Molecular analysis of the transferrin gene in a patient with hereditary hypotransferrinemia

We previously reported a patient with hereditary hypotransferrinemia who suffered from severe anemia and growth retardation and was diagnosed on the basis of an extremely low level of serum transferrin (TF). By an iso-electric focusing analysis, we found that the patient and his father shared a variant TF protein with an abnormal iso-electric point. The study suggested that the patient was a compound heterozygote with a variant allele, encoding the mutant TF, of paternal origin and a null allele of maternal origin. In the present study, we investigated the TF gene of the patient and his family. We showed that the patient and his father shared a variant TF gene bearing a GAA to AAA transition at codon 394. This nucleotide substitution causes a nonconservative amino acid change from glutamate to lysine in amino acid residue 375 of the TF protein. This single amino acid mutation is predicted to cause a conformational change in the coiled region of the carboxyl-terminal iron-binding lobe. As for the maternal null allele, no mutation was found in either the coding region or the exon-intron boundaries, suggesting an abnormality in the transcription or stability of mRNA of maternal allele origin.