A genetic polymorphism in the coding region of the gastric intrinsic factor gene (GIF) is associated with congenital intrinsic factor deficiency

Abstract

Congenital intrinsic factor (IF) deficiency is a disorder characterized by megaloblastic anemia due to the absence of gastric IF (GIF, GenBank NM_005142) and GIF antibodies, with probable autosomal recessive inheritance. Most of the reported patients are isolated cases without genetic studies of the parents or siblings. Complete exonic sequences were determined from the PCR products generated from genomic DNA of five affected individuals. All probands had the identical variant (g.68A>G) in the second position of the fifth codon in the coding sequence of the gene that introduces a restriction enzyme site for Msp I and predicts a change in the mature protein from glutamine(5) (CAG) to arginine(5) (CGG). Three subjects were homozygous for this base exchange and two subjects were heterozygous, one of which was apparently a compound heterozygote at positions 1 and 2 of the fifth codon ([g.67C>G] + [g.68A>G]). The other patient, heterozygous for position 2, had one heterozygous unaffected parent. Most parents were heterozygous for this base exchange, confirming the pattern of autosomal recessive inheritance for congenital IF deficiency. cDNA encoding GIF was mutated at base pair g.68 (A>G) and expressed in COS-7 cells. The apparent size, secretion rate, and sensitivity to pepsin hydrolysis of the expressed IF were similar to native IF. The allelic frequency of g.68A>G was 0.067 and 0.038 in two control populations. This sequence aberration is not the cause of the phenotype, but is associated with the genotype of congenital IF deficiency and could serve as a marker for inheritance of this disorder.

Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene

“…This analysis resulted in an observed allele frequency of 11.9% for the c.68G allele compared with 6.7% among 30 German newborns and 3.8% among 131 Spanish newborns as reported in ref. 24. Although the observed differences in frequency are likely just variations between populations, our results suggest that homozygosity for the c.68G polymorphism has no clinical significance in IFD.…”

Advances in the understanding of cobalamin assimilation and metabolism

“…A number of other single mutations leading to loss of function and polymorphisms have been identified (Tanner et al , 2005). Polymorphism in exon 1 (Q5R) was reported in four patients with low IF (Gordon et al , 2004). However, a larger study has identified this polymorphism at a frequency of 3–11% and may not be associated with decreased IF production (Ament et al , 2009) or low Cbl (Remacha et al , 2008).…”

Disorder of Red Blood Cells: Anemias

“…Th e congenital form is a rare disorder characterized by mutations in the IF gene localized on chromosome 11q13 and lack of IF production. In congenital IF defi ciency, gastric acid secretion and mucosal cytology are normal [74][75][76] . Th e acquired pernicious anemia, in most cases, is an autoimmune disorder characterized by chronic atrophic gastritis and reduced IF production due to the presence of autoantibodies against gastric parietal cells [73,77] .…”