P-globin genes

Some of this differential expression is achieved by having different regions of chromatin available for transcription in cells from various tissues. For example, the DNA containing the P-globin gene cluster is in active chromatin in the reticulocyte but in inactive chromatin in muscle cells. All the factors involved in the determination of active chromatin have not been elucidated. The presence of nucleosomes and of complexes of histones and DNA (see Chapter 36) certainly provides a barrier against the ready association of transcription fac-... 

Sickle cell disease again provides an excellent example of how recombinant DNA technology can be applied to the smdy of human disease. The substitution of T for A in the template strand of DNA in the P-globin gene changes the sequence in the region that corresponds to the sixth codon from... 

P-Thalassemla (MIM 141900) A very wide variety of mutations in the p-globin gene, including deletions, nonsense and frameshift mutations, and others affecting every aspect of its structure (eg, splice sites, promoter mutants)... 

RFLP analysis of the p-globin gene for genetic testing has been replaced, by PCR In combination with ASO probes on dot blots. The blot shown here corresponds to the family whose pedigree is shown in Figure T7-9. In the mutant allele, glutamate (E) at codon 6 is replaced by valine (V). 

A man with sickle cell disease and his phenotypically normal wife request genetic testing because they are concerned about the risk for their unborn child. DNA samples from the man and the woman and from fetal cells obtained by amniocentesis are analyzed using the PCR to amplify exon 1 of the p-globin gene. 

Answer D. DNA-based test would have to be used on the ceils obtained from amniocentesis. They would not express the p-globin gene. 

The human hemopexin gene has been cloned (38) and is located near the P-globin gene cluster on human chromosome 11 (39). The promoters of the human, rat, and mouse hemopexin genes have been cloned, and the human gene contains a liver specific element (40) and an interleukin-6 responsive element (41), consistent with the positive acute phase response ofhemopexin (33,34). 

As an example of the way in which the code is read. Fig. 2 shows small sections from the normal and a mutated form of the P-globin gene (see p. 280), as well as the corresponding mRNA and protein sequences. The point mutation shown, which is relatively frequent, leads to replacement of a glutamate residue in position 6 of the p-chain by valine (GAG GTG). As a consequence, the mutated hemoglobin tends to aggregate in the deoxy-genated form. This leads to sickle-shaped dis-... 

Haploinsufficiency, or when 50% of normal gene activity is inadequate a-Thalassemia trait and the a-globin gene P-Thalassemia trait and the P-globin gene... 

Fetal hemoglobin (HbF) HbF is a tetramer consisting of two a chains identical to those found in HbA, plus two gamma (y) chains (0272, see Figure 3.13). The y chains are members of the p-globin gene family (see p. 35). 

Electrophoresis of restriction fragments from the DNA of normal individuals yields a 1150-bp fragment using a probe specific for the P-globin gene. 

Figure 28-14 A "tailed circle" consisting of an enhancer linked to, but topologically separated from, a gene. One of the DNA strands of this plasmid bears two copies of an SV40 enhancer sequence, one copy inverted with respect to the other. This extra region protrudes from the circle and self-pairs to form a functional enhancer. The main body of the circle contains the p-globin gene, transcription of which is increased by the enhancer. Twisting of the enhancer has no effect on the winding of the strands on the main body of the circle nevertheless, the enhancer efficiently increases P-globin transcription. From Ptashne.355...

Figure 5.34. Transcription and Processing of the p -globin gene. The gene is transcribed to yield the primary transcript, which is modified by cap and poly(A) addition. The intervening sequences in the primary RNA transcript are removed to form the mRNA.

Figure 28.28. Splicing Defects. Mutation of a single base (G to A) in an intron of the P-globin gene leads to thalassemia. This mutation generates a new 3 splice site (blue) akin to the normal one (yellow) but farther upstream.

P-Thalassemia major results from mutations that interfere with translation or are involved in the initiation, elongation, or termination of globin chain synthesis. Mutations that interfere with translation account for almost 50% of ail die p-thalassemia mutations. Included in this are frame shift or nonsense mutations that produce premature termination codons that result in incomplete translation of the P-globin gene and nonproduction of the P-globin chain resulting in P -thalassemia. 

Heterozygous Hb C individuals are usually asymptomatic. Genetic counseling may be usefril where prospective parents have abnormalities in the P-globin gene. 

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