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

  title={Novel molecular defects of the $\delta$‐aminolevulinate dehydratase gene in a patient with inherited acute hepatic porphyria},
  author={Reiko Akagi and Ryo Shimizu and Kazumichi Furuyama and Manfred O. Doss and Shigeru Sassa},
Cloning and expression of the defective gene for δ‐aminolevulinate dehydratase (ALAD) from the second of 2 German patients with ALAD deficiency porphyria (ADP), who had been originally reported by Doss et al. in 1979, were performed. Cloning of cDNAs for the defective ALAD were performed using Epstein‐Barr virus (EBV)‐transformed lymphoblastoid cells of the proband, and nucleotide sequences of cloned cDNA were determined. Two separate mutations of ALAD cDNA were identified in each ALAD allele… 

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.

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.

Survival of two patients with severe δ-aminolaevulinic acid dehydratase deficiency porphyria

Urinary excretions of δ-aminolaevulinic acid and coproporphyrin III were excessively increased in the two patients with compound-heterozygous δ -aminola Evulinic Acid dehydratase deficiency porphyria.

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.

Single Amino Acid Mutations Alter the Distribution of Human Porphobilinogen Synthase Quaternary Structure Isoforms (Morpheeins)*

The structures of human PBGS morpheeins are analyzed for key interactions that would be predicted to affect the oligomeric assembly, and the metastable nature of the R240A hexamer supports the hypothesis that octameric and hexameric morphheeins of PBGS are very close in energy.

Heme biosynthesis and the porphyrias.

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

Heme biosynthesis and the porphyrias

Porphyria cutanea tarda (PCT) is the only porphyria that has both genetic and/or environmental factors that lead to reduced activity of uroporphyrinogen decarboxylase in the liver.


The case of a male patient with at least two possible causes for his symptoms, the diagnostic process and the outcome of Delta-aminolevulinic acid dehydratase porphyria is presented.

Porphyrias in Japan: Compilation of All Cases Reported through 2002

This survey revealed the difficulty of diagnosing porphyria in the absence of specific laboratory testing for por-phyrins and their precursors in urine, stool, plasma, and erythrocyte samples, and that as many as 71% of acute hepatic porphyrias cases were initially diagnosed as nonporphyria and later revised or corrected to porphyira.



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.

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

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

5-Aminolevulinic acid dehydratase deficiency porphyria: a twenty-year clinical and biochemical follow-up.

Incubation of erythrocyte lysates with ALA decreased porphyrin formation, whereas incubation with porphobilinogen produced p Morphyrin concentrations within reference values in both patients, confirming that ALAD activity is rate-limiting in these cells.

Hereditary hepatic porphyria due to homozygous δ‐aminolevulinic acid dehydratase deficiency: studies in lymphocytes and erythrocytes

Abstract. Activities of δ‐aminolevulinic acid (ALA) dehydratase and porphobilinogen (PBG) deaminase, and haem content were determined in EB‐virus transformed lymphocytes from two patients with

Human delta-aminolevulinate dehydratase: nucleotide sequence of a full-length cDNA clone.

Two cDNAs encoding human delta-aminolevulinate dehydratase (ALA-D) were identified, recloned into bacteriophage M13, and sequenced by primer extension, finding a cysteine- and histidine-rich binding site for zinc and an unusual region of charge complementarity surrounding the active lysine residue in the catalytic site.

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.

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.

Inherited deficiency of delta-aminolevulinic acid dehydratase.

Intial experiments support the hypothesis that the mutation in this family with an inherited deficiency of red cell ALA-D activity occurring over three generations may affect a regulatory gene, but enzyme purification and further study are required.

delta-Aminolevulinate dehydratase in human erythroleukemia cells: an immunologically distinct enzyme.

Findings indicate that ALA dehydratase in K562 cells is immunologically distinct from the normal enzyme.