Alternative titles; symbols
HGNC Approved Gene Symbol: ALDOB
SNOMEDCT: 20052008; ICD10CM: E74.12; ICD9CM: 271.2;
Cytogenetic location: 9q31.1 Genomic coordinates (GRCh38) : 9:101,420,560-101,435,774 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q31.1 | Fructose intolerance, hereditary | 229600 | Autosomal recessive | 3 |
Fructose-1,6-bisphosphate aldolase (EC 4.1.2.13) is a glycolytic enzyme that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. The enzyme is a tetramer of identical 40-kD subunits. Vertebrates have 3 aldolase isozymes, aldolase A (103850), B (ALDOB), and C (ALDOC; 103870), which are distinguished by their electrophoretic and catalytic properties. The sequence of the aldolases around the active-site lysine is highly conserved in evolution. Mammalian tissues express aldolase isozymes in a well-characterized pattern. Developing embryo produces aldolase A, which continues to be expressed in many adult tissues, sometimes at much higher levels than in embryo. In adult muscle, aldolase A can be as much as 5% of total cellular protein. In adult liver, kidney, and intestine, aldolase A expression is repressed and aldolase B is produced. In brain and other nervous tissue, aldolase A and C are expressed about equally. In transformed liver cells, aldolase A replaces aldolase B (Rottmann et al., 1984).
Rottmann et al. (1984) identified several aldolase B gene clones from a human liver cDNA library by using a rabbit aldolase A cDNA as a hybridization probe. The deduced protein contains 364 residues.
Hibi et al. (1986) isolated a monoclonal antibody from a human hybridoma clone and presented evidence showing that liver-type aldolase B was the antigen recognized by said human antibody.
The ALDOB gene contains 9 exons, the first of which is untranslated (Tolan and Penhoet, 1986).
Using a method for rapid gene mapping by dual laser chromosome sorting and spot-blot DNA analysis, Lebo et al. (1984) assigned aldolase B to chromosome 9.
For localization of the gene to chromosome 9, Henry et al. (1985) used a cloned cDNA probe for ALDOB and Southern blotting techniques to analyze DNA from rodent-human somatic cell hybrids. Study of gene dosage in 2 patients with unbalanced rearrangements involving chromosome 9 and in situ hybridization indicated localization to 9q13-q32, most probably to 9q21.3-q22.2.
Pilz et al. (1993) mapped the mouse homolog of the ALDOB gene to chromosome 4.
The homolog of the alpha-1-microglobulin gene (AMBP; 176870) and the PAX5 gene (167414), which are also on chromosome 9 in the human, were found to map to mouse chromosome 4.
Pseudogene
Lebo (1986) found that the aldolase pseudogene, which is located on 10q, has flanking sequences resembling those of ALDOB (on chromosome 9) and other sequences resembling the coding segments of ALDOA (103850), which Lebo (1986) mapped to chromosome 16.
Munnich et al. (1985) demonstrated that the B isoform of aldolase in the liver is under dietary control. Ingestion of a fructose diet induces ALDOB mRNA expression in the liver, which is otherwise low in resting, or fasting, conditions. Studies in animals indicated that aldolase B expression in the liver was under hormonal control by cortisone, thyroid hormones, insulin, and glucagon. Gene expression in the kidney and intestine was not as sensitive to hormonal manipulation.
In affected individuals from several unrelated families with hereditary fructose intolerance (HFI; 229600), Cross et al. (1988) identified homozygosity for a mutation in the ALDOB gene (A149P; 612724.0001). The findings indicated that this mutation may be a common cause of the disorder.
Cross and Cox (1990) identified deletions in the aldolase B gene in patients with fructose intolerance. Two were large deletions of 1.65 kb and 1.4 kb, respectively, whereas the third was a small 4-bp deletion (612724.0004).
Tolan (1995) reviewed 21 ALDOB mutations that had been reported to that time; 15 were single-base substitutions, resulting in 9 amino acid replacements, 4 nonsense codons, and 2 putative splicing defects, and the other 6 were deletions. Recurrent mutations were observed in exons 5 and 9.
Rellos et al. (2000) described the biochemical and biophysical characterization of 7 natural human aldolase B variants, identified in patients with hereditary fructose intolerance and expressed as recombinant proteins in E. coli, from which they were purified to homogeneity. The mutant aldolases were all missense variants and could be classified into 2 principal groups: catalytic mutants, with retained tetrameric structure but altered kinetic properties (e.g., W147R (612724.0012), R303W, and A337V), and structural mutants, in which the homotetramers readily dissociate into subunits with greatly impaired enzymatic activity (e.g., A174D (612724.0002) and N334K (612724.0006)). The results suggested that the integrity of the quaternary structure of aldolase B is critical for maintaining its full catalytic function.
Esposito et al. (2002) found that recombinant proteins carrying the W147R mutation or the N334K mutation showed significantly reduced catalytic efficiency, and those carrying the A149P (612724.0001) mutation resulted in an inactive protein. Recombinant aldolase B enzymes carrying the A174D mutation or the 6-bp deletion in exon 6 (612724.0011) could not be recovered in soluble form, suggesting loss of overall structural integrity.
Among 162 patients from 92 families with hereditary fructose intolerance, Davit-Spraul et al. (2008) identified 16 different mutations in the ALDOB gene, including 8 novel mutations. Most of the patients were French. The most common mutations were A149P (64%), A174D (612724.0002) (16%), and N335K (612724.0006) (5%). Screening for these 3 mutations alone confirmed the diagnosis in 69 (75%) of 92 probands.
Oppelt et al. (2015) found that the phenotype of Aldo2-null mice is a phenocopy of hereditary fructose intolerance. The null mice showed failure to thrive and liver dysfunction that was exacerbated by fructose ingestion. Livers of Aldo2-null mice exhibited rapid onset of hepatic steatosis that could be reversed by removal of fructose from the diet.
Cross et al. (1988) reported the first identification of a molecular lesion in the ALDOB gene in hereditary fructose intolerance (HFI; 229600). A G-to-C transversion in exon 5 of the ALDOB gene created a new recognition site for the restriction enzyme AhaII and resulted in an ala149-to-pro (A149P) substitution within a region critical for substrate binding. Utilizing this novel restriction site and the polymerase chain reaction (PCR), Cross et al. (1988) showed that the patient was homozygous. Three other patients with hereditary fructose intolerance unrelated to the original patient were found to have the same mutation; 2 were homozygous and 1 was compound heterozygous with another mutation in the ALDOB gene.
Cross and Cox (1989) used allele-specific oligonucleotide probes to detect the A149P mutation in other pedigrees. They found the same mutation in all 12 British patients examined. Diagnosis of both homozygotes and heterozygotes could be achieved by specific amplification of DNA derived from mouthwash samples followed by hybridization to allele-specific oligonucleotides.
In a study of patients with fructose intolerance drawn widely from Europe and the U.S., Cross et al. (1990) found the A149P mutation in 67% of alleles tested. The mutation was significantly more common in patients from northern than from southern Europe.
Brooks and Tolan (1993) studied the possible origin of the A149P mutation, which accounts for 57% of fructose intolerance chromosomes. In 15 homozygotes they found absolute linkage disequilibrium between the A149P mutation and a particular 2-site RFLP, suggesting a single origin and founder effect.
Dursun et al. (2001) screened 13 Turkish patients with hereditary fructose intolerance for 3 common mutations. Nine of the patients were homozygous for the A149P mutation, which corresponded to a frequency of about 55%.
Davit-Spraul et al. (2008) identified the A149P mutation, which they referred to as ALA150PRO (A150P), in 64% of mutant alleles from 162 patients from 92 families with hereditary fructose intolerance. Most of the patients were French.
Cross et al. (1990) identified an ala174-to-asp (A174D) substitution in the ALDOB gene in patients with hereditary fructose intolerance (HFI; 229600) from Italy, Switzerland, and Yugoslavia (overall frequency, 16%), but not in those from the United Kingdom, France, or the United States.
Davit-Spraul et al. (2008) identified the A174D mutation, which they referred to as ALA175ASP (A175D), in 16% of mutant alleles from 162 patients from 92 families with hereditary fructose intolerance.
In Sicilian patients with fructose intolerance (HFI; 229600) Cross et al. (1990) found a 1-bp deletion in codon 288 of the ALDOB gene, resulting in a frameshift and premature termination (L288delC). They estimated that screening for certain ALDOB mutations (612724.0001-612724.0003) with a limited number of allele-specific oligonucleotides would pick up more than 95% of cases of fructose intolerance.
In a patient with fructose intolerance (HFI; 229600), Dazzo and Tolan (1990) found compound heterozygosity for 2 mutations in the ALDOB gene: the common A149P mutation (612724.0001) and a 4-bp deletion in exon 4, causing a frameshift at codon 118 and a truncated protein of 132 amino acids.
In a patient with fructose intolerance (HFI; 229600), Kajihara et al. (1990) identified a homozygous 720C-A transversion in the ALDOB gene, resulting in a cys240-to-ter (C240X) substitution. Expression studies in E. coli showed that the mutation directly affected the function of the enzyme.
In 4 unrelated Yugoslavian patients with hereditary fructose intolerance (HFI; 229600) , Cross et al. (1990) identified a G-to-C transversion in exon 9 of the ALDOB gene, resulting in an asn334-to-lys (N334K) substitution. The mutation was present in homozygous state in 1 patient and compound heterozygous state in the other 3. Cross et al. (1990) also identified this mutation in compound heterozygous state in an Austrian and a British patient with fructose intolerance.
Sebastio et al. (1991) identified the N334K mutation in 11 unrelated Italian patients with hereditary fructose intolerance.
Davit-Spraul et al. (2008) identified the N334K mutation, which they referred to as an N335K mutation caused by a 1005C-G transversion in exon 9, in 5% of mutant alleles from 162 patients from 92 families with hereditary fructose intolerance. It was the third most common mutant allele identified in their study. Most of the patients were Turkish immigrants to Europe, suggesting that the mutation is more common in southeast Europe.
In a patient with fructose intolerance (HFI; 229600), Brooks et al. (1991) found compound heterozygosity for 2 mutations in the ALDOB gene: the common A149P substitution (612724.0001) and a 7-bp deletion/1-bp insertion at the 3-prime splice site of intron 8. They found the second mutation by amplification of the 8 protein-coding ALDOB exons, including splicing signals, by PCR, followed by dot-blot hybridization of the amplified DNA with allele-specific oligonucleotide (ASO) probes,
In affected members of a consanguineous family from eastern Turkey with fructose intolerance (HFI; 229600), Ali et al. (1994) identified a homozygous C-to-T transition in the ALDOB gene, resulting in an arg3-to-ter (R3X) substitution. The authors referred to the mutation as R3op.
In an Austrian woman with fructose intolerance (HFI; 229600) who was known to have 1 copy of the East European N334K mutation (612724.0006), Ali et al. (1994) found that the other allele had a C-to-T transition, resulting in an arg59-to-ter (R59X) substitution.
In a French patient with fructose intolerance (HFI; 229600) who was known to be heterozygous for an A174D mutation (612724.0002), Ali et al. (1994) also found a heterozygous G-to-A transition in the last base of intron 6, thereby altering the 3-prime splice acceptor site. This and the other 2 mutations reported by Ali et al. (1994) (612724.0008-612724.0009) were readily detected in the amplification refractory mutation system.
In a 6-year-old patient with hereditary fructose intolerance (HFI; 229600), Santamaria et al. (1999) detected a 6-bp deletion in exon 6 of the aldolase B gene that led to elimination of 2 amino acid residues, leu182 and val183, but left the message in-frame. On the other allele, the patient carried the asn334-to-lys mutation (see 612724.0006). The 3-dimensional structural alterations induced in the enzyme by the 6-bp deletion were elucidated by molecular graphics analysis using crystal structure of the rabbit muscle aldolase as a reference model. These studies showed that the elimination of leu182 and val183 perturbs the correct orientation of adjacent catalytic residues such as lys146 and glu187.
In 1 member of a kindred affected by hereditary fructose intolerance (HFI; 229600), Ali and Cox (1995) identified compound heterozygosity for a 4-bp deletion in exon 4 of the ALDOB gene (612724.0004) and a T-to-C transition in exon 5, which resulted in a trp147-to-arg (W147R) mutation. The W147R mutation was not detected in other affected members of the kindred or in more than 100 unrelated disease alleles.
In 6 unrelated Italian patients with hereditary fructose intolerance (HFI; 229600), Esposito et al. (2010) identified a 6.5-kb deletion in the ALDOB gene, resulting in the deletion of exons 2 to 6 and a null allele. All patients had the 6.5-kb deletion in compound heterozygosity with another pathogenic ALDOB allele. Analysis of the breakpoints indicated that the deletion was mediated by repetitive DNA sequences, but the authors could not rule out a founder effect.
In a patient with fructose intolerance (HFI; 229600), Esposito et al. (2010) identified a heterozygous 136A-T transversion in exon 3 of the ALDOB gene, resulting in an arg46-to-trp (R46W) substitution in a conserved residue. The mutation was not found in 300 control alleles. A second mutation or deletion in the ALDOB gene was excluded, indicating that the patient was heterozygous for the mutation. The patient had mild hypoglycemia and ketosis after ingestion of fructose and a marked aversion to sweets and fruit. In vitro functional expression assays showed that the R46W variant had 14-fold lower catalytic efficiency for fructose-1-phosphate compared to wildtype, with no apparent change for fructose bisphosphate. Structural analysis showed that the arg46 residue is far from the tetramer interface and has structural flexibility, but loss of the positively charged arg46 residue may alter binding of fructose-1-phosphate. The report emphasized that heterozygous ALDOB mutations may result in symptoms in some patients.
In a patient with fructose intolerance (HFI; 229600), Esposito et al. (2010) identified a heterozygous 1027T-C transition in exon 9 of the ALDOB gene, resulting in tyr343-to-his (Y343H) substitution in a conserved residue in the highly flexible C terminus. The mutation was not found in 300 control alleles. A second mutation or deletion in the ALDOB gene was excluded, indicating that the patient was heterozygous for the mutation. At age 8 months, the patient was hospitalized for a series of febrile episodes associated with severe liver dysfunction. She died 1 month later from unknown causes. In vitro functional expression studies showed that the Y343H variant had significantly decreased activity toward fructose-1-phosphate at high temperatures, suggesting structural perturbation. The report emphasized that heterozygous ALDOB mutations may result in symptoms in some patients.
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