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rs1800546

From SNPedia

Orientationminus
Stabilizedminus
Geno Mag Summary
(C;G) 3.5 Carrier for high risk of of hereditary fructose intolerance (HFI)
(G;G) 0 normal


Make rs1800546(C;C)
ReferenceGRCh38 38.1/142
Chromosome9
Position101427574
GeneALDOB
is asnp
is mentioned by
dbSNPrs1800546
ebirs1800546
HLIrs1800546
Exacrs1800546
Varsomers1800546
Maprs1800546
PheGenIrs1800546
hapmaprs1800546
1000 genomesrs1800546
hgdprs1800546
ensemblrs1800546
gopubmedrs1800546
geneviewrs1800546
scholarrs1800546
googlers1800546
pharmgkbrs1800546
gwascentralrs1800546
openSNPrs1800546
23andMers1800546
23andMe allrs1800546
SNP Nexus

SNPshotrs1800546
SNPdbers1800546
MSV3drs1800546
GWAS Ctlgrs1800546
GMAF0.003214
Max Magnitude3.5
WARNING! The orientation of this SNP was flipped from being on the FWD strand in the human genome assembly GRCh37 to being on the REV strand in assembly GRCh38, and now (August 2015) an alert SNPedia user alerted us to the fact that it has somehow flipped back to being on the FWD strand in dbSNP again, at least for the moment. This SNP is clearly prone to confusion.

23andMe has a second SNP (in addition to rs1800546) assaying this position, which is identified as i5012663.

OMIM612724
Desc
Variant0001
Relatedalso
ClinVar
Risk rs1800546(C;C)
Alt rs1800546(C;C)
Reference rs1800546(G;G)
Significance Pathogenic
Disease Hereditary fructosuria not provided
Variation info
Gene ALDOB
CLNDBN Hereditary fructosuria not provided
Reversed 1
HGVS NC_000009.11:g.104189856C>G
CLNSRC OMIM Allelic Variant
CLNACC RCV000000493.3, RCV000224056.1,



GET Evidence
ALDOB-A149P
aa_change Ala149Pro
aa_change_short A149P
impact not reviewed
qualified_impact Insufficiently evaluated not reviewed
overall_frequency 0.0034393
summary


rs1800546 is located on chromosome 9q31.1 within the aldolase B fructose bisphosphate ALDOB gene. rs1800546 is linked to approximately 65% of hereditary fructosuria (also known as fructose intolerance or HFI) cases in those of European ancestry. The incidence of HFI in those of European ancestry is estimated to be 1 in 20,000 births. HFI is an autosomal recessive condition. This SNP is an ambiguous flip prone to some confusion (see warning at top of page), but to be clear, in SNPedia the current orientation for the ancestral allele of this SNP is now G, while the risk-associated allele is C. [Note: Reports from DNA testing labs may be not be clear which strand is being reported.] Aldolase B is a critical enzyme involved in the breakdown of the sugar fructose through the glycolysis pathway. The nucleotide change results in an amino acid substitution at position 149 from alanine to proline (A149P).

CLINICAL OVERVIEW:[edit]

Aldolase B fructose bisphosphate catalyzes the reversible reaction of fructose-1-phosphate to glyceraldehyde and dihydroxyacetone-phosphate. Further conversion of these 3-carbon products allows the byproducts of fructose metabolism to enter into the glycolysis pathway. Homozygous loss of function of aldolase B leads to an inability of the body to break down fructose into byproducts for human consumption. Due to the continuation of the first step in fructose breakdown, the conversion of fructose to fructose-1-phosphate, a phosphate sink is created in these patients, in which all the available phosphate is consumed in the cell. This leads to the halt of gluconeogenesis and glycogenolysis. Symptoms usually begin at the time of weaning and include: bloating, abdominal pain, diarrhea, hypoglycemia, hyperuricemia, mental depression, jaundice, and cirrhosis that can lead to liver failure and death. Many patients display a food aversion to fructose-rich foods and practice strict avoidance of fructose-containing foods before their diagnosis. The current gold standard for testing of fructose intolerance is the hydrogen breath test, in which the patient is administered fructose in the clinical setting, and hydrogen levels are measured before and at intervals after administration of the bolus of fructose. An increase in hydrogen produced reflects the failure of the patient to absorb fructose, which is then metabolized by bacteria in the gastrointestinal system to give off hydrogen. The disadvantage of this test is that many patients respond to the fructose administration with signs of severe hypoglycemia including altered consciousness, diaphoresis, and seizures, sometimes resulting in death. Therefore, elucidation of the causes of HFI and available genetic testing can avert the extreme clinical risks associated with standard of care diagnosis. There is currently no cure for HFI, with the only treatment strict diet modifications to avoid fructose-containing foods.

RISK-ASSOCIATED SNP:[edit]

Numerous studies identify and characterize the deleterious nature of the A149P missense mutation, corresponding to rs1800546.

In 1988, Cross, et. al first described the genetic based for HFI in four patients as a G→C transversion in the coding sequence of exon 5 at position 149, resulting in an amino acid substitution of alanine to proline in a critical substrate binding region. PCR amplification revealed the A149P substitution in the proband and 4 members of the pedigree, showing the carrier status of the parents and one sibling, and the affected proband and another sibling, [PMID 3383242]

A case study of seven unrelated Italian patients with HFI was conducted in 2004 looking at the mutational spectrum within the aldolase B gene. The amplification refractory mutation system (ARMS) was used to perform sequencing of patient DNA for known and novel mutations in the aldolase B gene. The nine exons, splice junctions, and promoter region were sequenced in each patient. In contrast to American mutations, in which the two most common mutations A149P and A175D account for 85-90% of phenotypes, they account for only 65% of patients in Italians, with many more rare mutations accounting for the remainder of the genetic basis underlying HFI. [PMID 15532022]

In 2005, the structures of the wild type and mutant aldolase B were published by Malay, et. al., revealing a thermolabile mutant. The A149P mutant is reported to lose catalytic function at temperatures > 15°C, to lose tertiary structure at 33°C, and to lose its secondary structure at 45°C. The structural constraints placed by the mutant amino acid proline disrupt the secondary structure of the β-sheet, with further reaching implications for the nearby catalytic site, including the neighboring arginine at position 148 and its interactions with Glu189 and Arg303. The mutant structure was found to have only low levels of catalytic activity in vivo, with a T1/2 of 25°C, corresponding to almost no activity at body temperature of 37°C. [PMID 18541450]

In 2008, Davit-Spraul, et. al screened the molecular basis of HFI in 160 patients from 92 families by PCR-restriction. Patients for which mutations could not be found were further investigated using exon scanning and LR-PCR to search for novel mutations and deletions or insertions. In 75% of patients, the three most common mutations, including A149P, were identified. 15% of patients were found to have one A149P mutation with a rare or novel compound heterozygous mutation elsewhere in the aldolase B sequence. [PMID 15733923]

Other Selected References:

Wenzel, J. J., H. Rossmann, U. Kullmer, B. Oberman, E. Mengel, K. J. Lackner, and J. Lotz. "Chronic Diarrhea in a 5-Year-Old Girl: Pitfall in Routine Laboratory Testing with Potentially Severe Consequences." Clinical Chemistry 55.5 (2009): 1026-030. [PMID 19395441]

Cross, N. C. P., de Franchis, R., Sebastio, G., Dazzo, C., Tolan, D. R., Gregori, C., Odievre, M., Vidailhet, M., Romano, V., Mascali, G., Romano, C., Musumeci, S., Steinmann, B., Gitzelmann, R., Cox, T. M. Molecular analysis of aldolase B genes in hereditary fructose intolerance. Lancet 335: 306-309, 1990. [PMID 1967768]