They include single base substitutions, small insertions, or deletions within the gene or its immediate flanking sequences and affect almost every known stage of gene expression Fig.
The boxes represent the different categories of mutants. The vertical lines within the boxes represent the sites of the different mutations. Dominantly inherited mutants are found within shaded boxes. References to these mutations can be found in Forget , Weatherall and Clegg , and Thein and Wood Heterozygotes do not appear to have an unusually severe phenotype. Within this group of transcriptional mutants, ethnic variation in phenotype has been observed.
A wide variety of mutations interfere with processing of the primary mRNA transcript. These mutations can be base substitutions that change one or the other of invariant dinucleotides or short deletions that remove them.
Flanking the invariant dinucleotides are sequences that are fairly well conserved and a consensus sequence can be recognized at the exon—intron boundaries.
On the other hand, the substitution of C for T in the adjacent nucleotide, intron 1 position 6, only mildly affects normal RNA splicing even though it activates the same three cryptic donor sites as seen in the IVS mutants.
Mutations can occur in these sites creating a sequence that resembles more closely the normal splice site. During RNA processing the newly created site is used preferentially, leading to aberrant splicing. Some of these variants are not associated with elevated A 2 in heterozygous state e. References to these mutations can be found in Thein and Thein and Wood The mutant mRNA is hardly detected in affected erythroid cells presumably because the 19 bp segment of retained intronic sequence contains an in-phase premature termination codon.
Four mutations have been identified in exon 1 that are associated with activation of alternative splice sites. The remainder of the transcripts extend far beyond the normal polyadenylation site and are probably cleaved and polyadenylated after the next AATAAA consensus sequences, which occur about 0.
The rest are single base substitutions, two affecting the first A , three the second T and, three the third G nucleotide of ATG Jankovic et al. However, it is predicted that these alternative initiation codons would result in premature termination, and that mutant mRNAs would be nonfunctional and subjected to nonsense mediated decay surveillance.
These frameshifts lead to premature termination further downstream when the next nonsense codon is reached. One of the first nonsense mutations to be characterized and extensively studied was the mutation at codon 39 CAG to TAG Humphries et al. The vertical bar indicates the promoter region that is removed in common by these deletions except for the bp Asian Indian and the 7. Only about one-third of the breakpoints of these deletions have been defined; the white boxes and jagged ends indicate undefined breakpoints.
The 0. The second deletion was recently described in compound heterozygosity with HbS in a woman from Cape Verde Islands who presented with sickle cell disease Andersson et al. The deletion removes 7.
They are associated with unusually high levels of HbA 2 and variable increases of HbF in heterozygotes. Indeed, studies of an individual heterozygous for the 1. Newborns have anemia and hemolysis; some requiring intrauterine and perinatal blood transfusions to tide them over the perinatal period.
The severity of anemia and hemolysis is variable even within a family with identical mutations Verhovsek et al. Only heterozygotes have been identified; homozygotes, presumably would not survive early gestation. These deletions are rare and unique to the families in which they have been described.
As the molecular lesions of an increasing number of such cases were characterized, it became apparent that the defects were extremely heterogeneous; some mutations were highly complex involving deletions interrupted by insertions similar to the complex arrangement originally described in the Irish family Weatherall et al. The molecular defects include missense mutations, deletions or insertion of intact codons, nonsense mutations causing premature termination codons in exon 3, which leads to a failure of the nonsense mediated decay of the RNA Fig.
The half-life of this globin variant was less than 10 min, and the abnormal hemoglobin was not detectable by standard techniques.
Other examples of missense variants include Hb Chesterfield Thein et al. Most of the other abnormal hemoglobins were not detected by routine hemoglobin electrophoresis.
Deletions or insertions of entire codons allow the reading frame to remain in phase, and the remaining amino acids are normal. Both Hb Korea Park et al. Presence of the predicted truncated variant, however, was implicated from a large difference between the total radioactivity incorporated into newly synthesized chains and the total amount of protein in globin biosynthesis studies.
Beta thalassemia mutation ppt to pdf
The mutation was associated with unusually severe anemia and intraerythroblastic inclusions, transmitted as a single allele in five generations of the family. These in-phase termination mutants appear to have differential effects on triggering the surveillance mechanism of nonsense mediated decay NMD.
NMD is an in-house mRNA quality-control mechanism that degrades abnormal mRNAs that arise from mistakes in gene expression such as those caused by premature termination codons. These elongated variants have abnormal carboxy-terminal ends made up of hydrophobic sequences causing their instability.
Because the heme contact site codons—mostly located in exon 2—are retained, these elongated variants should have some tertiary structure, be less susceptible to proteolytic degradation, and presumably, form the characteristic inclusion bodies. Indeed, prominent inclusions were noted in individuals heterozygous for Hb Geneva Beris et al.
The Corfu mutation has been described as separate lesions in two different populations.
It has been noted that carriers for this mutation have highly variable HbA 2 levels despite similar hematological parameters and globin-chain synthesis ratios. Unusually high levels of HbA 2 over 6. Transposable elements may occasionally disrupt human genes and result in their inactivation.
In the last 10 years several rare trans -acting mutations that affect HBB and its linked HBD gene have been identified. Somatic deletions involving HBB gene have been described in three unrelated families of French Badens et al. Uniparental isodisomy of a segment of chromosome 11p containing the HBB cluster has also been described in two cases.
In one family of Chinese origin Chang et al. I thank Claire Steward for help with preparation of the manuscript and Helen Rooks for help in preparation of some of the figures.
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