ΒΙΟΧΗΜΙΚΗ ΓΕΝΕΤΙΚΗ

Kεφάλαιο 7

Λάρισα, 2007

7.1. Major pathway of phenylalanine metabolism. Different enzymatic defects in this pathway cause (1) classical PKU, (2) tyrosinase-negative oculocutaneous albinism, (3) AKU, and (4) tyrosinemias.

Table 7-1. Disorders of Metabolism (Ι)

Name Prevalence Mutant gene productChromosomal

location

Carbohydrate Disorders

Classical galactosemia 1/35,000 to 1/60,000

Galactose-1-phosphate uridyl transferase

9p13

Hereditary fructose intolerance 1/20,000 Fructose 1,6-bisphosphate aldolase

9q13-q32

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

Table 7-1. Disorders of Metabolism (II)

Amino Acid Disorders

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

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

Organic Acid Disorders

Methylmalonic acidemia 1/20,000 Methylmalonyl-CoA mutase 6p

Propionic acidemia Rare Propionyl-CoA carboxylase 13q32; 3q

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

Energy Production Defects

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

Heavy Metal Transport Defects

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

Table 7-1. Disorders of Metabolism (III)

Name Prevalence Mutant gene productChromosomal

location

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-6-phosphate transport

Liver, kidney, intestine, neutrophils

II (Pompe) Lysosomal acid α-glucosidase

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 medium-chain fatty acids can traverse the mitochondrial membrane without carnitine-mediated 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-Lemli-Opitz 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 N-acetyltransferase

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-l-iduronidase, 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-l-iduronidase. 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; non-neuropathic)

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 (late-infantile)

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

CYP2D6

Cytochrome P450 2D6 Codeine Individuals homozygous for an inactivating mutation do not metabolize codeine to morphine and thus experience no analgesic effect

CYP2C9

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 S-methyltransferase

Azathioprine Individuals homozygous for an inactivating mutation develop severe toxicity if treated with standard doses of azathioprine

ADRB2

β-Adrenergic receptor Albuterol Individuals homozygous for a polymorphism get worse with regular use of albuterol

KCNE2

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.)

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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 two-allele 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)

DiseaseChromosome 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

Albinism, oculocutaneous

(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

  13q BRCA2 tumor suppressor/DNA repair protein

  22q CHEK2 DNA repair protein

Li-Fraumeni syndrome 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)

13q5q7q

Connexin-26 gap junction proteinActin polymerization regulatorPendrin (anion transporter; mutations also found in Pendred syndrome)

  11q α-Tectorin

Diabetes

(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

Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (II)

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 3p2p

MLH1 DNA mismatch repair proteinMSH2 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

Hirschsprung disease

(type 1)* 10q RET tyrosine kinase proto-oncogene

(type 2) 13q Endothelin receptor type B

Huntington disease 4p Huntingtin

Hypercholesterolemia (familial) 19p LDL receptor

Long QT syndrome

Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (III)

(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

Myotonic dystrophy 19q Protein kinase

  3q Zinc finger protein

Myoclonus epilepsy (Unverricht-Lundborg)

21q Cystatin B cysteine protease inhibitor

Neurofibromatosis type 1 17q Neurofibromin tumor suppressor

Neurofibromatosis type 2 22q Merlin (schwannomin) tumor suppressor

Parkinson disease

(familial) 4q α-Synuclein

(autosomal recessive early-onset) 6q Parkin

Phenylketonuria 12q Phenylalanine hydroxylase

Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (IV)

Retinitis pigmentosa* (more than 20genes cloned to date; representative examples shown here)

3q6p11q

RhodopsinTULP1 tubby-like proteinRod 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

Tuberous sclerosis

(type 1)* 9q Hamartin tumor suppressor

(type 2) 16p Tuberin tumor suppressor

Usher syndrome*

(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

Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (V)

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.

Table 8-3. Examples of Disease Genes That Have Been Mapped and Cloned* (VI)