Hb Groene Hart: a new Pro-->Ser amino acid substitution at position 119 of the alpha1-globin chain is associated with a mild alpha-thalassemia phenotype.
Alpha-Thalassemia (thal) is generally considered to be an expression defect caused mostly by deletions silencing one or more alpha-globin genes. Although nondeletional alpha-thalassemia is considered rare, in our laboratory we frequently observe alpha-thal phenotypes induced by point mutations. We report a new point mutation generating an abnormal hemoglobin (Hb) associated with a mild alpha-thal phenotype in two members of a Moroccan family, who presented with mild but persistent microcytic hypochromic parameters and a balanced beta/alpha synthetic ratio. All attempts to separate an abnormal native or denatured fraction were unsuccessful using electrophoresis, isoelectrofocusing (IEE), ion exchange and reversed phase high performance liquid chromatography (HPLC), denaturing polyacrylamide gel electrophoresis (PAGE), and electrospray mass spectrometry (ES/MS). The anomalous protein was only predictable by DNA analysis. The mutated gene product, not separable with any of the techniques used, could be a monomer unsuitable for tetramer formation, which is proteolyzed at an early stage. Alternatively, this mutation could perhaps lead to an abnormal splicing. The CCTCT sequence generated by the mutant, not found in the translated region of the gene, but normally present at the end of the IVS-II, could induce a possible exon skipping. This mutant could generate a mild or a critical Hb H disease in combination with one of the common alpha0-thal deletion defects.
Harteveld
Cornelis L
CL
Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
van Delft
Peter
P
Plug
Rob
R
Versteegh
Florens G A
FG
Hagen
Balt
B
van Rooijen
Irene
I
Kok
Peter J M J
PJ
Wajcman
Henri
H
Kister
Jean
J
Giordano
Piero C
PC
D000328:Adult; D019943:Amino Acid Substitution; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D005260:Female; D005914:Globins / Q000235:genetics*; D006455:Hemoglobins, Abnormal / Q000235:genetics*; D006801:Humans; D008297:Male; D009426:Netherlands; D010641:Phenotype; D017354:Point Mutation; D017085:alpha-Thalassemia / Q000235:genetics*
D006455:Hemoglobins, Abnormal; C475066:hemoglobin Groene Hart; D005914:Globins