Increased prevalence of mutant null alleles that cause hereditary fructose intolerance in the American population

Abstract

Mutations in the aldolase B gene (ALDOB) impairing enzyme activity toward fructose-1-phosphate cleavage cause hereditary fructose intolerance (HFI). Diagnosis of the disease is possible by identifying known mutant ALDOB alleles in suspected patients; however, the frequencies of mutant alleles can differ by population. Here, 153 American HFI patients with 268 independent alleles were analyzed to identify the prevalence of seven known HFI-causing alleles (A149P, A174D, N334K, Δ4E4, R59Op, A337V, and L256P) in this population. Allele-specific oligonucleotide hybridization analysis was performed on polymerase chain reaction (PCR)-amplified genomic DNA from these patients. In the American population, the missense mutations A149P and A174D are the two most common alleles, with frequencies of 44% and 9%, respectively. In addition, the nonsense mutations Δ4E4 and R59Op are the next most common alleles, with each having a frequency of 4%. Together, the frequencies of all seven alleles make up 65% of HFI-causing alleles in this population. Worldwide, these same alleles make up 82% of HFI-causing mutations. This difference indicates that screening for common HFI alleles is more difficult in the American population. Nevertheless, a genetic screen for diagnosing HFI in America can be improved by including all seven alleles studied here. Lastly, identification of HFI patients presenting with classic symptoms and who have homozygous null genotypes indicates that aldolase B is not required for proper development or metabolic maintenance.

Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice

“…One patient group that suffers dire consequences from the widespread use of added sugars is individuals with hereditary fructose intolerance (HFI), an autosomal recessive disease with an incidence near 1:30,000, although the frequency may be higher due the difficulty of its diagnosis (6,7). The disease arises from a deficiency in aldolase B activity in the liver, kidney, and small intestine.…”

Mutations in the promoter region of the aldolase B gene that cause hereditary fructose intolerance

“…Both of these tests are invasive, carry significant risk, and can cause uncomfortable side effects. Less invasive methods to diagnose HFI include whole-gene sequencing or allele-specific oligonucleotide (ASO) hybridization analysis that requires only a small blood sample (Tolan and Brooks 1992; Coffee et al 2009), and requires knowledge of HFI mutations. Of the known HFI-causing mutations, seven are common and make up 82% of HFI alleles worldwide.…”

A Novel Frameshift Mutation of the ALDOB Gene in a Korean Girl Presenting with Recurrent Hepatitis Diagnosed as Hereditary Fructose Intolerance

“…These three mutations account for 68% of HFI alleles worldwide but they are common mostly in northern European populations 14. The American population shows uniquely high prevalence of two nonsense mutations, p.Δ4E4 and p.R59Op 15. Spain also shows high prevalence of Δ4E4 surpassing p.A174D, p.N334K.…”