Contributions
Abstract: PB2494
Type: Publication Only
Background
α-thalasemia is a common disease charcterized mainly deletions of one or several α genes which is known as α-thalassemia deletion. On the other hand, point mutations are also observed in critical regions of the α genes such as the consensus zones of the introns or in the polyadenylation sequences, which can alter the processes of transcription, translation or in the posttradutional processing of the mRNA, originating the so-called α-thalassemia no deletion. So far, more than 100 mutations have been described. One of the least frequent mechanisms is the nonsense mutations, those that generate the substitution of a triplet coding for an amino acid by a stop codon and therefore the protein synthesis stops prematurely. At present 9 mutations of this type have been documented, 6 that affect the HBA2 gene and 3 that affect the HBA1 gene.
Aims
We present a new mutation in CD16 of the HBA1 gene, where the change AAG> TAG generates a stop codon.
Methods
The propositus, a 48-year-old woman from Madrid, was studied because she had maintained microcytosis without iron deficiency. The Hb A2 and Hb F levels were measured by ion exchange HPLC (VARIANT II). Hemoglobin was studied by capillary zone electrophoresis and ionic exchange HPLC (β-thalassemia Short Program). The most frequent α globin mutations were discarded by multiplex PCR (Alpha-Globin StripAssay ki) and molecular characterization was undertaken using automatic sequencing.
Results
The propositus presented microcytosis with hypochromia and with normal reticulocytes. No abnormal hemoglobins were detected and Hb A2 and Hb F levels were within normality. Molecular characterization of the α1-globin gene by automatic sequencing identified the novel transversion mutation HBA1:c.49A>T, which resulted in an amino acid change from Lys>Stop at codon 16 of exon 1 in the heterozygous state [α116(A14)Lys>Stop; HBA1:c.49A>T]. This was confirmed by sequencing of the other strand.
Conclusion
This type of mechanism is very rare among the globin genes, in fact, between the γ genes (A and G) has not been detected, in the β globin gene (HBB) has been identified 18 times (18/913) , in the δ gene only in three (3/126) and in the α globin 9 genes (9/799).
This new mutation is the fourth described in the HBA1 gene and the tenth nonsense among the alpha globin genes. The first nonsense mutation described in the alpha globin genes was in 1987 in a black family in the USA, since then and until the current 21st century no other had been described, probably as a result of advances and refinement of biology techniques as the automation of genetic sequencing, which has allowed an increase in the ability of analysis.
This new mutation has a mild phenotype in the heterozygous state. Short gene products might eventually undergo nonsense mediated decay, while any anomalous short protein will be removed through the ubiquitin mediated proteolytic pathway resulting in the mild phenotype of an α-thal (αTα/αα) genotype. Probably the severe end of the clinical spectrum, when it is inherited with a deletion mutation of two genes.
Session topic: 28. Thalassemias
Keyword(s): Thalassemia
Abstract: PB2494
Type: Publication Only
Background
α-thalasemia is a common disease charcterized mainly deletions of one or several α genes which is known as α-thalassemia deletion. On the other hand, point mutations are also observed in critical regions of the α genes such as the consensus zones of the introns or in the polyadenylation sequences, which can alter the processes of transcription, translation or in the posttradutional processing of the mRNA, originating the so-called α-thalassemia no deletion. So far, more than 100 mutations have been described. One of the least frequent mechanisms is the nonsense mutations, those that generate the substitution of a triplet coding for an amino acid by a stop codon and therefore the protein synthesis stops prematurely. At present 9 mutations of this type have been documented, 6 that affect the HBA2 gene and 3 that affect the HBA1 gene.
Aims
We present a new mutation in CD16 of the HBA1 gene, where the change AAG> TAG generates a stop codon.
Methods
The propositus, a 48-year-old woman from Madrid, was studied because she had maintained microcytosis without iron deficiency. The Hb A2 and Hb F levels were measured by ion exchange HPLC (VARIANT II). Hemoglobin was studied by capillary zone electrophoresis and ionic exchange HPLC (β-thalassemia Short Program). The most frequent α globin mutations were discarded by multiplex PCR (Alpha-Globin StripAssay ki) and molecular characterization was undertaken using automatic sequencing.
Results
The propositus presented microcytosis with hypochromia and with normal reticulocytes. No abnormal hemoglobins were detected and Hb A2 and Hb F levels were within normality. Molecular characterization of the α1-globin gene by automatic sequencing identified the novel transversion mutation HBA1:c.49A>T, which resulted in an amino acid change from Lys>Stop at codon 16 of exon 1 in the heterozygous state [α116(A14)Lys>Stop; HBA1:c.49A>T]. This was confirmed by sequencing of the other strand.
Conclusion
This type of mechanism is very rare among the globin genes, in fact, between the γ genes (A and G) has not been detected, in the β globin gene (HBB) has been identified 18 times (18/913) , in the δ gene only in three (3/126) and in the α globin 9 genes (9/799).
This new mutation is the fourth described in the HBA1 gene and the tenth nonsense among the alpha globin genes. The first nonsense mutation described in the alpha globin genes was in 1987 in a black family in the USA, since then and until the current 21st century no other had been described, probably as a result of advances and refinement of biology techniques as the automation of genetic sequencing, which has allowed an increase in the ability of analysis.
This new mutation has a mild phenotype in the heterozygous state. Short gene products might eventually undergo nonsense mediated decay, while any anomalous short protein will be removed through the ubiquitin mediated proteolytic pathway resulting in the mild phenotype of an α-thal (αTα/αα) genotype. Probably the severe end of the clinical spectrum, when it is inherited with a deletion mutation of two genes.
Session topic: 28. Thalassemias
Keyword(s): Thalassemia