C" exons, 125 C gene segment, splicing of, 123

Aagenes syndrome, copper retention in, 171 Abnormal DNA sequence, germ-line V gene component and, 117 Acceleration globulin, 3, see also Factor V Acrodermatitis enteropathica" 153, 192, 195-196 in breast-fed small premature infants, 197-198 Activated clotting factors, inhibition of, 6, see also Blood coagulation factors; factor entries Activated partial thromboplastin time, 7 Activated partial thromboplastin time test defect, 10 Activation peptide, 18-19 Active zymogens, prekallikrein and Factor XII as, 8 Afibrinogenemia, 48-50 Age effect, in intellectually impaired females, 101-103 Alaskan malamute chondrodysplasia, 198-199 Albumin, in copper transport, 163 American Association of Mental Deficiency, 83 Amino acids copper binding to, ISS DNA coding for, 20-21 Anemia copper deficiency and, 153 iron therapy in, 201 Antibody gene expression, lymphocyte differentiation and, 134-137 Antibody gene families, of mice, 115 Antibody genes binding sites and, 117 human, see Human antibody genes study of, 117 Antibody molecules C H regions in, 118 classes of, 118 Antigenic determinants, binding sites to, 117 Antihemophilic factor, 3, see also Factor VIII a-2-antiplasmin, 63-64 a-2-antiplasmin inhibitor,s Antiproteinase, 5 Antithrombin III, 5, 58-60 Antithrombin III deficiency, 58-59 APTT, see Activated partial thromboplastin time Arginine, in fibrinogen Munchen, 50 Arterioductular hypoplasia syndrome, copper retention in, 172 Asparagine, in fibrinogen Munchen, 50 AT-III, see Antithrombin III Auxotrophic mutants, in bacterial metabolism, 151 Bacterial metabolism, auxotrophic mutants in study of, 151 Band q28 abnormality, in X-linked mental retardation, 87 B-cell differentiation, immunodeficiency disorders and, 136 Bedlington terrier, copper toxicosis in, 166, 173 BH4-dependent phenylalanine hydroxylase 303

304 activity, 233-234, see also Tetrahydrobiopterin Biopterin, 266-267, 283 Bleeding diatheses, prothrombin deficiency and,25 Blood clotting factors, molecular genetics in study of, 64-65, see also Blood coagulation; factor entries Blood clotting mechanisms, 1-7 Blood coagulation active site sequences of, 16 genetics of, 1-65 reactions involved in, 6 schematic diagram of, 6 surface contact factors in, 7-15 Blood coagulation factors, 7-17, see also Blood coagulation; factor entries; Surface contact factors B-Iymphocyte differentiation, DNA rearrangements and, 134 B-Iymphocyte ontogeny, diagram of, 135 Bovine cdna probe, 20 Bovine factor VIII: C, 36 Brain damage, in phenylketonuria, 218-219 Breast-fed infants, acrodermatitis in, 197-198 Breast milk, zinc level in, 194 Ca 2 + -dependent antigenic conformer, of factor IX, 23 Cadmium, metallothionein and, 204 CH I domain, 126 C H 2 domain, 126 C H 3 domain, 126 CH 4 domain, 126 C,,2 domain, 126 Calcium ion, in factor V, 32-33 camp-dependent protein kinase, 234 '1-Carboxyglutamic acid domain of, 18 formation of, 21 mutations and, 21-23 Catalytic region, of serine protease enzymes, 20 cdna, partial nucleotide sequences for, 53 cdna clones, HCD protein and, 137 cdna probes, in prenatal diagnosis, 31 Central nervous system copper enzymes in, 157 in phenylketonuria, 221 Cerebrospinal fluid, pterins in, 272-273 Cerebrospinal fluid levels, of biogenic amine neurotransmitter metabolites, 282 Ceruloplasmin, 156, 159-162 in copper transport, 164 in Wilson's disease, 168-169 C~ exons, 126 C" exons, 125 C gene segment, splicing of, 123 C~ gene family, 125-128 C genes, nonallelic, 127-128 evolutionary past of, 133 in mice, 127 C K genes, 122-123 C, genes, 122-123 C" genes, 125 C H genes human, see Human CH genes of mice, 118 Chondrodysplasia, in Alaskan malamute, 198-199 Christmas factor, 4, see also Factor IX Chromium, 202-203 Chymotrypsin, 16 Cloned cdna, fibrinogen synthesis and, 52 Coagulation proteases, inhibitors of, 58-61, see also Blood coagulation Cobalt, 152, 201-202 Complimentary DNA clones, HCD protein and, 137 Connecting domain, 18 Contact activation, in blood coagulation, 6 Contact factors, deficiencies of, 8-13, see also Surface contact factors Copper, 152, 154-191 absorption of, 154 amino acid binding to, 155, 163-164 background information on, 154-167 body content of, 154 daily intake and excretion of, 154 distribution to tissues, 156 Copper deficiency in crinkled mice, 187-189 effects of, 157 knowledge of, 153 Menkes' disease and, 174-178 in mottled mouse mutants, 180-187 in quaking mice, 190-191

305 Copper deficiency (cont.) in X-linked brain disease, 179-180 in X-linked cutis laxa, 178-179 Copper-deficient enzymes, in mottled mouse mutants, 181-182 Copper distribution, in Menkes' disease, 176 Copper enzymes, 156-159 in nervous system, 157 synthesis, sites of, 156 Copper excretion in sheep, 155 in Wilson's disease, 169 Copper isotopes, oral administration of, 155 Copper mutants copper deficiency and, 174-191 copper toxicity and, 167-174 in Wilson's disease, 167-171 Copper proteins, 159-162 Copper retention, in Wilson's and other diseases, 168-172 Copper toxicity, Wilson's disease and, 167-171 Copper toxicosis in Bedlington terriers, 173 in normal sheep, 174 Copper transport albumin and, 163 ceruloplasmin in, 164 current knowledge of, 163-167 metallothionein in, 165-167 postulated steps in, 162 somatic cell genetic analysis of X-linked mutations in, 186-187 species differences in, 157, 167 Copper transport systems, 156 Corrected chromosome, in gene conversion, 131 Cow's milk, zinc level in, 194 C/o. polypeptide region, 123 Crinkled mice, copper deficiency in, 187-189 CRM- (cross-reacting material negative) mutations, 10 CRM - variations, in pre kallikrein deficiency, 13 CRM+ (cross-reacting material positive) hemophilia B, 22 CRM + variants, 26-28 in factor XII deficiency, 11 CRM+ variants (cont.) in factor XII and prekallikrein, 10 in pre kallikrein deficiency, 13 Cs sequences, 125 CH subclass gene family, 130 CH switch regions, 132 Cutis laxa, X-linked, 178-179 Cytochrome c oxidase, 156-159 Cytogenetic marker, in mental retardation, 85 D clusters, 130 DHPR, see Dihydropteridine reductase Differential RNA splicing, 119 7,8-Dihydrobiopterin synthetase, 267 Dihydropteridine reductase, 227-230 BH4 and 6MPH4 activity with, 271 distribution of in animal tissues, 240-241 human values for, 243 hyperphenylalaninemia and, 250, 255-265 molecular properties of, 231 in normal fibroblasts, 258 Dihydropteridine reductase deficiency biopterin in, 263 in hyperphenylalaninemia, 255-265 pathophysiology of, 259-261 in peripheral blood cells, 257 therapy in, 261-265 tyrosine and, 250 wide distribution of, 257 Dihydroxypheny1acetic acid, 274 6,7-Dimethy1tetrahydropterin, 226-227 Disulfide rings, 45 DMPH4, see 6,7-Dimethyltetrahydropterin DNA antibody fragments, DNA po1ymorphisms and, 138-139 DNA coding, of amino acids, 20-21 DNA rearrangements B-lymphocyte differentiation in, 134 chromosome translocations in, 138 general features of, 134 Ig molecules and, 113 V-gene formation and, 116 DNA segments, gene conversion in, 130 DNA sequences germ-line V -gene component of, 117 in Ig polypeptide production, 115-116 DNA strand, recombining chromosomes and, 129 Dopamine ~-hydroxylase, 156-158

306 Dopamine l3-monooxygenase, 156 dump, conversion to dtmp, 95 Dwarfism, in zinc deficiency, 193 Dysfibrinogenemia, 48-51 Epstein-Barr virus, primary B lymphocyte infection by, 136 Erythrocyte phosphoglucomutase, 285 Essential trace elements, current knowledge of, 152-154, see also Trace elements Estradiol level, in mar(x) syndrome, 91 Eukaryotic structural genes, organization of, 20 Exons C" domain, 125 eukaryotic structural genes and, 20 in C~ genes, 126 heavy-chain hinge, 126 Factor I, 3, 44-53, see also Fibrinogen Factor II, 3 mutant molecules in, 28-29 as zymogen, 15 Factor V, 3 Ca 2 + binding to, 32-33 concentration in human plasma, 33 CRM+ and CRM- variants in, 33 genetics of, 33-34 in ex granules of human platelets, 32 murine monoclonal antibody to, 34 parahemophilia and, 31-33 synthesis in liver, 33 Factor V deficiency, bleeding and, 33 Factor VII, 3 mutant molecules in, 28-29 as zymogen, 15 Factor VIII, 2-3, 35-44 biological roles of, 35 as complex plasma glycoprotein, 35 genetic engineering and, 44 genetics of, 39-42 recessive X-linked hemophilia A and, 40 structure of, 35 von Willebrand's disease and, 35 Factor VIII deficiency, 39-44 genetic counseling in, 42-44 inheritance of, 25 Factor VIII: C, 36-38 Factor VIII: CAg, 36-38 Factor VIIIR: WF, heterologous antibodies to, 38-39, see also von Willebrand factor Factor IX, 2, 4 Ca 2 + -dependent antigenic conformer of, 23 mutant molecules in, 29-30 as zymogen, 15 Factor IX deficiency, 22 inheritance of, 25-26 prenatal diagnosis of, 31 Factor IX variants, with localized antigenic defect, 27-28 Factor X, 2, 4 mutant molecules in, 28-29 as zymogen, 15 Factor X activation, in blood coagulation, 6 Factor XI, 2, 4, 7-15 Factor XI deficiency, as Jewish disease, 11 Factor XII, 2,4, 7-15 as active zymogen, 8 Factor XII deficiency, 11-12 Factor XIII, 4, 53-57 genetics of, 56-57 polymorphisms of, 56 thrombin in activation of, 54 Factor XIII deficiency, congenital, 57 Factor XIII deficiency phenocopies, 57 Factor XIIIa, 54 fibrin polymer stabilization by, 55 synthesis of, 55 Female heterozygotes for marker (X), 99-104 age factor and, 100-103 Fibrin, 'I chains of, 54 Fibrin clot formation of, 1-2, 6 lysis of, I thrombin generation and, 2 Fibrin monomers, 45 Fibrinogen, 3, 44-53, see also Factor I amino acid sequence of, 52 ex chain of, 45 13 chain of, 45-46 'I chain of, 45-46 as fibrin monomer, 46-47 genetics of, 51-53 plasmin and, 47

Fibrinogen (cont.) polymerization of, 47 structure of, 45-46 Fibrinogen chains, mrna in synthesis of, 52 Fibrinogen deficiency, 48-51 Fibrinogen Detroit, 50 Fibrinogen Munchen, 50 Fibrinogenolysis, plasminogen activator of, 63 Fibrinoligase, 4, 53-57, see also Factor XIII Fibrinolysis, 61-64 in blood coagulation, 5-6 defined, 1 plasminogen activator and, 63 Fibrin polymers, stabilization of by factor XIIIa, 55 Fibrin-stabilizing factor, 4, see also Factor XIII Flaujeac-Fitzgerald-Williams factor, 5-15, see also High-molecular-weight kininogen Fletcher factor, 4, 9, 12-13, see also Pre kallikrein Foiling's disease, 219 Friesian cattle, parakeratosis of, 196-197 FSF, see Fibrin-stabilizing factor FUdr, in blood cultures, 95 Gamma heavy chains, 125 Gene conversion corrected chromosome in, 131 DNA segments in, 130-131 Gene correction, defined, 131 Gene therapy, factor IX deficiency in, 25 Genetic counseling in factor VIII deficiency, 42-44 in marker(x)-linked mental retardation, 108-109 Germ-line V-gene components, 3' region of, 132 Germ-line V-genes abnormal DNA sequences and, 117 subfamilies of, 130 GLA, see 'V-Carboxyglutamic acid domain Glutamic acid residues, 'V-carboxylation of, 23 Guthrie blood phenylalanine test, 251 307 Hageman factor, 4, 8, see also Factor XII Hageman factor deficiency, 11-12 Hageman factor system, molecular model of contact activation of, 10 HCD, see Heavy-chain disease Heavy-chain constant regions, in antibody molecules, 118 Heavy-chain disease, 137 Heavy-chain hinge exons, establishment of, 126, see also Exons Hemophilia, 35-44 as physiological polymorphism, 64 prenatal diagnosis in, 43 Hemophilia A, 40 Hemophilia B, 22 Hemostasis, defined, I, see also Blood coagulation Hepatolenticular degeneration, 166-171 Hereditary hyperzincemia, 198 Heterozygous females for marker (X) cytogenic features of, 99-104 in X-linked mental retardation, 93-94 5-HIAA, see 5-Hydroxyindoleacetic acid High-molecular-weight kininogen, 7-15 High-pressure liquid chromatographic methods, in biopterin and neopterin level measurement, 283 'VI Hinge, in polypeptides, 127 'V 3 Hinge, in polypeptides, 127 Histidine residue, in copper transport, 163 Homologous nonallelic recombination classes of, 129 between immunoglobulin gene segments, 128-132 molecular features of, 131 Homovanillic acid, 260, 274 Human antibody genes, 113-139 Human C~ genes evolutionary past of, 133 relationships among, 128 Human CH genes, 124-128 Human C L genes, 122 Human chromosomes, and human antibody genes K, k, and heavy, 137-138 Human factor VIlI:C, molecular weight of, 37, see also Factor VIII: C Human haptoglobin ~ chain, blood coagulation factors and, 16-17

308 Human Ig genes, 113-139 nucleotide sequence homology with mouse Ig genes, 132 Human J H family, 124 Human light-chain constant-region loci, 123 Human liver phenylalanine hydroxylase, 236-237 catalytic properties of, 238 lysolecithin and, 238 physical properties of, 240 Human ILl0cus, 125 Human V genes, 121-122 HV A, see Homovanillic acid 5-Hydroxyindoleacetic acid, 260 Hyperphenylalaninema BH4 synthesis defects in, 265-280, 286 defined, 249 differential diagnosis of, 280-285 dihydropteridine reductase deficiency in, 255-265 phenylalanine hydroxylase deficiency in, 280-281 phenylketonuria and, 248 pterin and related therapy in, 268-280 Hyperzincemia, hereditary, 198 IgA antibody, subclasses of, 126-127 IgA antibody molecule, 118 IgD antibody molecule, 118, 136 IgE antibody, subclasses of, 127-128 IgE antibody molecule, 118 IgO antibody, subclasses of, 126-127, 129 IgO antibody molecule, 118 Ig genes, see also Human Ig genes; Mouse Ig genes IgO molecules effector functions of, 13 3 hinge regions of, 133 IgM antibody molecule, 118, 136 Ig mrna, from myeloma tumors, 113 Ig polypeptide, production of, 115 Imbecilitas phenylpyruvica, 219 Immunodeficiency disorders, B-cell differentiation and, 136 Immunoglobulin genes RNA splicing and, 119 sequence conservation and divergence in, 132-134 Immunoglobulin gene segments, homologous nonallelic recombination among, 128-132, see also IgA antibodies Immunoglobulin gene sequences, RNA splicing and, 119-120 Immunoglobulin molecules, genes encoding, 113 Immunoglobulin polypeptide production, 115-116 Indian childhood cirrhosis, copper retention in, 171 Intervening sequences, nontranslated, 20 Intron breakpoints, 129-130 Introns, 20 IQ, mar(x) syndrome and, 97-100 Iron, 200-201 Iron transport, genetic defects of, 150, 200-201 Isoniazid, factor XIII deficiency and, 58 IVS, see Intervening sequences J H genes, 124, 130 J K genes, 124, 130 J gene segment, splicing of, 123 Kayser-Fleischer rings, 168 Kininogen, 5, 7-15 Kringles, 16-17 Lethal milk, 197, see also Milk Liver factor V synthesis in, 33 vitamin K-dependent factor synthesis in, 21 Low-molecular-weight kininogen, 13 Luteinizing hormone level, in mar(x) syndrome, 91 Lymphocyte differentiation, antibody gene expression in relation to, 134-137 Lysis, of fibrin clot, I Lysolecithin, in phenylalanine hydroxylase stimulation, 238, 246 Lysyl oxidase, 156, 158 a-2-macroglobulin, 60-61 physical structure of, 60 Macroorchidism, in mar(x)-linked mental retardation, 89-91 Manganese, 152, 199-200

309 Manganese deficiency, 199 Manganese mutants, 200 Marker(X) absence of in X-linked mental retardation, 93 in cells other than lymphocytes, 95-96 in cultured lymphocytes, 94-95 example of in orcein-stained preparations, 86 female age and, 100-103 in heterozygous females, 99 mental retardation and, 85-86 Marker(X) chromosome, X-linked mental retardation and, 84 Marker(X)-linked mental retardation, 83-109, see also X-linked mental retardation biochemical investigations in, 91-92 clinical features of, 88-92 cytogenetic features of, 94-104 endocrine levels in, 91-92 facial features in, 90 genetic counseling in, 108-109 heterozygous females with, 99-104 intellectual development in, 92 macroorchidism in, 89-91 mutation rate for, 106-107 neuropathology of, 92 phenotype in, 88-89 prevalence of, 104-106 segregation in, 107-108 testicular volumes in, 89 testosterone level in, 91 Marker(X) syndrome, 87, 97-99, see also Marker(X)-linked mental retardation age factor in, 97 IQ and, 97-100 prevalence of, 104-106 testicle size in, 89-91 MCA, see Monochloracetic acid Menkes' disease, 174-178 copper distribution in, 176 depigmentation in, 175 incidence of, 175 metallothionein in, 185-186 mild form of, 177-178 primary molecular defect in, 183-186 X-linked, 179 Mental retardation cytogenic marker in, 85 Mental retardation (cant.) defined, 83 male excess in, 84 marker-linked, see Marker(X)-linked mental retardation in phenylketonuria, 220 X-linked, see X-linked mental retardation Metabolism, vs. transport and utilization of trace elements, 150 Metallothionein cadmium and, 204 in copper transport, 165-167 in Menkes' disease, 185 overproduction of, 198 Methotrexate, in blood cultures, 95 6-Methyltetrahydropterin blood-brain barrier and, 270 in hyperphenylalaninemia therapy, 271-280 structure of, 226 Milk, lethal, 197, see also Breast milk; Cow's milk Molecular genetics, in study of bloodclotting factors, 65 Molybdenum, 203-204 Monochloracetic acid, factor XIII and, 54 Monophenol monooxygenase, 156 Mottled mouse mutants copper deficiency in, 180-187 copper-dependent enzymes in, 181-182 primary molecular defect in, 183-186 Mouse C~ gene family, 127 Mouse gene families, germ-line gene segments of, 115, 118 Mouse Ig genes, 114-121 nucleotide sequence homology with human Ig genes, 132 mrna in fibrinogen synthesis, 52 immunoglobulin and, 113 MT, see Metallothionein Mucosal ferritin, 201 Mucosal transferrin synthesis, 201 Multiple germ-line C, genes, 122 Mutant molecules carrier detection and, 30-31 in factor IX, 29-30 in factor X, 28-29 in plasma proteins, 28-31

310 Mutants, auxotrophic, 151 Mutations, 149-204 as experiments in study of trace element transport systems, 150-152 identification of, 151 iron transport, 150, 200-201 terminology in, 150 toxic trace elements in, 150 in trace element transport in humans and animals, 152 Myeloma tumors, Ig mrna and, 113 NADPH, phenylalanine hydroxylation and, 228-230 Neopterin, 266-267, 283 Neopterin/biopterin ratio, 283-284 New South Wales, mental retardation in, 85, 104 N-terminal disulfide knot, 45 Parahemophilia, factor V deficiency as, 33 Parakeratosis, of Friesian cattle, 196-197 Partial thromboplastin time, 7 Phenylalanine conversion to tyrosine, 227 in glucagon release, 234 metabolism of, 218 nutritional tolerance to, 254 Phenylalanine challenge test, 254-255 Phenylalanine hydroxylase, 225-242, see also Phenylalanine hydroxylating system as affected enzyme in PKU, 243-244 assays for, 252-254 catalytic properties of, 239-240 in human liver, 236-237 lysolecithin stimulation by, 246 molecular properties of, 231 production of, 232 properties of, 246-247 in rat liver enzyme, 227 Phenylalanine hydroxylase activity, BH4- dependent, 226, 233, 268 Phenylalanine hydroxylase deficiency, in hyperphenylalaninemia, 280-281 Phenylalanine hydroxylase gene, linkage with erythrocyte phosphoglucomutase, 285 Phenylalanine hydroxylase stimulator protein, 230 Phenylalanine hydroxylating system, 225-242 components of, 230, 280 enzymes of, 229 Phenylalanine level, in phenylketonuria, 221-222 Phenylalanine load, biopterin level following, 282 Phenylalaninemia, 248 ambiguous meaning of, 249 Phenylketonuria, 217-286 atypical,25l-255 BH4 therapy in, 262-264 blood phenylalanine in, 221 brain damage in, 218-219 central nervous system and, 221 classic, 219, 242-248 diagnosis of, 223, 281 diet in, 224-225 discovery of, 217-220 dual meaning of term, 248-249 historical and general characteristics of, 219-225 human liver enzyme and, 237 mental retardation in, 220 missing component in, 242-245 molecular defect in, 245-248 phenylalanine hydroxylase activity in, 237-238, 243-244 pterin and related therapy in, 224, 262 transmission of, 223 variants of, 248-285 Phenylpyruvic amentia, 219 Philadelphia chromosome, 138 Phosphoglucomutase, 285 Phosphorylation-dephosphorylation, in phenylalanine hydroxylase activation, 234 PHS, see Phenylalanine hydroxylase stimulator protein PK U, see Phenylketonuria Plasma proteins, in blood coagulation process, 1-5 Plasma thromboplastin antecedent, II, see also Factor XI Plasma thromboplastin component, 4, see also Factor IX Plasmin, 61-62 Plasminogen, 5, 61-62 evolution of, 16

311 Plasminogen (cont.) genetically abnormal form of, 62 Plasminogen activator, 5,62-63 POINTER program, 107 flo Polypeptides, gamma heavy chains and, 125 Porcine factor VIII: C, 37 Prekallikrein, 2, 4, 7-15, see also Fletcher factor as active zymogen, 8 Pre kallikrein deficiency, CRM + and CRM- variants in, 13 Primary biliary cirrhosis, copper retention in, 171 Proconvertin, 3, see also Factor VII Protein C, 5, 16, 20 Proteolysis, limited, 8 Prothrombin, 3, see also Factor II molecular weight of, 18 Prothrombin activation, in blood coagulation, 6 Prothrombin complex, 15-31 Prothrombin deficiency, inheritance of, 25 Prothrombin time, 7 PTA, see Plasma thromboplastin antecedent Pterins, in CSF and plasma, 272 Pterin therapy, in atypical PKU, 262, 268-269 Pterin transformations, in phenylalanine conversion to tyrosine, 227-228 PTT, see Partial thromboplastin time Quaking mice, copper deficiency in, 190-191 Quinonoid-dehydrobiopterin, 229 Rat liver phenylalanine hydroxylase, 227 isoenzymes of, 236 as phosphoprotein, 235 phosphorylation of, 234 properties of, 233 Recombinant DNA techniques, in trace element transport studies, 152 RNA precursor, splicing of C and J sequences in, 123 RNA splicing alternate pathways of, 120 Ig genes and, 119 Ig molecules and, 113 Selenium, 152-153, 202 Sepiapterin, 267 Serine proteases, see also Vitamin K- dependent clotting factors inherited variants of, 24-26 mutant molecules and, 28 structure of, 16-21 synthesis of, 21-23 vitamin K-dependent, 15-31 Serotonin, brain turnover of, 274 Serum prothrombin conversion accelerator, 3, see also Factor VII Sheep, copper toxicosis in, 174 Sheep liver enzyme, 241-242 dihydropteridine reductase as, 227 SPINCOMPL program, 14 Stuart factor, 2, 4, see also Factor X Superoxide dismutase, 156-160 Surface contact factors in blood coagulation, 7-15 genetics of, 8-13 list of, 9 physiological and interactive roles of, 8 possible significance of, 13-15 Tandemly repeated oligonucleotides, 132 Testosterone level, in mar(x) syndrome, 91 Tetrahydrobiopterin, 230-233, 242, 245 biosynthesis from GTP, 250, 266 as essential component of phenylalanine hydroxylase system, 226, 228 nonenzymatic regeneration of, 228 in PKU therapy, 262-264 as pterin coenzyme, 230 structure of, 226 Tetrahydrobiopterin synthesis defects, 265-280 Thrombin generation, fibrin clot formation and,2 Thromboplastin, 4 Thyroid hormone level, in mar(x) syndrome, 91 Total parenteral nutrition of human subjects, 153 in zinc deficiency, 192 Toxic milk mice, 172-173 TPN, see Total parenteral nutrition Trace elements in animal and human nutrition, 149-150

312 Trace elements (cant.) current knowledge of, 152-154 mutations affecting, 149-204 transport and utilization of, 150 Trace element transport systems, mutations in study of, 150-152 Trypsin, 16 Tyrosinase, 156, 159 Vanillyl mandelic acid, 250 V-D-J joining event, 134 V-gene component, abnormal DNA sequence and, 117 V-gene formation, DNA rearrangements and, 116 V genes, human, 121-122 V H genes, human, 121 V K genes, human, 121 Vitamin K-dependent clotting factors, see also Serine proteases deficiency states of, 25 genomic organization of domains in, 20-21 humoral agents in control of, 23 mutant alleles and, 27 plasma level control of, 23-24 structure and function of, 16-18 synthesis in liver, 21 Vitamin K-dependent serine proteases, 15-31, see also Serine proteases carboxy-terminal catalytic region of, 19-20 Vitamin K 2,3-epoxidase activity, 21 Von Willebrand factor, 38 Von Willebrand's disease, 35-44 severe classic, 40 types IIA and lib, 41 V-region diversity, mutation of germ-line V-gene segments as source of, 117-118 Wilson's disease, 166-171 copper absorption in, 169 copper excretion in, 169 copper retention in, 168-170 Wilson's disease (cant.) incidence of, 168 liver transplantation in, 170 Xanthine oxidase, molybdenum in, 203-204 X chromosome, mental retardation and, 84-85 X-linked brain disease, copper deficiency in, 179-180 X-linked cutis 1axa, 178-179 X-linked genes male mental retardation and, 84 prevalence of, 104-\05 X-linked mental retardation, 83-109 band q28 abnormality in, 87,96 cytogenetic features of affected males in, 96-99 families with history of, 87 heterozygous females in, 93-94 without marker X, 93 prevalence of, 104-106 recognition of, 84-85 Xq28 marker in, 87, 96 X-replication studies in, 103-104 Xq marker, in X-linked mental retardation, 87-88 Zinc, 191-199 abundance in human body, 192 background information on, 191-195 in wound healing, 193 Zinc absorption, 194 Zinc balance, 193-194 Zinc binding ligand, in breast milk, 194 Zinc deficiency in acrodermatitis enteropathica, 153 in humans, 153 knowledge of, 152-153 reproductive performance and, 193 in wound healing, 153, 193 Zinc deficiency syndromes, 192-193 Zinc enzymes, number of, 191 Zinc mutants, 195-199 Zinc transport, 194 Zymogen, activation peptide of, 18-19