A novel mutation of δ‐aminolaevulinate dehydratase in a healthy child with 12% erythrocyte enzyme activity

  title={A novel mutation of $\delta$‐aminolaevulinate dehydratase in a healthy child with 12\% erythrocyte enzyme activity},
  author={Reiko Akagi and Yumiko Yasui and Pauline Harper and Shigeru Sassa},
  journal={British Journal of Haematology},
Cloning, expression and phenotype studies of the defective gene for δ‐aminolaevulinate dehydratase (ALAD) in a family with an asymptomatic girl who had ALAD deficiency were carried out. The proband was identified by neonatal ALAD screening, and had erythrocyte ALAD activity at 12% of the normal control. She was heterozygous for ALAD deficiency, which was inherited from her father. Nucleotide sequence analysis of the cloned ALAD cDNA revealed C36 to G and T168 to C mutations on the same allele… 

Novel molecular defects of the δ‐aminolevulinate dehydratase gene in a patient with inherited acute hepatic porphyria

Cloning and expression of the defective gene for δ‐aminolevulinate dehydratase (ALAD) from the second of 2 German patients with ALAD deficiency porphyria (ADP) demonstrate that the proband was associated with 2 novel molecular defects of the ALAD gene and account for the extremely low ALAD activity in his erythrocytes.

Molecular analysis of delta-aminolevulinate dehydratase deficiency in a patient with an unusual late-onset porphyria.

Findings indicate that while the proband was heterozygous for ALAD deficiency, the G(397) to A transition resulting in the G133R substitution is responsible for ADP, and the clinical porphyria developed presumably due to an expansion of the polycythemic clone in erythrocytes that carried the mutant alad allele.

Dual gene defects involving δ‐aminolaevulinate dehydratase and coproporphyrinogen oxidase in a porphyria patient

This patient represents the first case of porphyria where both CPO and ALAD deficiencies were demonstrated at the molecular level, and a novel nucleotide transition G835→C, resulting in an amino acid change, G279R.

Highly heterogeneous nature of delta-aminolevulinate dehydratase (ALAD) deficiencies in ALAD porphyria.

This study represents the first complete analysis of 9 mutants of ALAD identified in ADP and indicates the highly heterogeneous nature of mutations in this disorder.

Co-synthesis of Human δ-Aminolevulinate Dehydratase (ALAD) Mutants with the Wild-type Enzyme in Cell-free System—Critical Importance of Conformation on Enzyme Activity—

Findings indicate that cell-free synthesis of ALAD proteins reflects enzymatic activities found in patients, and suggest that, in addition to the direct effect of mutations on the catalytic activity, conformational effects play an important role in determining enzyme activity.

ALAD porphyria is a conformational disease.

It is proposed that the disequilibrium of morphheein assemblies broadens the definition of conformational diseases beyond the prion disorders and that ALAD porphyria is the first example of a morpheein-based conformational disease.

The third case of Doss porphyria (δ-amino-levulinic acid dehydratase deficiency) in Germany

It is suggested that the observed compound heterozygosity of the ALAD gene may be responsible for Doss porphyria in the proband, which is now almost free of clinical symptoms.

5-Aminolaevulinic Acid Dehydratase, Porphobilinogen Deaminase and Uroporphyrinogen III Synthase

X-ray structures of the enzyme from humans and a thermophilic bacterium have enabled models of the catalytic process to be proposed, and current proposals involve the binding of both substrate moieties by formation of Schiff bases with two invariant active site lysine residues.

Heme biosynthesis and the porphyrias.

  • J. Phillips
  • Medicine, Biology
    Molecular genetics and metabolism
  • 2019



delta-Aminolevulinate dehydratase deficient porphyria: identification of the molecular lesions in a severely affected homozygote.

Both missense mutations resulted in the synthesis of enzyme subunits such that the activity of the homooctameric enzyme was markedly reduced, thereby causing the severe infantile-onset phenotype in the affected homozygote.

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

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, are defined.

δ‐aminolevulinic acid dehydrase (porphobilinogen synthase) in two families with inherited enzyme deficiency

Quantitative assays and the segregation pattern in both families suggest a 3‐allele‐system for the inheritance of ALA‐D deficiency, compatible with a single normal allele in heterozygotes responsible for enzyme activity.

Human delta-aminolevulinate dehydratase (ALAD) gene: structure and alternative splicing of the erythroid and housekeeping mRNAs.

Genomic clones containing human delta-aminolevulinate dehydratase (ALAD), the second enzyme in the heme pathway, were isolated and the entire sequence was determined in both orientations, finding an inverted repeat that may have resulted from gene conversion.

Aminolaevulinate Dehydratase Porphyria in Infancy. A Clinical and Biochemical Study

  • S. ThunellL. HolmbergJ. Lundgren
  • Medicine
    Journal of clinical chemistry and clinical biochemistry. Zeitschrift fur klinische Chemie und klinische Biochemie
  • 1987
Homozygous deficiency of aminolaevulinate dehydratase (porphobilinogen synthase, EC was diagnosed in a small child with recurrent attacks of pain, vomiting, hyponatraemia and symptoms of polyneuropathy engaging motor functions including respiration.

Biochemical Diagnosis of an Hereditary Aminolaevulinate Dehydratase Deflciency in a 63-Year-Old Man

Porphyrin metabolism was investigated in a 63-year-old male patient who developed a subacute onset polyneuropathy with predominance of motor signs in the upper limb, which revealed the existence of several heterozygous members in this family.

Hereditary tyrosinemia and the heme biosynthetic pathway. Profound inhibition of delta-aminolevulinic acid dehydratase activity by succinylacetone.

Findings indicate that tyrosinemia is a disorder of special pharmacogenetic interest because succinylacetone profoundly inhibits heme biosynthesis in normal cells through a blockade at the ALA dehydratase level, leading to clinical and metabolic consequences that mimic another genetic disease, AIP.

On the enzymic defects in hereditary tyrosinemia.

It is suggested that the severe liver and kidney damage in hereditary tyrosinemia may be due to the accumulation of these tyrosine metabolites and that the primary enzyme defect in hereditary Tyrosinema may be decreased activity of fumarylacetoacetase.

X-ray structure of 5-aminolaevulinate dehydratase, a hybrid aldolase

Lead ions, which inhibit ALAD potently, replace the zinc bound to the enzyme's unique triple-cysteine site and therefore represents an intriguing combination of both metallo- and Schiff base-aldolases.

Crystallization of 5‐aminolaevulinic acid dehydratase from Escherichia coli and Saccharomyces cerevisiae and preliminary X‐ray characterization of the crystals

High resolution synchrotron data sets were obtained from both E. coli and yeast ALAD crystals by cryocooling to 100 K and the best crystals were obtained in the presence of the covalently bound inhibitor laevulinic acid.