Codon 24 (TAT>TAG) and Codon 32 (ATG>AGG) (Hb Rotterdam): Two Novel α2 Gene Mutations Associated with Mild α-Thalassemia Found in the Same Family After Newborn Screening

Abstract

We report two novel alpha2-globin gene mutations found in the same Surinamese family. The proband, a newborn presenting during neonatal screening with 21.3% Hb Bart's (gamma4), proved to be a carrier of the common -alpha(3.7) deletion and a novel codon 32 (ATG>AGG) transversion that we named Hb Rotterdam. The father carried the same point mutation with borderline hemoglobin (Hb), MCV and low MCH values. The mother presented with a significant microcytic hypochromic anemia and also carried the -alpha(3.7) deletion and a second novel TAT>TAG transversion generating a stop codon at position 24. Shortly thereafter, Hb Rotterdam was again found in two unrelated adult females and in a Canadian newborn, all of African origin, suggesting that Hb Rotterdam could be a frequently occurring alpha(T) determinant in the Black population. Screening and characterization of the mutations, phenotype/genotype correlation and the issue of reporting newborn carriers of alpha-thalassemia (alpha-thal) are discussed.

Relationship between neonatal screening results by HPLC and the number of α-thalassaemia gene mutations; consequences for the cut-off value

“…One a trait (FAST peak ¼ 21.3%) was caused by a combination of the 2 3.7 a deletion and a new point mutation named Hb Rotterdam. 21 Most samples (n ¼ 46; FAST peak 12.2 -30.3%) had a heterozygote --SEA deletion, while one had a 2 20.5 deletion (FAST peak ¼ 20.9%). Furthermore one child had a deletion between HS-40 and 3.7kb downstream HBA1 (FAST peak ¼ 24.5%) and two children had a deletion between HBA2P and 0.5kb downstream HbA1 (FAST peak 21.7% and 24.1%).…”

Severe α-Thalassemia Intermedia Due to a Compound Heterozygosity for the Highly Unstable Hb Adana (HBA2: c.179G>A) and a Novel Codon 24 (HBA2: c.75T>A) Mutation

“…As previously reported by Liebhaber et al (4), the α2-globin gene is predominantly expressed, 2- to 3-fold higher than the α1-globin gene. Recently, a mild thalassemia syndrome due to compound heterozygosity for the codon 24 ( HBA2 : c.75T > G) of the α2-globin gene and a single α-globin gene deletion were described in a Surinamase patient (5). Here we report a different mutation at the same codon 24 ( HBA2 : c.75T > A).…”

Nondeletional Hb Queens Park [α32(B13)Met→Lys]/Hb H (β4) Disease

“…Three mutations at codon 32, Hb Amsterdam [HBA2:c.99G>A (Met→Ile)], Hb Rotterdam [HBA2:c.98T>G (Met→Arg)] and Hb Queens Park, have been reported by the same research group (15,18,19). The first two mutations occur on the α2-globin gene and were found in subjects of Surinamese origin, while Hb Queens Park occurs on the α1-globin gene and was found in a Burmese man and a Thai boy (this study) (Figure 2).…”

“…With concurrence to the previous study (15), substitution at position 32 from methionine to lysine was predicted to alter protein hydrophobicity and charge at buried site, disrupt ligand binding site (PSIC score difference 3.267), be pathological and affect protein function (SIFT score 0.00). An impaired splicing mechanism had been suggested for the codon 32 mutation, though it failed to indicate change in the acceptor recognition sequence (15,19). Splicesite prediction of AT G>AAG at codon 32 was also performed using NetGene2 (http://www.cbs.dtu.dk/services/NetGene2/) and SplicePort (http://spliceport.cs.umd.edu/).…”