Role of SLC40A1 R-178G Gene Mutation on Pathophysiology of Iron Deficient Sickle Cell Anemia Patients

Abstract

Introduction: Solute carrier family 40 member 1(SLC40A1) is a protein coding gene. The protein encoded by this gene is
a cell membrane protein that plays a key role in the majority of iron transportation by balancing cellular and systemic iron
levels. Defects in this gene are a cause of hemochromatosis type 4 (HFE4) and Hemochromatosis type 1 diseases. Iron overload and a non-responsive phenotype are also associated with the hereditary variants of iron deficiency anemia. Based
on this, it was proposed that the presence of this mutation could influence iron absorption and provide protection against
the severity of iron deficiency in sickle syndrome. SLC40A1 gene mutations may have a useful clinical result in the severity
of the disease due to their diverse role in iron metabolism.

Materials & Methods: A total of 140 iron-deficient sickle syndrome patients were recruited for the study with an equal
number for controls. The sickle cell sub-type was diagnosed by a cation exchange high performance liquid chromatography
(HPLC) and complete blood count analysis was done by automated hematoanalyzer. Screening of iron deficiency was done
by serum ferritin analysis using ELISA method. Genomic DNA was isolated from peripheral blood by kit method and DNA
quantification was done by Nano drop analytical Software system. SLC40A1 R178G genotype analysis was performed by
PCR-RFLP method using HpyAV restriction enzyme.

Results: Among the Sickle cell disease (SCD) patients, 17 were heterozygous and 09 were homozygous for SLC40A1(R178G)
mutation; while 13 controls were heterozygous and 5 patients were homozygous for SLC40A1(R178G) mutation. We reported
the significant elevation of serum ferritin and hemoglobin level in SLC40A1(R178G) mutation while a decrease in the ESR
and CRP levels were observed.

Conclusion: The findings of the study suggested high impact of SLC40A1(R178G) mutation in pathophysiology of iron
deficient SCD and shows positive correlation. It may act as the predictor of disease severity. Detection of this mutation in
iron-deficient SCD patients is useful in treatment decision.

Based on this finding, clinicians can be more confident about iron status in SCD patients. Data from this research can be
used to understand the status of iron overload in mutant versus non-mutant conditions. The Data of the study provides a
genotype–phenotype correlation of SLC40A1 (R178G) mutation in iron-deficient SCD patients.

Conflict of Interest: None

Source of Support: This study is funded by Indian Council of Medical Research, New Delhi, India