Aminolaevulinate Dehydratase Porphyria in Infancy. A Clinical and Biochemical Study

Thunell, Stig; Holmberg, Lars; Lundgren, Jakob

doi:10.1515/cclm.1987.25.1.5

Cited by 36 publications

(36 citation statements)

References 24 publications

(25 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ALAD purified from various mammalian sources, including humans (30), is known to be a homo-octamer, comprising 8 identical subunits of 36,000 (1). It is interesting to specu- Fig.…”

Section: Discussionmentioning

confidence: 99%

Cloning and expression of the defective genes from a patient with delta-aminolevulinate dehydratase porphyria.

Ishida¹,

Fujita²,

Fukuda³

et al. 1992

J. Clin. Invest.

View full text Add to dashboard Cite

Cloning and expression of the defective genes for b-aminolevulinate dehydratase (ALAD) from a patient with inherited ALAD deficiency porphyria (ADP) were carried out. Cloning of cDNAs for the defective ALAD were performed from EBVtransformed lymphoblastoid cells of the proband, and nucleotide sequences were determined. Two separate point mutations resulting in a single amino acid change in each ALAD allele were identified. One, C718 -* T, termed 'Gl', occurred in the allele within the substrate-binding site, producing an Arge4 --Trp substitution; the other, G'0' --A, termed 'G2', occurred downstream of this site in the other allele, resulting in an Ala'4 Thr substitution. Using the reverse transcription-polymerase chain reaction, the mother, the brother, and the sister were shown to have the Gi defect. Expression of the G1 cDNA in Chinese hamster ovary cells produced ALAD protein with little activity; the G2 cDNA produced the enzyme with 50% normal activity. Pulse-labeling studies demonstrated that the G1 enzyme had a normal half life, while the G2 enzyme had a markedly decreased half life. These data thus define the separate point mutations in each ALAD allele, as well as the altered properties of the two enzymic proteins encoded by the mutant genes in a patient with ADP. (J.

show abstract

“…ALAD purified from various mammalian sources, including humans (30), is known to be a homo-octamer, comprising 8 identical subunits of 36,000 (1). It is interesting to specu- Fig.…”

Section: Discussionmentioning

confidence: 99%

Cloning and expression of the defective genes from a patient with delta-aminolevulinate dehydratase porphyria.

Ishida¹,

Fujita²,

Fukuda³

et al. 1992

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…AIP is a dominant porphyria due to half-normal levels of the third enzyme in the heme biosynthesis pathway. Furthermore, affected individuals with the recessive ALAD-deficient porphyria manifest chronic neurologic manifestations (20)(21)(22). Finally, asymptomatic heterozygotes for the latter porphyria develop acute lead poisoning when exposed to low levels of lead (23,24).…”

Section: Introductionmentioning

confidence: 99%

Influence of the common human delta-aminolevulinate dehydratase polymorphism on lead body burden.

Wetmur

1994

Environ Health Perspect

View full text Add to dashboard Cite

&Aminolevulinate dehydratase (ALAD) is the second enzyme in the heme biosynthesis pathway. ALAD is a zinc metalloenzyme, and its inhibition by lead substitution for zinc is one of the most sensitive indicators of blood-lead accumulation, a measure of recent lead exposure. Stoichiometry calculations indicate that a significant portion of blood lead is stored in ALAD. Human ALAD exhibits a charge polymorphism, with about 20% of Caucasians expressing the rarer ALAD2 allele. Human ALAD1 and ALAD2 cDNAs and the 16-kb ALAD gene have been cloned and sequenced. A simple polymerase chain reaction test has been established and validated for determining ALAD genotypes. Two population studies have indicated that lead-exposed individuals with the ALAD allele have blood-lead levels about 10 pg/dl greater than similarly exposed individuals carrying only the ALAD1 allele. Ongoing work is directed toward determining the biochemistry underlying the allele-specific accumulation of blood lead, and toward determining the contribution of human ALAD genotype to lead accumulation in other tissues in transgenic mouse models and to final lead deposition in bone in both mouse and man. -Environ Health Perspect 102(Suppl 3): 215-219 (1994)

show abstract

“…These results were not due to differences in water intake or anemia. This possibility was a concern since it has been shown that a low blood iron status can increase lead absorption; conversely, it has also been proposed that lead can cause anemia (Eisinger, 1978;Schifman et al, 1982;Thunell et al, 1987). In our experiments, intake of water containing lead and hematocrit measures did not show significant differences among the animals in any of our exposure protocols and thus did not produce an anemic state in the animals.…”

Section: Discussionmentioning

confidence: 55%

A Murine Model of Genetic Susceptibility to Lead Bioaccumulation

et al. 1997

View full text Add to dashboard Cite

Previous reports have shown that blood lead levels in humans are associated with a polymorphic form of (5-aminolevulinate dehydratase (ALAD), an enzyme of heme biosynthesis that binds and is inhibited by lead. We hypothesized that ALAD levels may influence the distribution and accumulation of lead in the blood and target organs. To assess this, we studied strains of mice that differ in the numbers of copies of the ALAD gene. Our findings showed that mice with a duplication of the ALAD gene (DBA) accumulated twice the amount of lead in their blood and had higher lead levels in kidney and liver than mice with a single copy of the gene (C57) exposed to the same oral doses of lead during adulthood. Hybrid animals showed intermediate blood lead levels. Levels of blood zinc protoporphyrin (ZPP) increased with lead exposure in C57 animals while they were not affected in DBA mice, suggesting protection from production of this abnormal enzyme in mice with a duplication of the gene. Except for these protective effects in the formation of ZPP in DBA animals, duplication of the ALAD gene was found to increase lead accumulation. We conclude that although these mouse strains do not precisely replicate the polymorphism observed in humans, they may be used as a model to study genetic influences in lead bioaccumulation. Understanding genetic factors that affect susceptibility to lead-induced intoxication could have important implications for public health and intervention initiatives. These mouse strains may represent a useful model for future study of the role of ALAD in lead intoxication.

show abstract

Aminolaevulinate Dehydratase Porphyria in Infancy. A Clinical and Biochemical Study

Cited by 36 publications

References 24 publications

Cloning and expression of the defective genes from a patient with delta-aminolevulinate dehydratase porphyria.

Cloning and expression of the defective genes from a patient with delta-aminolevulinate dehydratase porphyria.

Influence of the common human delta-aminolevulinate dehydratase polymorphism on lead body burden.

A Murine Model of Genetic Susceptibility to Lead Bioaccumulation

Contact Info

Product

Resources

About