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ΒΙΟΧΗΜΙΚΗ ΓΕΝΕΤΙΚΗ Kεφάλαιο 7 Λάρισα, 2007 7.1. Major pathway of phenylalanine metabolism. Different enzymatic defects in this pathway cause (1) classical PKU, (2) tyrosinasenegative oculocutaneous albinism, (3) AKU, and (4) tyrosinemias. Table 7-1. Disorders of Metabolism (Ι) Name Prevalence Chromosomal location Mutant gene product Carbohydrate Disorders Classical galactosemia 1/35,000 1/60,000 to Galactose-1-phosphate transferase uridyl Hereditary fructose intolerance 1/20,000 Fructose aldolase Fructosuria ∼1/100,000 Fructokinase 2p23 Hypolactasia (adult) Common Lactase 2q21 Diabetes mellitus type 1 1/400 (Caucasians) Unknown Polygenic Diabetes mellitus type 2 1/20 Unknown Polygenic Maturity-onset diabetes of youth (MODY) ∼1/400 Glucokinase (60%) 7p13 1,6-bisphosphate 9p13 9q13-q32 Table 7-1. Disorders of Metabolism (II) Name Prevalence Mutant gene product Chromosomal location Phenylketonuria 1/10,000 Phenylalanine hydroxylase 12q24 Tyrosinemia (type 1) 1/100,000 Fumarylacetoacetate hydrolase 15q23-25 Maple syrup urine disease 1/180,000 Branched-chain α-ketoacid dehydrogenase (multiple subunits) Multiple loci Alkaptonuria 1/250,000 Homogentisic acid oxidase 3q2 Homocystinuria 1/340,000 Cystathionine β-synthase 21q2 Oculocutaneous albinism 1/35,000 Tyrosinase 11q Cystinosis 1/100,000 CTNS 17p13 Cystinuria 1/7,000 SLC3A1 (type 1) 2p SLC7A9 (types II & III) 19q13 Amino Acid Disorders Lipid Disorders MCAD 1/20,000 Medium-chain acyl-CoA dehydrogenase 1p31 LCAD Rare Long-chain acyl-CoA dehydrogenase 2q34-q35 SLO 1/10,000 Δ7-sterol reductase 11q12-q13 Methylmalonic acidemia 1/20,000 Methylmalonyl-CoA mutase 6p Propionic acidemia Rare Propionyl-CoA carboxylase 13q32; 3q Organic Acid Disorders Table 7-1. Disorders of Metabolism (III) Name Prevalence Mutant gene product Chromosomal location Urea Cycle Defects Ornithine transcarbamylase deficiency 1/70,000 to 1/100,000 Ornithine carbamyl transferase Xp21 Carbamyl phosphate synthetase deficiency 1/70,000 to 1/100,000 Carbamyl phosphate synthetase I 2p Argininosuccinic acid synthetase deficiency 1/70,000 to 1/100,000 Argininosuccinic acid synthetase 9q34 Cytochrome C oxidase deficiency Rare Cytochrome oxidase peptides Multiple loci Pyruvate carboxylase deficiency Rare Pyruvate carboxylase 11q Pyruvate dehydrogenase complex (E1) deficiency Rare Pyruvate decarboxylase, E1α Xp22 NADH-CoQ reductase deficiency Rare Multiple nuclear genes Multiple loci Wilson disease 1/50,000 ATP7B 13q14 Menkes disease 1/250,000 ATP7A Xq13 Hemochromatosis 1/200 to 1/500 (European) HFE 6p21 Acrodermatitis enteropathica Rare SLC39A4 8q24 Energy Production Defects Heavy Metal Transport Defects 7.2 Major pathways of galactose metabolism. The most common enzymatic abnormality producing galactosemia is a defect of GAL-1-P uridyl transferase. Defects of galactokinase or of UDP-galactose 4-epimerase are much less common causes of galactosemia. 7.3 Summary of glucose, fructose, and glycogen metabolism. Enzymatic defects in this pathway cause (1) hyperglycemia, (2) Von Gierke disease, (3) fructosuria, (4) hereditary fructose intolerance, (5) Cori disease, (6) Anderson disease, (7) Tarui disease, and (8) FBPase deficiency. Table 7-2. Glycogen Storage Disorders Type Defect Major affected tissues Ia (Von Gierke) Glucose-6-phosphatase Liver, kidney, intestine Ib Microsomal glucose-6phosphate transport Liver, kidney, intestine, neutrophils II (Pompe) Lysosomal acid αglucosidase Muscle, heart IIIa (Cori) Glycogen debranching enzyme Liver, muscle IIIb Glycogen debranching enzyme Liver IV (Anderson) Branching enzyme Liver, muscle V (McArdle) Muscle phosphorylase Muscle VI (Hers) Liver phosphorylase Liver VII (Tarui) Muscle phosphofructokinase Muscle Table 7-3. Phenylalanine Content of Some Common Foods Food Measure Phenylalanine (mg) Turkey, light meat 1 cup 1662 Tuna, water-packed 1 cup 1534 Baked beans 1 cup 726 Lowfat milk, 2% 1 cup 393 Soy milk 1 ounce 46 Breast milk 1 ounce 14 Broccoli (raw) 3 tablespoons 28 Potato (baked) 2 tablespoons 14 Watermelon ½ cup 12 Grapefruit (fresh) ¼ fruit 13 Beer 6 ounces 11 Gelatin dessert ½ cup 36 7.4 Sources of calories of individuals with PKU at different ages. The amount of no-protein medical foods and low-protein medical foods eaten increases with age as the need for energy and protein increases. (Courtesy Kathleen Huntington and Diane Waggoner, University of Oregon Health Sciences.) 7.5 Summary of fatty acid metabolism: (1) fatty acid entry into a cell, (2) activation and transesterification, (3) mitochondrial uptake, (4) oxidation via β-oxidation, and (5) formation of ketone bodies. Note that mediumchain fatty acids can traverse the mitochondrial membrane without carnitinemediated transport. 7.6 A child with Smith-Lemli-Opitz syndrome. Note the broad nasal root, upturned nasal tip, and inner epicanthal folds that are characteristic of this disorder. (Nowaczyk MJ, Whelan DT, Hill RE [1998] Smith-LemliOpitz syndrome: phenotypic extreme with minimal findings. Am J Med Genet 78:419-423.) Table 7-4. Mucopolysaccharidoses* Name Mutant enzyme Clinical features Hurler/Scheie α-1-Iduronidase Coarse face, hepatosplenomegaly, corneal clouding, dysostosis multiplex,† mental retardation Hunter Iduronate sulfatase Coarse face, hepatosplenomegaly, dysostosis multiplex, mental retardation, behavioral problems Sanfilippo A Heparan-N-sulfamidase Behavioral problems, dysostosis multiplex, mental retardation Sanfilippo B α-N-Acetylglucosaminidase Behavioral problems, dysostosis multiplex, mental retardation Sanfilippo C Acetyl-CoA: α-glucosaminide Nacetyltransferase Behavioral problems, dysostosis multiplex, mental retardation Sanfilippo D N-Acetylglucosamine-6-sulfatase Behavioral problems, dysostosis multiplex, mental retardation Morquio A N-Acetylglucosamine-6-sulfatase Short stature, bony dysplasia, hearing loss Morquio B β-Galactosidase Short stature, bony dysplasia, hearing loss Maroteaux-Lamy Aryl sulfatase B Short stature, corneal clouding, cardiac valvular disease, dysostosis multiplex Sly β-Glucuronidase Coarse face, hepatosplenomegaly, corneal clouding, dysostosis multiplex *Hunter syndrome is an X-linked recessive disorder; the remaining MPS disorders are autosomal recessive. †Dysostosis multiplex is a distinctive pattern of bony changes including a thickened skull, anterior thickening of the ribs, vertebral abnormalities, and shortened and thickened long bones. 7.7 A, A boy with a mutation in α-liduronidase, which causes Hurler syndrome. Note his coarse facial features, crouched stance, thickened digits, and protuberant abdomen. B, Transgenic mice with a targeted disruption of α-liduronidase. Progressive coarsening of the face is apparent as 8-week-old mice (left) grow to become 52-week-old mice (right). (Courtesy Dr. Lorne Clarke, University of British Columbia.) Table 7-5. Lysosomal Storage Disorders* Name Mutant enzyme Clinical features Tay-Sachs β-Hexosaminidase (A isoenzyme) Hypotonia, spasticity, seizures, blindness Gaucher (type 1; nonneuropathic) β-Glucosidase Splenomegaly, hepatomegaly, bone marrow infiltration, brain usually spared Niemann-Pick, type 1A Sphingomyelinase Hepatomegaly, corneal opacities, brain deterioration Fabry α-Galactosidase Paresthesia of the hands and feet, corneal dystrophy, hypertension, renal failure, cardiomyopathy GM1 gangliosidosis (infantile) β-Galactosidase Organomegaly, dysostosis multiplex,† cardiac failure Krabbe β-Galactosidase Hypertonicity, blindness, deafness, seizures, (galactosylceramide-specific) atrophy of the brain Metachromatic leukodystrophy Aryl sulfatase A Ataxia, weakness, blindness, brain atrophy (lateinfantile) Sandhoff β-Hexosaminidase (total) Optic atrophy, spasticity, seizures Schindler α-N-Acetylgalactosaminidase Seizures, optic atrophy, retardation Multiple sulfatase deficiency Aryl sulfatase A, B, C Retardation, coarse facial features, weakness, hepatosplenomegaly, dysostosis multiplex *Of the lysosomal storage disorders included in this table, Fabry syndrome is X-linked recessive and the remainder are autosomal recessive. †Dysostosis multiplex is a distinctive pattern of bony changes including a thickened skull, anterior thickening of the ribs, vertebral abnormalities, and shortened and thickened long bones. 7.8 Schematic diagram of the urea cycle. AS, Argininosuccinase; ASA, argininosuccinic acid synthetase; CPS, carbamyl phosphate synthetase; NAGS, N-acetylglutamate synthetase; OTC, ornithine transcarbamylase. 5.18 The circular mitochondrial DNA genome. Locations of protein-encoding genes (for reduced nicotinamide adenine dinucleotide [NADH] dehydrogenase, cytochrome c oxidase, cytochrome c oxidoreductase, and ATP synthase) are shown, as are the locations of the two ribosomal RNA genes and 22 transfer RNA genes (designated by single letters). The replication origins of the heavy (OH) and light (OL) chains and the noncoding D loop (also known as the control region) are shown. (Modified from Wallace DC [1992] Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 256:628-632.) 7.9 Comparison of hemosiderin stain of normal liver (upper left) with hemosiderin stain of livers from individuals affected with hemochromatosis (upper right, lower right, and lower left). Note the varying degree of increased deposition of hemosiderin livers of HH homozygotes. This damages the liver, impairs its function, and can lead to cirrhosis and liver cancer. 2.1 The anatomy of the cell. 7.10 A child with acrodermatitis enteropathica caused by mutations in SLC39A4, encoding a protein necessary for intestinal absorption of zinc. The resulting deficiency of zinc produces a characteristic scaly, red rash around the mouth, genitals, buttocks, and limbs. (Courtesy Dr. Virginia Sybert, University of Washington.) Table 7-6. Examples of Effects of Gene Polymorphisms on Drug Response Gene Enzyme/Target Drug Clinical response CYP2 D6 Cytochrome P450 2D6 Codeine Individuals homozygous for an inactivating mutation do not metabolize codeine to morphine and thus experience no analgesic effect CYP2 C9 Cytochrome P450 2C9 Warfarin Individuals heterozygous for a polymorphism need a lower dose of warfarin to maintain anticoagulation NAT2 N-Acetyl transferase 2 Isoniazid Individuals homozygous for "slow-acetylation" polymorphisms are more susceptible to isoniazid toxicity TPMT Thiopurine Smethyltransferase Azathioprine Individuals homozygous for an inactivating mutation develop severe toxicity if treated with standard doses of azathioprine ADRB 2 β-Adrenergic receptor Albuterol Individuals homozygous for a polymorphism get worse with regular use of albuterol KCNE 2 Potassium channel, voltage-gated Clarithromycin Individuals heterozygous for a polymorphism are more susceptible to life-threatening arrhythmias SUR1 Sulfonylurea receptor 1 Sulfonylureas Individuals heterozygous for polymorphisms exhibit diminished sensitivity to sulfonylurea-stimulated insulin secretion F5 Coagulation factor V (Leiden) Oral contraceptives Individuals heterozygous for a polymorphism are at increased risk for venous thrombosis 7.11 Different combinations of single nucleotide polymorphisms (SNPs) are found in different individuals. The locations of these SNPs can be pinpointed on maps of human genes. Subsequently, they can be used to create profiles that are associated with differences in response to a drug, such as efficacy and nonefficacy. (Adapted from Roses A [2000] Pharmacogenetics and the practice of medicine. Nature 405:857-865.) Αρχές Ιατρικής Γενετικής Kεφάλαιο 8 Λάρισα, 2007 8.1 The number of coding genes mapped to specific chromosome locations. As of March 2003, the number of genes identified is just over 14,000. (From Guyer MS, Collins FS [1995] How is the Human Genome Project doing, and what have we learned so far? Proc Natl Acad Sci U S A 92:10841-10848; the Online Genome Data Base and the Ensembl data base, April, 2005. 8.2 Loci A and B are linked on the same chromosome, so alleles A1 and B1 are usually inherited together. Locus C is on a different chromosome, so it is not linked to A and B, and its alleles are transmitted independently of the alleles of A and B. 8.3A The genetic results of crossover. A, No crossover: A1 and B1 remain together after meiosis. B, A crossover between A and B results in a recombination: A1 and B2 are inherited together on one chromosome, and A2 and B1 are inherited together on another chromosome. C, A double crossover between A and B results in no recombination of alleles. (Modified from McCance KL, Huether SE [1998] Pathophysiology, 3rd ed. Mosby, St Louis.) 8.4 Crossover is more likely between loci that are far apart on chromosomes (left) than between those that are close together (right). 8.5 A, An NF1 pedigree in which each member has been typed for the 1F10 polymorphism. Genotypes for this twoallele marker locus are shown below each individual in the pedigree. Affected pedigree members are indicated by a shaded symbol. B, An autoradiogram for the 1F10 polymorphism in this family. 8.6 An NF1 pedigree in which each member has been typed for the 1F10 polymorphism. The marker genotypes are shown below each individual in the pedigree. 8.7 The LOD score (y axis) is plotted against the recombination frequency (x axis) to determine the most likely recombination frequency for a pair of loci. 8.8 A genetic map of chromosome 9, showing the locations of a large number of polymorphic markers. Because recombination rates are usually higher in female meiosis, the distances between markers (in centiMorgans) are larger for females than for males. (From Attwood J, Chiano M, Collins A, et al. [1994] CEPH consortium Map of chromosome 9. Genomics 19:203-214.) 8.9 An autosomal dominant disease gene is segregating in this family. A, A closely linked two-allele RFLP has been typed for each member of the family, but linkage phase cannot be determined (uninformative mating). B, A closely linked six-allele STRP has been typed for each family member, and linkage phase can now be determined (informative mating). 8.10 A family in which markers A, B, C, D, and E have been typed and assessed for linkage with an autosomal dominant disease-causing mutation. As explained in the text, recombination is seen between the disease locus and marker A in individual III-2 and between the disease locus and marker D in individual III-5. 8.11 A fundus photograph illustrating clumps of pigment deposits and retinal blood vessel attenuation in retinitis pigmentosa. (Courtesy Dr. Don Creel, University of Utah Health Sciences Center.) 8.12 Linkage disequilibrium between the myotonic dystrophy (DM) locus and two linked loci, A and B. The DM mutation first arises on the chromosome with the A1B2 haplotype. After a number of generations have passed, most chromosomes carrying the DM mutation still have the A1B2 haplotype, but, as a result of recombination, the DM mutation is also found on other haplotypes. Because the A1B2 haplotype is seen in 70% of DM chromosomes but only 25% of normal chromosomes, there is linkage disequilibrium between DM and loci A and B. Because locus B is closer to DM, it has greater linkage disequilibrium with DM than does locus A. 8.13 Ankylosing spondylitis, caused by ossification of discs, joints, and ligaments in the spinal column. Note the characteristic posture. (Modified from Mourad LA [1991] Orthopedic Disorders. Mosby, St Louis.) Table 8-1. Association of Ankylosing Spondylitis and the HLA-B27 Allele in a Hypothetical Population* Ankylosing spondylitis HLA-B27 Present Absent Present 90 1,000 Absent 10 9,000 *This table shows that individuals with ankylosing spondylitis are much more likely to have the HLA-B27 allele than are normal controls. 8.14 Localization of a disease gene through deletion mapping. A series of overlapping deletions is studied in which each deletion produces the disease phenotype. The region of overlap of all deletions defines the approximate location of the disease gene. 8.15 Mapping a DNA segment to a chromosome location through in situ hybridization. 8.16 Gene mapping by somatic cell hybridization. The human and rodent cells that fused are selected with the use of a medium such as HAT. The hybrid cells preferentially lose human chromosomes, resulting in clones that each have only a few human chromosomes. Each clone is examined to determine whether the gene is present, thus assigning the gene to a specific chromosome. 8.17 A Southern blot used in a somatic cell hybridization gene mapping experiment (compare with panel shown in Table 8-2). Human and mouse bands differ in size because the two species have different recognition sequences. The human gene probe hybridizes only to the hybrid cells 1, 3, 4, and 7, showing that the probe hybridizes only when chromosome 9 is present (see Table 8-2). Table 8-2. Somatic Cell Hybridization Panel* Clone DNA segment 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Y 1 + - - - + - + + + + - + + - - + - + - + - - - + - 2 - + + + - + - - + - - - + + + - - + + + + - - 3 + - - - - + + + + + - - - + - + - + - + + - + - - 4 + + - + - - - + - + - + + - - - + - + - - + - - - 5 - - + + + + + - - - + - - + - + - + - - + + - + + 6 - + - + - - + - - - + + - + + - + - + - - - + + - 7 + - + - + - + + + + - + - - - + + - + - + + - + - 8 - - + + + - - + + + - + - + + - + + - - - - + + - - - *Note that the DNA segment being tested shows a positive hybridization signal to clones 1, 3, 4, and 7. Each of these clones contains chromosome 9, whereas clones 2, 5, 6, and 8 do not contain this chromosome. This pattern localizes the DNA segment to chromosome 9. 8.18 Radiation hybrid mapping. A cell line containing a human chromosome is irradiated to produce chromosome breaks. The resulting human chromosome fragments are fused with rodent chromosomes so that they will survive. The presence of human chromosome material in rodent cells can be detected by the presence of Alu sequences. Closely linked loci, such as A and B, are frequently found on the same chromosome fragment, whereas loosely linked loci, such as A and C, are infrequently found on the same chromosome fragment. 8.19 The creation of human DNA libraries. Left, A total genomic library is created using a partial restriction digest of human DNA and then cloning the fragments into vectors such as phage, cosmids, or YACs. Right, A cDNA library is created by purifying mRNA from a tissue and exposing it to reverse transcriptase to create cDNA sequences, which are then cloned into vectors. 8.20 A probe was tested against eight clones taken from a human YAC library. The probe hybridized with two of the clones (lanes 6 and 7), indicating overlap between the DNA in the probe and the DNA in each of the two YAC clones. 8.21 The use of STSs to indicate overlap between DNA segments in establishing a contig map. Overlap is indicated when PCR primers for a specific STS amplify DNA from different DNA segments taken from a genomic library. 8.22 An example of a YAC contig map on chromosome 5 in the region of the adenomatous polyposis coli (APC) gene. 8.23 The exon trapping technique. The human DNA segment is placed in a plasmid vector using recombinant DNA techniques. The plasmid vector is cloned into a yeast or mammalian cell that contains appropriate transcriptional machinery. Mature mRNA is isolated and converted to cDNA. The cDNA sequence can then be amplified with PCR to determine its length. If the human DNA segment contains an exon or exons, the resulting fragment will be longer than if it does not. 8.24 An example of a Northern blot, showing the hybridization of a cDNA probe from the EVI2A gene (a gene embedded within an intron of the NF1 gene) with mRNA from adrenal gland, brain, and fibroblasts. This result indicates that EVI2A is expressed in the brain at a much higher level than in the other two tissues. (Courtesy Dr. Richard Cawthon, University of Utah Health Sciences Center.) Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (I) Disease Chromosome location Gene product α-1-Antitrypsin deficiency 14q Serine protease inhibitor α-Thalassemia 16p α-Globin component of hemoglobin β-Thalassemia 11p β-Globin component of hemoglobin Achondroplasia 4p Fibroblast growth factor receptor 3 Polycystic kidney disease 16p Polycystin-1 membrane protein 4p Polycystin-2 membrane protein 6p Fibrocystin-possible receptor protein (type 1) 11q Tyrosinase (type 2) 15q Tyrosine transporter Alzheimer disease* 14q Presenilin 1 1q Presenilin 2 19q Apolipoprotein E 21q β-Amyloid precursor protein Amyotrophic lateral sclerosis 21q Superoxide dismutase 1 Angelman syndrome 15q Ubiquitin-protein ligase E3A Ataxia telangiectasia 11q Cell cycle control protein Beckwith-Wiedemann syndrome 11p Insulin-like growth factor II Bloom syndrome 15q RecQ helicase Breast cancer (familial) 17q BRCA1 tumor suppressor/DNA repair protein Albinism, oculocutaneous Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (II) Li-Fraumeni syndrome 13q BRCA2 tumor suppressor/DNA repair protein 22q CHEK2 DNA repair protein 17p P53 tumor suppressor 22q CHEK2 DNA repair protein Charcot-Marie-Tooth disease (at least 17 loci now identified) (type 1A)* 17p Peripheral myelin protein 22 (type 1B) 1q Myelin protein zero (type 2A1) 1p KIF1B motor protein (type 2B1) 1q Lamin A/C nuclear envelope protein (type 4A) 8q Ganglioside-induced differentiation-associated protein-1 (type 4B1) 11q Myotubularin-related protein-2 (type X1) Xq Connexin-32 gap junction protein Cystic fibrosis 7q Cystic fibrosis transmembrane regulator (CFTR) Deafness, nonsyndromic (more than 75 genes identified to date; representative examples shown here) 13q 5q 7q Connexin-26 gap junction protein Actin polymerization regulator Pendrin (anion transporter; mutations also found in Pendred syndrome) 11q α-Tectorin (MODY1) 20q Hepatocyte nuclear factor-4α (MODY2) 7p Glucokinase (MODY3) 12q Hepatocyte nuclear factor-1α (MODY4) 13q Insulin promoter factor-1 (MODY5) 17q Hepatic transcription factor-2 (MODY6) 2q NeuroD transcription factor Diabetes Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (III) Duchenne/Becker muscular dystrophy Xp Dystrophin Ehlers-Danlos syndrome* 2q Collagen (COL3A1); there are numerous types of this disorder, most of which are produced by mutations in collagen genes Ellis van Creveld syndrome 4p Protein with possible leucine zipper domain Familial polyposis coli 5q APC tumor suppressor Fragile X syndrome Xq FMR1 RNA-binding protein Friedreich ataxia 9q Frataxin mitochondrial protein Galactosemia 9p Galactose-1-phosphate-uridyltransferase Hemochromatosis (adult) 6p Transferrin receptor binding protein Hemophilia A Xq Clotting factor VIII Hemophilia B Xq Clotting factor IX Hereditary nonpolyposis colorectal cancer 3p 2p MLH1 DNA mismatch repair protein MSH2 DNA mismatch repair protein 2q PMS1 DNA mismatch repair protein 7p PMS2 DNA mismatch repair protein 2p MSH6 DNA mismatch repair protein 14q MLH3 DNA mismatch repair protein (type 1)* 10q RET tyrosine kinase proto-oncogene (type 2) 13q Endothelin receptor type B Huntington disease 4p Huntingtin Hypercholesterolemia (familial) 19p LDL receptor Hirschsprung disease Long QT syndrome Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (IV) (LQT1)* 11p KVLQT1 cardiac potassium channel α subunit (LQT2) 7q HERG cardiac potassium channel (LQT3) 3p SCN5A cardiac sodium channel (LQT5) 21q KCNE1 cardiac potassium channel β subunit (LQT6) 21q KCNE2 cardiac potassium channel Marfan syndrome type 1 15q Fibrillin-1 Marfan syndrome type 2 3p TGF-beta receptor 2 Melanoma (familial)* 9p Cyclin-dependent kinase inhibitor tumor suppressor 12q Cyclin-dependent kinase 4 19q Protein kinase 3q Zinc finger protein Myoclonus epilepsy (UnverrichtLundborg) 21q Cystatin B cysteine protease inhibitor Neurofibromatosis type 1 17q Neurofibromin tumor suppressor Neurofibromatosis type 2 22q Merlin (schwannomin) tumor suppressor (familial) 4q α-Synuclein (autosomal recessive early-onset) 6q Parkin Phenylketonuria 12q Phenylalanine hydroxylase Myotonic dystrophy Parkinson disease Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (V) Retinitis pigmentosa* (more than 20 genes cloned to date; representative examples shown here) 3q 6p 11q Rhodopsin TULP1 tubby-like protein Rod outer segment membrane protein-1 6p Peripherin/RDS 4p Retinal rod photoreceptor cGMP phosphodiesterase, β subunit Xp Retinitis pigmentosa GTPase regulator 4p Retinal rod cGMP-gated channel, α subunit Retinoblastoma 13q pRB tumor suppressor Rett syndrome Xq Methyl CpG binding protein Sickle cell disease 11p β-Globin component of hemoglobin Smith-Lemli-Opitz syndrome 11q 7-Dehydrocholesterol reductase Stargardt disease 1p ATP-binding cassette transporter Tay-Sachs disease 15q Hexosaminidase A (type 1)* 9q Hamartin tumor suppressor (type 2) 16p Tuberin tumor suppressor (type 1B) 11q Myosin VIIA (type 1C) 11p Harmonin (PDZ domain-containing protein) (type 1D) 10q Cadherin-23 (type 1F) 10q Protocadherin-15 (type 2A) 1q Usherin (extracellular matrix protein) (type 3A) 3q Predicted transmembrane protein Tuberous sclerosis Usher syndrome* Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (VI) Waardenburg syndrome (type 1 and 3)* 2q PAX3 transcription factor (type 2A) 3p MITF transcription factor (type 2D) 8q SNAI2 transcription factor (type 4) 13q Endothelin B receptor (type 4) 20q Endothelin 3 (type 4) 22q SOX10 transcription factor Wilms tumor* 11p WT1 zinc finger protein tumor suppressor Wilson disease 13q Copper transporting ATPase von Willebrand disease 12q von Willebrand clotting factor *Additional disease-causing loci have been mapped and/or cloned.