Helix-Hemoglobin Constant Spring

29 Mar

right circular cylinder. It resembles the thread of a bolt. Helix a genus of gastropod containing common garden snails. Species from this genus are favorite experimental animals for the experimental analysis of molluscan development. helix-destabilizing proteins any protein that binds to single-stranded regions of duplex DNA cre- ated by “breathing” (q.v.), and thereby causes un- winding of the helix; e.g., helicase (q.v.); also called relaxation proteins or melting proteins. helix-turn-helix motif a term describing the three- dimensional structure of a segment that character- izes certain DNA-binding proteins.

Regulatory pro- teins like the lambda and cro repressors (q.v.) are examples. The protein bends so that two successive alpha helices are held at right angles by a turn that contains four amino acids. One of the two helices lies across the major groove of the DNA, while the other sits within the major groove, where it can make contacts with these nucleotides of the DNA that are in a specific sequence. This “recognition he- lix” modulates the expression of the gene to which it binds. See Antennapedia, DNA grooves, motifs, myc. Helminthosporium maydis See Bipolaris maydis (the preferred nomenclature). helper T lymphocytes a T lymphocyte that ampli- fies the activity of B lymphocytes, other T lympho- cytes, and macrophages. Once a helper T lympho- cyte recognizes an antigen, it divides and its progeny start to synthesize and secrete a variety of lympho- kines (q.v.).

These cause B lymphocytes to divide and differentiate into plasma cells, inactive precur- sor T cells to develop into cytotoxic T lymphocytes, and macrophages to be recruited and activated. See AIDS, cytotoxic T lymphocyte, T lymphocyte. helper virus a virus that, by its infection of a cell already infected by a defective virus, is able to sup- ply something the defective virus lacks, thus en- abling the latter to multiply. See satellite RNA. HEMA the gene, located at Xq28, which encodes factor 8, the antihemophilic factor (q.v.). HEMA contains 189 kilobases of DNA and is one of the largest human genes. It has 26 exons and 25 introns. One of these (number 22) is gigantic (32 kb), and it contains a CpG island (q.v.). This serves as a bidirec- tional promoter for two genes (A and B).

Gene A contains no introns and is transcribed in the opposite direction from factor 8. Gene B is transcribed in the same direction as factor 8. Its first exon is in intron 22, and this exon is spliced to exons 23-26 to form the complete transcript. The A and B transcripts are found in many different tissues, but the functions of the proteins they encode are not known. Two addi- tional copies of gene A also lie about 500 kilobases upstream of HEMA. Intrachromosomal recombina- tion between the A gene within intron 22 and either of these duplicates can yield an inversion that dis- rupts HEMA. Such inversions are thought to cause 25% of all cases of hemophilia A. The gene is ex- pressed in the liver. The first human mutations caused by transposable elements were discovered in HEMA. See Appendix C, 1988, Kazazian et al.; he- mophilia. hemagglutinins 1. antibodies involved in specific aggregation of red blood cells. 2.

glycoproteins, formed on the surfaces of cells infected with certain viruses (e.g., influenza virus) or on the surfaces of enveloped viruses released from such cells, that can aggregate red blood cells of certain species. 3. lectins (q.v.). hematopoiesis the formation of red blood cells. hematopoietic pertaining to hematopoiesis. HEMB the gene, located at Xq27, which encodes factor 9, the plasma thromboplastin component (q.v.). HEMB is much smaller than HEMA. HEMB contains 34 kilobases of DNA and is made up of 8 exons. Most individuals suffering from hemophilia B have deletions in the factor 9 gene. The liver is the site of transcription and translation of the HEMB mRNA. See gene, hemophilia. heme an iron-containing molecule that forms the oxygen-binding portion of hemoglobin (q.v.). Heme consists of a tetrapyrrole ring, named protoporph- orin IX, and a ferrous ion. An oxygen molecule can reversibly bind to the iron atom which in turn is co- valently attached to the nitrogens of the four pyrrole molecules. Heme-containing proteins also occur in

Hemoglobin Constant Spring

bacteria and archaeans, where they generate signals in response to their binding oxygen. Presumably the signals are of adaptive significance to these microor- ganisms. See bilirubin. Hemimetabola a superorder of primitive insects having incomplete metamorphosis (mayflies, dragon flies, stoneflies, roaches, etc.). Synonymous with Ex- opterygota. See Appendix A. hemimetabolous referring to those insects in which metamorphosis is simple and gradual. Each insect gradually acquires wings during a period of growth interrupted by several molts. Immature forms are called nymphs if terrestrial, naiads if aquatic. Contrast with holometabolous. hemipteran a true bug; a member of the order Hemiptera. See Appendix A.

hemizygous gene a gene present in single dose. It may be a gene in a haploid organism, or a sex-linked gene in the heterogametic sex, or a gene in the ap- propriate chromosomal segment of a deficiency het- erozygote. hemochromatosis impaired functioning of a tissue or organ due to the storage of excessive amounts of iron in its cells. Hereditary hemochromatosis is the result of homozygosity of a recessive gene (HLA-H) on the short arm of human chromosome 6. The gene appears to be one of the most common disease- producing genes, at least in populations of European origin. People with one copy of HLA-H absorb in- creased amounts of iron from their diets but do not show symptoms of hemochromatosis. When both copies of the flawed gene are present the disease oc- curs, but usually after the reproductive period is over. Premenopausal females rarely show symptoms, possibly because of iron loss due to bleeding during menstruation.

It is possible in the past that heterozy- gotes had a selective advantage in regions where their diets contained suboptimal amounts of iron. hemocoel a body cavity of arthropods and mol- luscs that is an expanded part of the blood system. The hemocoel never communicates with the exte- rior, and never contains germ cells. hemocyte an amoeboid blood cell of an insect. It is analogous to a mammalian leukocyte. hemoglobin the oxygen-carrying pigment (molec- ular weight 64,500 daltons) of red blood cells. Each hemoglobin molecule is a spheroid with dimensions 50 × 55 × 65A˚. In red blood cells where hemoglobin is very concentrated, the molecules are only about 10A˚ apart. However, they can still rotate and flow past one another. Hemoglobin is a conjugated pro- tein composed of four separate chains of amino acids and four iron-containing ring compounds (heme groups). The protein chains of adult hemoglobin (HbA) occur as two pairs, a pair of alpha chains and a pair of beta chains. Each alpha chain contains 141 amino acids, and each beta chain contains 146 amino acids.

Normal human adults also have a mi- nor hemoglobin component (2%) called A2. This he- moglobin has two alpha chains and two delta pep- tide chains. The delta chains have the same number of amino acids as the beta chains, and 95% of their amino acids are in sequences identical to those of the beta chains. The hemoglobin of the fetus (HbF) is made up of two alpha chains and two gamma chains. Each gamma chain also contains 146 amino acids. There are two types, G gamma and A gamma, which differ only in the presence of glycine or ala- nine, respectively, at position 136. The earliest em- bryonic hemoglobin tetramer consists of two zeta (alphalike) and two epsilon (betalike) chains. Begin- ning about the eighth week of gestation, the zeta and epsilon chains are replaced by alpha and gamma chains, and just before birth the gamma chains begin to be replaced by beta chains.

See Appendix C, 1960, Perutz et al.; 1961, Dintzis, Ingram; 1962, Zucker- kandl and Pauling; leghemoglobin. hemoglobin Bart’s hemoglobin made up of ho- motetramers of gamma globin chains. In alpha tha- lassemia, the underproduction of alpha globin chains stimulates the expression of gamma globin genes. As a result, gamma globin tetramers become predomi- nant. In fetuses homozygous for deletions in alpha hemoglobin genes, the level of Bart’s hemoglobin is 80%-100%, and hydrops fetalis (q.v.) results. The hemoglobin was identified at St. Bartholomew’s Hospital in London.

This venerable hospital, founded in 1123, is nicknamed “Bart’s.” See hemo- globin fusion genes. hemoglobin C a hemoglobin with an abnormal beta chain. Lysine is substituted for glutamic acid at position 6. Hemoglobin C is thought to protect against malaria by interfering with the production of adhesion knobs on the surface of infected red blood cells. AC and CC erythrocytes show reduced adhe- sion to endothelial monolayers. Therefore parasit- ized cells are more likely to be swept into the spleen and destroyed. See hemoglobin S. hemoglobin Constant Spring a human hemoglo- bin possessing abnormal alpha chains that contain 172 amino acids, rather than the normal number of 141. Hb Constant Spring seems to be the result of a nonsense mutation that converted a stop codon into

Hemoglobin fusion genes

Hemoglobin genes

a codon specifying an amino acid (glutamine, in this case). The 30 additional amino acids must be coded by adjacent base sequences that normally are not transcribed, or, if transcribed, not translated. The designation Constant Spring comes from the region of the island of Jamaica where the mutant hemoglo- bin was discovered. hemoglobin fusion genes abnormal hemoglobin genes arising as a result of unequal crossing over be- tween genes sharing homologous nucleotide se- quences.

Examples are the fused gamma-beta gene that codes for the non-alpha chain of Hb Kenya and the variety of fused delta-beta genes that code for the non-alpha chains of the Hb Lepore (q.v.). hemoglobin genes the genes coding for human hemoglobins are located on chromosomes 11 and 16. As illustrated above, chromosome 11 contains the epsilon chain gene, two gamma chain genes (symbolized by Gγ and Aγ), a delta chain gene, and a beta chain gene. Chromosome 16 contains a zeta gene and two alpha chain genes (α1 and α2). There are also DNA segments that are structurally similar to the expressed hemoglobin genes.

These pseudo- genes were probably functional in the past but are now incapable of generating a product because of mutations they contain. These pseudogenes are rep- resented by black boxes in the diagram above. The globin genes on chromosome 16 (the alpha-like clus- ter) and on chromosome 11 (the beta-like cluster) are thought to have arisen by the duplication of a single ancestral gene some 450 million years ago. The table below shows the segmental organization of the transcription units (TUs) from the globin genes. All contain 5′ and 3′ ends (which are not translated), three exons (E1, E2, E3), and two introns (I1 and I2) that are spliced out of the mature mRNA. The numbers represent base pairs.

The major differ- ence between the two gene clusters is that the sec- ond introns of the beta-like genes contain about six times as many base pairs as the second introns of alpha-like genes. Transcription begins 40 to 50 base pairs upstream of E1, and ends about 100 base pairs downstream from E2. Subsequently the 5′ end re- ceives a methylated cap (q.v.), and the 3′ end loses a segment of about 25 nucleotides but gains a tail of 50 or more adenylic acids. See Appendix C, 1961, Ingram; 1976, Efstratiadis et al.; 1977, Tilghman et al.; 1979, Fritsch et al.; 1985, Saiki et al.; 1986, Con- stantini et al.; compound heterozygote, gene, heredi- tary persistence of hemoglobin F, myoglobin gene, polyadenylation, posttranscriptional processing, sickle-cell anemia, thalassemias, transcription unit. hemoglobin H See hemoglobin homotetramers, thalassemias. hemoglobin homotetramers abnormal hemoglo- bins made up of four identical polypeptides. Exam- ples are Hb Bart’s (only gamma chains) and Hb H (only beta chains).

hemoglobin Kenya See hemoglobin fusion genes. hemoglobin Lepore an abnormal hemoglobin named after the Italian family in which it was first found. The protein contains a pair of normal alpha chains and a pair of abnormal chains, each chain made up of 146 amino acids. Each abnormal chain appears to be a hybrid molecule consisting of an N- terminal end containing amino acids in a sequence characteristic of the left end of the delta chain and a C-terminal end containing amino acids in a sequence characteristic of the right end of a beta chain. He- moglobin Lepore is presumed to have arisen by un-

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