tetrapyrrole formation

Acute intermittent porphyria in Sweden. Molecular, functional and clinical consequences of some new mutations found in the porphobilinogen deaminase gene

The acute porphyrias: a diagnostic and therapeutic challenge in internal and emergency medicine

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