Hb Iberia [α104(G11)Cys → Arg,TGC>CGC (α2) (HBA2:c.313T>C)], a Newα-Thalassemic Hemoglobin Variant Found in the Iberian Peninsula: Report of Six Cases

Abstract

We report a new structural defect of the α2-globin chain presenting with moderate microcytic hypochromic anemia, in six individuals from three unrelated families, living in Portugal and Spain. α-Globin gene deletions were ruled out by gap-polymerase chain reaction (gap-PCR) and multiplex ligation-dependent probe amplification (MLPA). Direct sequencing of the α2-globin gene revealed a substitution of codon 104 [α104(G11)Cys→Arg, TGC>CGC (α2) (HBA2:c.313T>C)]. This new variant, not detectable by high performance liquid chromatography (HPLC) or electrophoresis, was called Hb Iberia, as it was observed for the first time in families from the Iberian Peninsula. Although the mutant allele is transcribed, as indicated by the balanced mRNA α/β ratio, the abnormal α2 chain could not form a stable tetramer as the cysteine and arginine residues, located at the α1β1 contact, differ in size, charge and hydrophobicity. Hb Iberia is the third mutation described at codon 104 on the α-globin genes, namely, Hb Sallanches (α2, TGC>TAC) and Hb Oegstgeest (α1, TGC>AGC), also characterized as unstable hemoglobins (Hbs), present on an α-thalassemic phenotype.

Stability of Maleimide-PEG and Mono-Sulfone-PEG Conjugation to a Novel Engineered Cysteine in the Human Hemoglobin Alpha Subunit

“…Hemoglobin polymorphisms reveal severe protein instability in Hb from people with Cys104 mutations in their HbA1 or HbA2 genes. Reported mutations include HbA2 αCys104Arg [Hb Iberia, ( Bento et al, 2012 )], HbA2 αCys104Tyr [Hb Sallanches, ( Morle et al, 1995 )], HbA1 αCys104Ser [Hb Oegstgeest, ( Harteveld et al, 2005 )] and HbA1 αCys104Trp (alpha codon 10 TGC-TGG). In these cases, the protein is too unstable to be detectable in heterozygotes or associated with thalassemia in homozygotes.…”

Hb Plasencia [α125(H8)Leu→Arg (α2)] is a Frequent Cause ofα+-Thalassemia in the Portuguese Population

“…Although α-thal is commonly associated with the -α 3.7 and -α 4.2 deletions (6), two novel α-thalassemic Hb variants have already been described in the Portuguese population, Hb Evora (HBA2: c.106T>C; p.Ser36Pro) (7) and Hb Iberia (HBA2: c.313T>C; p.Cys105Arg) (8). Hb Plasencia can easily be 184 E. Cunha et al identified by restriction enzyme digestion.…”