Molecular mechanisms of dominant expression in porphyria

被引:59
作者
Badminton, MN [1 ]
Elder, GH [1 ]
机构
[1] Cardiff Univ, Sch Med, Dept Med Biochem & Immunol, Cardiff Porphyria Serv, Cardiff CF14 4XN, S Glam, Wales
关键词
D O I
10.1007/s10545-005-8050-3
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Partial deficiency of enzymes in the haem synthetic pathway gives rise to a group of seven inherited metabolic disorders, the porphyrias. Each deficiency is associated with a characteristic increase in haem precursors that correlates with the symptoms associated with individual porphyrias and allows accurate diagnosis. Two types of clinical presentation occur separately or in combination; acute life-threatening neurovisceral attacks and/or cutaneous symptoms. Five of the porphyrias are low-penetrance autosomal dominant conditions in which clinical expression results from additional factors that act by increasing demand for haem or by causing an additional decrease in enzyme activity or by a combination of these effects. These include both genetic and environmental factors. In familial porphyria cutanea tarda (PCTF), environmental factors that include alcohol, exogenous oestrogens and hepatotropic viruses result in inhibition of hepatic enzyme activity via a mechanism that involves excess iron accumulation. In erythropoietic protoporphyria (EPP), co-inheritance of a functional polymorphism in trans to a null ferrochelatase allele accounts for most clinically overt cases. In the autosomal dominant acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria), acute neurovisceral attacks occur in a minority of those who inherit one of these disorders. Although various exogenous (e.g. drugs, alcohol) and endogenous factors (e.g. hormones) have been identified as provoking acute attacks, these do not provide a full explanation for the low penetrance of these disorders. It seems probable that genetic background influences susceptibility to acute attacks, but the genes that are involved have not yet been identified.
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页码:277 / 286
页数:10
相关论文
共 39 条
[21]  
KAUPPINEN R, 1992, MEDICINE, V71, P1
[22]   The Human Gene Mutation Database [J].
Krawczak, M ;
Cooper, DN .
TRENDS IN GENETICS, 1997, 13 (03) :121-122
[23]   IDENTIFICATION OF THE MOST COMMON MUTATION WITHIN THE PORPHOBILINOGEN DEAMINASE GENE IN SWEDISH PATIENTS WITH ACUTE INTERMITTENT PORPHYRIA [J].
LEE, JS ;
ANVRET, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (23) :10912-10915
[24]  
Linet MS, 1999, AM J EPIDEMIOL, V149, P1010
[25]  
Meerman L, 2000, SCAND J GASTROENTERO, V35, P79
[26]   A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria [J].
Meissner, PN ;
Dailey, TA ;
Hift, R ;
Ziman, M ;
Corrigall, AV ;
Roberts, AG ;
Meissner, DM ;
Kirsch, RE ;
Dailey, HA .
NATURE GENETICS, 1996, 13 (01) :95-97
[27]   Acute porphyrias: Pathogenesis of neurological manifestations [J].
Meyer, UA ;
Schuurmans, MM ;
Lindberg, RLP .
SEMINARS IN LIVER DISEASE, 1998, 18 (01) :43-52
[28]   Self-rated psychosocial consequences and quality of life in the acute porphyrias [J].
Millward, LM ;
Kelly, P ;
Deacon, A ;
Senior, V ;
Peters, TJ .
JOURNAL OF INHERITED METABOLIC DISEASE, 2001, 24 (07) :733-747
[29]   Hepatic uroporphyrinogen decarboxylase activity in porphyria cutanea tarda patients: The influence of virus C infection [J].
Moran, MJ ;
Fontanellas, A ;
Brudieux, E ;
Hombrados, I ;
de Ledinghen, V ;
Couzigou, P ;
de Verneuil, H ;
De Salamanca, RE .
HEPATOLOGY, 1998, 27 (02) :584-589
[30]   Acute intermittent porphyria: prevalence of mutations in the porphobilinogen deaminase gene in blood donors in France [J].
Nordmann, Y ;
Puy, H ;
DaSilva, V ;
Simonin, S ;
Robreau, AM ;
Bonaiti, C ;
Phung, LN ;
Deybach, JC .
JOURNAL OF INTERNAL MEDICINE, 1997, 242 (03) :213-217