12.7 THALASSEMIAS : These are genetic disorders of nee synthesis — @- and A-thalassemias are cause a the mutations affecting the synthesis © respectively aand #eglobin chains. Thalassemias are characterized by reduced or stopped synthesis of the affected globin, a compensatory rise in the synthesis of other globin chains which replace the missing globin in hemoglobin molecules to form abnormal hemoglobin, premature destruction of erythrocytes, anemia and bone marrow expansion. The affected globin chain is poor in amount in hemoglobin molecules in o*- and f*-thalas- semias, but absent in a°- and B°-thalassemias because of deletion of the relevant genes. A homozygous individual, inheriting the mutant thalassemic gene from both parents, suffers from severe and often fatal anemia (thalassemia major), needing frequent blood transfusions for keeping alive. A heterozygous individual, inheriting the thalassemic gene from only one parent, is either apparently normal or only mildly anemic (thalassemia minor). Thalassemias occurfrequently in Mediterranean regions, Central ang * equatorial Africa, North Europe, South-east Asia, Philippines and India. Thalassemia minor patients have higher resistance against Plasmodium falciparum. This facilitates the spread of thalas- semic genes in malaria-endemic regions. a-Thalassemias : These result from mutations in the @ gene cluster of human chromosome 16 — more commonly from deletion mutations and unequal crossing-overs, and less commonly from frameshift mutations, nonsense mutations, and mis-sense point mutations; ¢€.g., a mis-sense point mutation of a-2 gene, changing a Leu codon toa Pro codon and thereby giving rise to the abnormal Hb Quong Sze; a reverse-stop mutation of a2 gene, changing a terminator codon to a Gin codon and thereby producing longer mutant @ chains Hb Constant Spring. =@-Thalassemias include (i) the asymptomatj Silent-carrier trait ot a-thal-1 witha single ageng — deleted, (ii) mildly anemic @-thalassemia trait gy a-thal-2 with two missing @ genes, (iii) mode. rately anemic HbH disease with three deleted g genes and carrying significant amounts of abnormal homotetrameric HbH (fy), and (iy) severe and lethal hrydropis fetalis with all four g genes deleted and carrying embryonic ¢ globin chains in place of @ chains in the abnormal hemoglobin. The abnormal homotetrameric hemo- globins such as HbH (B,) and Hb Bart’s (¥4) of @-thalassemia cases possess hyperbolic O, saturation kinetics instead of sigmoid kinetics, no Bohr effect of Pco,, and little significance in 0, transport. -Thalassemias : These result from mutations in the B gene cluster of chromosome 11, such as deletions of B genes causing £9-thalassemias, point mutations of transcription-initiating promoter sites of A genes affecting / gene transcription, point muta tions affecting an existing splice site or creating ® new splice site to alter RNA processing; aneframeshift and nonsense mutations of 8 genes. In 7 f-thalassemias, the rate of B chain translation is reduced, there are compensatory rises in the | synthesis of d and y chains, and #deficient | hemoglobins such as HbA, (65) and HbF ~ (QY>) rise in blood. For example, in 6f-thalas- semia patients with both dand f genes of their B like gene cluster deleted, the compensatory Over production of fetal ychains may produce sul HbF (@, 75) to make them asymptomatic. Inf B thalassemia, erythrocytes contain Wo normal @ chains and two abnormalStructure allt tt (b) In less than 5% cases of substitution, a amino acid-coding or sense codon is changed n a terminator or stop codon. This gives rise to to inactive peptide shorter than the normal one i several C-terminal amino acids due to ms premature termination of translation (nonsen , stop peHGn In one type of B°-thalassemi a example, a stop mutatio i , n changes th AAG (specifying lysi ges the 17th codo ying lysine) i : : g lysine) in the globin mRNAop codon UAG; this term the st i inates the 10 ‘on of #glo! in prematurely and t i rats ly has no A-globin. ey ac! (in nearly 75% cases of Substi tution. inged to another one, Specifying a acid. The translated Peptide cong es from the normal peptide in reg vale amino acid (imis-sense mutay ists mutational change of the codon AAA encoding lysine) to GAA (encoding glutamate) substitutes 2 lysine by a glutamate in the translated ptide- Still, if the original and the substituted min acids possess similar sidechains or junctional groups, e.g., both having cationic polar sidechains or short nonpolar aliphatic sidechains. the mutational change in the primary structure of the protein may not appreciably alter its tertiary structure and biological activities (acceptable mis- sense mutation). But if the mutation substitutes a charged polar amino acid by a nonpolar one, a cationic amino acid by an anionic one, or a short- chain nonpolar aliphatic amino acid by a long, branched or aromatic nonpolar amino acid, the tertiary structure of the protein may be so affected that its biological activities are lost or substantially lowered (unacceptable mis-sense mutation). In sickle cell anemia, for example, HbS carries abnormal £-globin chains having valine in place of glutamate as the 6th amino acid residue because of an unacceptable mutation changing a GAG ', Acodon different ‘quently Pect of a ion). For is chat ao ~~ “SECULAR BIOLoGy Codons ; these elor by adding addition: another stop codo thalassemia, th ngate the peptide abnormally ait C-terminal amino acids until nls encountered. In one type of falas le Stop codon UAA at the 142nd Position in the @-globin mRNA has been changed into AAA encoding lysine; this elongates the o- globin chain from its normal 141-residue length to 172 residues. (e) Substitution of a base at the intron-exon junction of an mRNA gene alters the base Sequence at the corresponding splice junction of the pre-mRNA transcript. Alternatively, base- substitution at some distance from the original splice junction may create a new splice junction at that site. Such splice junction mutations affect the post-transcriptional modification of the mRNA. transcript by either abolishing the splicing or producing it at a cryptic splice site away from the original splice junction. The resulting mutant mRNA translates a grossly abnormal peptide. (f) Substitution at a promoter site (e.g., TATA box) may affect the initiation of gene transcriptionpromoter mutation). This lowers the rate of nRNA synthesis and so, of protein translation. Promoter and splice junction mutations cause some forms of #-thalassemias.OT ee eee *_ so SEE SES EE psychosis and seizures. Thalassemias are fatal autosomal recessive single-gene traits with — abnormal hemoglobins. Hemophilia A is a serious bleeding disorder caused by an X-linked recessive single-gene defect to the blood coagulation factor VIII. Maple syrup urine disease, resulting from an autosomal recessive genetic deficiency of the branched-chain a@-keto acid decarboxylase, causes brain damage, mental retardation, convulsive seizures, poor muscle tone and respiratory failure; it is fatal unless treated promptly with a diet poor in branched-chain amino acids.