Alternative titles; symbols
HGNC Approved Gene Symbol: ALAD
SNOMEDCT: 64081000;
Cytogenetic location: 9q32 Genomic coordinates (GRCh38): 9:113,386,312-113,401,284 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q32 | {Lead poisoning, susceptibility to} | 612740 | Autosomal recessive | 3 |
| Porphyria, acute hepatic | 612740 | Autosomal recessive | 3 |
The ALAD gene encodes delta-aminolevulinate dehydratase, also known as porphobilinogen synthase (PBGS; EC 4.2.1.24), a cytosolic enzyme that catalyzes the second step in the porphyrin and heme biosynthetic pathway. It forms the monopyrrole ring porphobilinogen from 2 molecules of delta-aminolevulinate (ALA) (Ishida et al., 1992).
Wetmur et al. (1986) identified 2 cDNAs encoding ALAD which they claimed represented the first report of a cDNA clone for a human heme biosynthetic enzyme. They found that the nucleotide sequences of the 2 cDNA clones differed at either position 730 or 733 and encoded 2 different charged amino acids, which was likely the basis for the polymorphic charged isozymes of human ALAD.
Kaya et al. (1994) determined that the ALAD gene spans 15.9 kb and contains 2 alternative noncoding exons, 1A and 1B, and 11 coding exons, 2 through 12. The housekeeping transcript, which includes exon 1A and not 1B, was identified in a human adult liver cDNA library, while an erythroid-specific transcript, which contains exon 1B and not 1A, was detected in a human erythroleukemia cDNA library. The promoter region upstream of housekeeping exon 1A was GC-rich and contained 3 potential Sp1 elements and a CCAAT box. Further upstream, there were 3 potential GATA-1 binding sites and an AP1 site. The promoter region upstream of erythroid-specific exon 1B had several CACCC boxes and 2 potential GATA-1 binding sites. Kaya et al. (1994) transduced HeLa and K562 cells with chloramphenicol acetyltransferase (CAT) constructs containing either exon 1A or 1B. Those containing exon 1A were expressed in HeLa cells, whereas the erythroid-specific construct containing exon 1B was not. In contrast, the housekeeping and erythroid constructs were both expressed in erythroleukemia cells.
In linkage studies, Amorim et al. (1982) excluded linkage of the ALAD gene with MNSs, Fy, Jk, Rh, HLA, ACP1, and PGM1. Close linkage (theta 0.05 or less) was also excluded for K, PI, GPT, PGP, PGM3, GLO, and BF. Haptoglobin showed a lod score of 0.922 at theta of 0.20 or less.
Eiberg et al. (1983) demonstrated linkage of ALAD to the ABO-AK1-ORM linkage group on chromosome 9q. The most likely sequence was judged to be ABO-AK1-ALADH-ORM. The lod and recombination values were as follows: ABO-AK1 (6.27, 0.13); ABO-ALADH (5.38, 0.21); ABO-ORM (5.06, 0.27); AK1-ORM (1.63, 0.17); ALADH-ORM (7.05, 0.13) and AK1-ALADH (2.45, 0.11).
Amorim et al. (1984) presented data supporting the chromosome 9 assignment in man. Beaumont et al. (1984) assigned ALAD to chromosome 9 by somatic cell hybrid studies. They used two enzyme assays: one specific for the human enzyme and one indicative of both rodent and human enzymes. The ratio of the values was used to discriminate between positive and negative clones. Wang et al. (1984) assigned the ALAD gene to 9q by study of human-mouse somatic cell hybrids with methods that specifically distinguished the mouse and human enzymes. Potluri et al. (1987) localized ALAD to 9q34 by in situ hybridization using a radio-iodine-labeled human ALAD cDNA.
In connection with a pulsed field gel electrophoresis analysis of the 9q32-q34 region, which contains a gene for tuberous sclerosis-1 (191100), Harris et al. (1993) found that the ALAD locus was the most proximal of the genes they studied.
ALADH is linked to ACO1 (100880) and GALT (606999) in the mouse (Nadeau and Eicher, 1982).
Battistuzzi et al. (1981) described electrophoretic polymorphisms of aminolevulinate dehydratase, and showed that the enzyme is encoded by an autosomal gene with 2 common codominant alleles (frequencies, 0.94 and 0.06). Petrucci et al. (1982) studied the polymorphism of ALADH in Italy.
Kapotis et al. (1998) found that the frequencies of the ALADH1 and ALADH2 alleles in Greece are 0.955 and 0.0455, respectively. Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
In a Swedish boy with severe infantile onset of acute hepatic porphyria (612740), Plewinska et al. (1991) identified compound heterozygosity for 2 mutations in the ALAD gene (125270.0001 and 125270.0002). ALAD activity in erythrocytes was less than 5% of control values.
ALAD porphyria is a rare autosomal recessive disorder documented, at the time of the report of Jaffe and Stith (2007), in only 5 patients, all compound heterozygotes for mutations in the ALAD gene. The human PBGS enzyme exists as an equilibrium of functionally distinct quaternary structure assemblies, known as 'morpheeins,' in which one functional homo-oligomer can dissociate, change conformation, and reassociate into a different oligomer. In the case of human PBGS, the 2 assemblies are a high-activity octamer and a low-activity hexamer. Jaffe and Stith (2007) quantified the morpheein forms of human PBGS for the common and porphyria-associated variants. Heterologous expression in E. coli, followed by separation of the octameric and hexameric assemblies on an ion-exchange column, showed that the percentages of hexamers for F12L (125270.0006) (100%), R240W (125270.0004) (80%), G133R (125270.0001) (48%), A274T (125270.0005) (14%), and 2 other variants were appreciably larger than for the wildtype proteins K59 and N59 (see 125270.0003) (0% and 3%, respectively). All 8 porphyria-associated variants showed an increased propensity to form the hexamer, according to a kinetic analysis. Thus, all porphyria-associated human PBGS variants shift the morpheein equilibrium for PBGS toward the less active hexamer. Jaffe and Stith (2007) proposed that the disequilibrium of morpheein 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.
In a Swedish boy with severe infantile-onset of acute hepatic porphyria (612740) previously reported by Fujita et al. (1987), Plewinska et al. (1991) identified compound heterozygosity for 2 mutations in the ALAD gene: a 397G-A transition in exon 5 resulting in a gly133-to-arg (G133R) substitution inherited from the mother, and an 823G-A transition in exon 11 resulting in a val275-to-met (V275M; 125270.0002) substitution inherited from the father. Both mutations occurred at CpG dinucleotides. The G133R substitution occurred at the carboxyl end of the highly conserved zinc-binding site in the enzyme subunit. The mutations resulted in markedly reduced enzyme activity at less than 5% of normal values. The couple had experienced 4 successive spontaneous abortions (Fujita et al., 1987).
For discussion of the val275-to-met (V275M) mutation in the ALAD gene that was found in compound heterozygous state in a patient with severe infantile-onset of acute hepatic porphyria (612740) by Plewinska et al. (1991), see 125270.0001.
Expression of the 2 common alleles, ALAD*1 (p = 0.9) and ALAD*2 (q = 0.1), results in a polymorphic enzyme system with 3 isozymes of distinct charge, designated 1-1, 1-2, and 2-2. Individuals heterozygous (2pq = 0.18) or homozygous (frequency = 0.01) for the ALAD*2 allele had significantly higher blood lead levels than did ALAD*1 homozygotes, when exposed to low or high levels of lead in the environment. Wetmur et al. (1991) found that the only difference in the ALAD*2 cDNA as compared with the ALAD*1 sequence was a G-to-C transversion of nucleotide 177 in the coding region. The change created an MspI restriction site. This base substitution predicted the replacement of a positively charged lysine by a neutral asparagine (K59N), an amino acid change consistent with the more electronegative charge of the ALAD-2 subunit. The rapid and accurate determination of the ALAD genotype permits molecular-based screening of populations to identify individuals who are genetically more susceptible to lead poisoning.
In a patient with delta-aminolevulinate dehydratase porphyria (612740) previously reported by Doss et al. (1979) and Sassa et al. (1991), Ishida et al. (1992) identified compound heterozygosity for 2 mutations in the ALAD gene: a 718C-T transition resulting in an arg240-to-trp (R240W) substitution within the substrate-binding site, and an 820G-A transition resulting in an ala274-to-thr (A274T; 125270.0005) substitution. Functional expression studies in Chinese hamster ovary cells showed that the R240W mutant enzyme had little activity, whereas the A274T mutant enzyme had about 50% residual activity. Pulse-labeling studies demonstrated that the R240W enzyme had a normal half-life, whereas the other enzyme had a markedly decreased half-life. Although the proband had severe porphyric symptoms, other members of the family displayed no symptomatology even though ALAD activity was half-normal. The fact that the patient survived may be due to the residual activity contributed by the A274T enzyme. A more marked deficiency may not have been compatible with life.
For discussion of the ala274-to-thr (A274T) mutation in the ALAD gene that was found in compound heterozygous state in a patient with delta-aminolevulinate dehydratase porphyria (612740) by Ishida et al. (1992), see 125270.0004.
In a 23-year-old Caucasian man with porphyria where both coproporphyrinogen (121300) and ALAD deficiencies (612740) were demonstrated at the molecular level, Akagi et al. (2006) detected a heterozygous 36C-G transversion in exon 2 of the ALAD gene that caused a substitution of leucine for phenylalanine at codon 12 (F12L). Akagi et al. (1999) had described this mutation in heterozygosity in an asymptomatic Swedish girl and showed it to result in an ALAD protein with no enzyme activity. Nucleotide sequence analysis of CPOX cDNA revealed a novel mutation resulting in a missense amino acid change (612732.0013).
In a 17-year-old German boy with acute ALAD-deficient porphyria (612740), Doss et al. (2004) identified compound heterozygosity for 2 mutations in intron 3 of the ALAD gene: a C-to-A transversion and a C-to-T transition (125270.0008), both at -11 bp upstream of the exon 3 start site, and predicted to result in altered splicing. Each unaffected parent was heterozygous for 1 of the mutations. The patient had abdominal pain, polyneuropathy, and ALAD activity at about 10% of normal control values.
For discussion of the splice site mutation in the ALAD gene that was found in compound heterozygous state in a patient with acute ALAD-deficient porphyria (612740) by Doss et al. (2004), see 125270.0007.
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