Rs1800546

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 is therefore currently prone to confusion.

rs1800546 is located on chromosome 9q31.1 within the aldolase B fructose bisphosphate ALDOB gene. rs1800546 is linked to approximately 65% of hereditary fructose intolerance (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. Since this is a minus strand SNP as of GRCh38, it is an ambiguous flip prone to some confusion, but to be clear, in SNPedia the orientation for the ancestral allele of this SNP is now C, while the risk-associated allele is G. [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:
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:
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,

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.

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.

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.

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.

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.