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Biochemical Genetics in Medicine 1
Author(s) -
MOTULSKY ARNO G.
Publication year - 1967
Publication title -
acta pædiatrica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.772
H-Index - 115
eISSN - 1651-2227
pISSN - 0803-5253
DOI - 10.1111/j.1651-2227.1967.tb15291.x
Subject(s) - hemolytic anemia , mutation , compound heterozygosity , genetics , medicine , mutant , hemoglobin , heterozygote advantage , biology , gene , immunology , allele
Summary 1. The history of human biochemical genetics is reviewed with special references to Garrod's and Pauling's contributions. 2. Recent knowledge on the correlation of gene structure and protein structure is reviewed. 3. The influence of various mutations on the hemoglobin molecule is discussed. Heterozygote structural mutations affecting the critical active site of the hemoglobin molecule may lead to hemolytic anemia, drug sensitivity, polycythemia and methemoglobinemia. Other mutants are usually harmless. Another class of hemoglobin mutants–the thalassemias–cause diminished hemoglobin chain production and may lead to severe anemia in the ho‐mozygote state. 4. Many different glucose‐6‐phosphate dehydrogenase mutations have been discovered. Some are rare mutants, others are common and, as the sickle trait, owe their frequency to a selective advantage vis‐a‐vis falciparum malaria. The African type of G6PD mutant is caused by a structural mutation which causes more rapid degradation of the enzyme during red cell ageing. The chemically most unstable mutants are associated with chronic hemolytic disease. 5. Mutations of controlling elements as contrasted to structural mutations have not yet been proven in man, but hereditary persistence of fetal hemoglobin and oroticaciduria can best be explained by control mutations. 6. Differences in drug response and drug reactions may be caused by genetically determined biochemical variability. G6PD deficiency may cause drug hemolytic anemia. Pseudocholinesterase alterations may cause sensitivity or resistance to succinylcholine and differences in the acetylation of some drugs are genetically controlled. 7. Biochemical screening is feasible for a variety of disorders and is strongly indicated since certain forms of mental retardation may be prevented by early treatment, e.g., phenylketonuria. 8. Carrier detection of many heterozygote traits is possible. Overlap in enzyme activity between heterozygotes and normals may be caused by the existence of isoalleles in the normal population. Screening of heterozygotes of X‐linked diseases (muscular dystrophy and hemophilia) is practically more important in family counseling than screening for heterozygotes of autosomal diseases.