Genetic Disease study notes - restriction enzymes (endonucleases) - enzymes, mostly from bacteria, which cleave DNA at specific sequences - exons are expressed - Southern blot- probe to search for particular DNA sequence in fragments separated by electrophoresis - Northern blot - search for mRNA - Western - search for protein - PCR - used to identify small quantities of DNA - congentital disease - a disease present at birth - G banding - technique which visualizes bands on chromosomes, improving our ability to localize genes and recognize minor karyotypic problems - lyonization - inactivation, early in embryogenesis, of all but one of the X chromosomes in each cell; once occurred, the same X chromosome will be inactivated in all of that cell's progeny, where it will be the BArr body, or sex chromatin - somatic mosaicism - when all cells in a person do not have essentially the same genetic makeup; can result from a mutation in one cell during the early stages of embryogenesis, or even from the fusion of two fertilized eggs to produce one person (chimerism) - balanced polymorphism - heterozygote enjoys an advantage that has allowed selection for the gene, making the homozygous common - genetic disease categories cytogenetic disorders autosomal disorders sex chromosome disorders parental imprinting problems single-gene disorders autosomal dominant disorders autosomal recessive disorders sex-linked disorders mitochondrial gene disorders polygenic disorders Cytogenic disorders - aneuploidy results from failure of homologous chromosomes to move into separate progeny cells; this may be from nondisjunction during the first meitotic division, or anaphase lag in any other cell division - autosomal monosomy or no X chromosome causes early loss of the embryo; all trisomies except tri 21 produce infants who will usually die during hte first few months of life, around half of early spontaneous abortions has a trisomy; unless a parent carries a balanced translocation, or when parental age is a factor, there is no real tendency for these problems to recur - fragile chromosome syndromes - Bloom's syndrome, Fanconi's anemia, and ataxia-telangiectasis; all pts have high risk of cancer - Trisomy 21: Down's syndrome - affects around 1 in 700; advanced maternal age is a factor; 1 in 25 of mother's over 45; 20% extra chromosome is of paternal origin; 95% have 3 separate 21's, 4% have a translocation, 1% are mosaics; - several signs - flattened face, open mouth, big tongue, mongolism, mental retardation, lack of muscle tone at birth, simian crease, radiographic abnormalities, brushfeld spots on iris, heart defects, gentle, shy demeanor - future health problems - hypothyroidism, conductive hearing loss, bad respiratory infections, various leukemias, Alzheimer's (always develops in pts after 40) - half are dead by age 30 - other autosomal problems - trisomy 18 (Edward's syndrome) - tiny jaw, overlapping fingers, rocker-bottom feet - trisomy 13 (Patau's syndrome) - tiny head, arhinecephaly, tiny eyes, polydactyly, scrambled viscera - deletion of the short arm of chromosome 5 is cat-cry syndrome - children are profoundly retarded, but some survive into adulthood - Prader-Willi and Angelman syndromes - a major mystery of contemporary genetics; been well-characterized for many decades, each affects 1 child in 1000; Prader-Willi pts are dull, cross-eyed, almond shaped epicanthic folds, hypotonia, small hands and feet, growth delay, and hypogonadism; they overeat, hide food, and become very obese; prone to outbursts and violence; these pts lack the normal gene from thier father Angelman pts are severly retarded, microcephaly, and huge jaws; have jerky, puppet-like movements and laugh alot; lack the normal gene from their mother; they inherited mom's gene deletion - sex chromosomal disorders - rules - a Y chromosome is necessary and sufficient to make a phenotypic male, provided the body can make use of testosterone - the more extraneous X chromosomes, the more abnormal the person - you will usually miss the diagnosis after birth, and may only make it late in adult life - Kleinfelter's syndrome - when a man has more than one X chromosome; 1 in 850; etiology is unknown, and maternal age is a factor - at puberty, small testes, long arms and legs, often small penis; - Leydig cells do not function well, serum gonadotropins are high, Leydig cells are hyperplastic, plasma testosterone is low, and estrogens are high, sn tubules are always underdeveloped - manu have libidos and ejaculations; almost all are sterile - XXY guys have lower IQs, slower learning, but are seldom retarded; XXYs are over-represented in prison populations; violent XXYs are rare - XYY syndrome (supermale) - around 1 in 1000 has an extra Y chromosome; usually taller, have worse acne, higher hFSH, hLH, and testosterone, and slightly lower IQs - one study noted, (1) they have lower IQs and higher testosterone levels, and slightly over-representd; (2) among tall men of any karyotype, rate of conviction correlates with plasma testosterone wit hlittle contribution from karyotype; (3) typical crime for XYY is wife-beating; (4) not striking difference - Turner's syndrome - result of monosomy for the short arm of the X chromosome; about 1 in 2000 women; half are XO, rest have an isochromosome of the long arm of X, or have partial deletion of hte short arm of X, or are mosaics - major problem is failure of feminization at adolescence - pts have webbed-neck, shield chest, cubitous valgus, most not diagnosed until teens, if fail to menstrate, then Turner's is most common cause; also have coarctation of hte aorta - Multi-X females (super female) - around 1 woman 1000 has three or more X chromosomes; most 47 XXX are normal, 48 XXXX and 49 XXXXX are retarded - Hermaphrodites and intersex states - genteic sex - determined by if you have a Y chromosome (really TDF) - gonadal sex - determined by histology of the gonads (little eggs and follicles, or little tubules and Leydig cells, or both (hermaphrodites)) - ductal sex - determined by whether the mullerian or wolffian ducts developed - phenotypic sex - determined by external genitalia - majority of hermaphrodites are 46 XX, with translocation of the Y to another chromosome - pseudohermaphrodites - disparity between gonadal and phenotypic sex - female pseudohermaphrodite - has penis and ovaries, usually because of exposure to male hormones before birth; usual problem is glitch in glucocorticoid synthesis; penis is really a big clitoris - male pseudohermaphrodite - has a vula and testis; infant has problem with testosterone biosynthesis; infant may lack testosterone receptors (testicular feminization); - gender dysphoria - transexualism, boy insists he's a girl Mendelain Disorders - enzyme defects cause substates to accumulate, and/or prevent formation ofa good end product - defects in receptors and transport systems produce various malabsorption syndromes, urinary wasting syndromes, unresponsiveness to hormones, problems mobilizing lipoproteins - altered non-enzyme proteins include altered structure and function, and abnormal quantities - altered response to drugs - if lack G6PD, you get hemolytic anemia from various oxidizing drugs, fava beans; Autosomal Dominant Disease - when a person has only one good gene where most people have two, the person can expect to make 50% as much of the good protein as do most other people - fall into 5 categories 1) problems with quantity or arrangement of large structural proteins 2) problems with regulator proteins and receptors, which permit relatively good quality life 3) deficiency in proteins which are in short supply even in health 4) anti-oncogene deletion syndromes, in which a second hit on the normal cell turns it to a tumor cell 5) the mutant gene makes a harmful protein - common autosomal dominant diseases do not kill or disable until the patient has had a good chance of having a family - Marfan's syndrome - heterogenous group of genetic disorders with connective tissue problems - patients are tall, with very long extremities; arm span exceeds height - joints are hyperextendable - generally slender - ectopia lenses; globe is long and cornea flat - aortic dissection kills about 1/3 - as patient gets older, aortic valve becomes lax - chromosome 15; codes for fibrillin, a protein that codes for elastin - two models 1) lathyrism - caused by feeding sweet peas to turkeys and resulting in fatal aortic dissection, results from B-aminoproprionitrile inhibiting lysine oxidase, which cross-links collagen and elastin fibers 2) Menke's kinky hair disease - prevents normal handling of copper, prevents function of lysine oxidase - Ehlers-Donlos Syndrome - family of variably inherited diseases which leave a person with poorly-woven collagen - overly-extensible; skin injurs easily, and heals poorly - Familial hypertrophic cardiomyopathy - due to missense in key portions of the B-cardiac myosin chain - Familial hypercholesterolemia - 1 in 500; also minor forms - lack enough good apoprotein B-100 (LDL) receptors, therefore they have trouble with 1) hepatic clearance of VLDL leftovers for recycling, then leaving plasma to turn into LDL's 2) hepatic clearance of LDL's from the plasma, laeving high plasma LDL levels 3) receptor-mediated uptake of LDL's by other cells leaving more around to be taken up by the mononuclear phagocytes by their receptor-independent method - disregulated uptake of LDL's by macrophage clusters leads to xanthomas - disregulated uptake of LDL's by phagocytes of the arterial intima probably causes atherosclerosis - classic familial hypercholesterolemia features 50% reduction in B-100 apoprotein receptor effectiveness Autosomal Recessive Diseases - many body proteins are in such abundant supply that if a person has only half as much of that protein there is no obvious problem 1) deficiencies or defects in highly specialized preteins 2) hemoglobinopathies requiring more than one dose of a gene - in contrast to autosomal dominant, autosomal recessive often result from consanguineous matings, often apparent at birth, have unknown mutation rates, and generally show complete penetrance - if autosomal dominant is common, then heterozygote may offer some advantage - sickle cell against malaria - hemochromatosis carriers have less trouble maintaining iron body stores - CF carriers probably are more resistant to gram- intestinal infections - albinism - inability to synthesize melanin - deficiency in tyrosinase - patients suffer from light-sensitive eyes and skin, skin cancers, and eye cancers - alkaptonuria - lack of homogenistic acid oxidase - these products accumulate in the urine and cartilages - articular cartilages wears out early, causing precocious arthritis of the spine and big joints - lysosomal storage diseases - Tay-Sachs disease - lack of hexaminose A, causing accumulation of GM2-ganglioside - around 1 in 30 are carriers (ashkenazic) - neurons especially effected - babies normal at birth, then become blind, retarded, and limp - brain and head enlarge due to accumulation of lipid - cherry red spot on eye - heterozygotes extra resistant to TB - Niemann-Pick disease - lack of one of several enzymes to break down shpingomyelin - type A (no sphingomyelinase) - accumulation of spin. and cholesterol in neurons and the body's fixed phagocytes, notably liver and spleen - type B have large livers and spleens but no CNS involvement - Gaucher's disease - lack of glucocerebrocidase - Type I - subtotal deficiency of glucocerebrosides; 1 in 12 Ashkenazi is a carrier; massively enlarged spleens, and livers and nodes; most accumulations from olr RBC; develop pancytopenia; skeletal problems from marrow being packed with ever expanding cells; - Type II - mutation is different and neurons are progressively destroyed; children have progressive menal retardation and die after a few years (not a ethnic disease) - Type III - intermediate severity, causes progressive dementia beginning in teens - mucopolysaccharidoses - problems degrading glycosaminoglycans - Hurler's syndrome (gargoyle children with progressive mental retardation) to sanfilipo (severly mental deterioration) and morquio (dwarves with bad aortic valves and normal intelligence) - Hunter's is sex-linked; mild to severe accumulation of mucopolysaccharides; coronary arterial intima is also narrowed, resulting in infarcts - glycogen storage diseases - Type I - (Von Gierke's disease, G6PD deficiency)- patients have big livers and most of the problems are due to hypoglycemia - Type II - (Pompe's disease) - patients have involvement of all organs, and die young of heart disease - Type V - patients are poor athletes, and get bad muscle cramps and damage when they try; glycogen is deposited beneath the sarcolemma Sex-linked Diseases - chromosomes X and Y have only a short homologous regions at the tip of the short arm; locus for pseudoautosomal inheritance; - rules - 1)affect all males with the gene 2) affect a woman only if (1) she had two affected X-chromosomes; (2) she suffers from really unfortunate lyonization; (3) the disease is expressed when individually lyonized cells are affected; (4) she has Turner's syndrome (XO) or testicular feminization (XY) - only 2 conditions known to be carried on the Y-chromosome are: 1) being a man 2) having lots of hair grow on your ears when you get old - Fabry's disease - deficiency of the enzyme that breaks down ceramide trihexose - accumulates in blood vessels and elsewhere - involved in renal glomeruli; also some brain involvement - Fragile X syndrome - about half of the cases of familial retardation now appear due to a single genetic defect - almost as common as Down's - distinctively large testes, affect in the IQ range of 35-50 Mitochondrial Inheritance - diseases carried on the extranuclear DNA of the mitochondria - get mitochondria from our mothers - all of these diseases are progressive, and affect cells non-uniformly - first cloned mitochondrial disease gene was for Leber's hereditary optic atrophy - progressive visual impairment - then Kearns-Sayre (prog. external opthalmoplegia, retinal pigmentation, heart block, cerebellar ataxia) and progressive external opthalmoplegia were found to be caused by various deletions of the mitochondrial genome - myoclonus epilepsy with ragged red fibers - inherited maternally; mutation in the lysine transfer RNA gene; the ragged red fibers look that way because of proliferated, dysfunctional mitochondria packed around their edges - other mitochondrial diseases are coded by the nuclear DNA - maternal inheritance is a near synonym for mitochondrial inheritance Polygenic disorders - diseases and conditions in which heredity clearly plays a dominant role, but for which there is clearly no single gene, include: - alcoholism, atherosclerosis, baldness, breast cancer, common eye problems, cleft palate, diabetes mellitus, high BP, idiopathic gout, neural tube defects, pyloric stenosis, schizophrenia - evidence for polygenic inheritance 1) adoption studies demonstrate that nature is more important than nurture for this disease 2) there is no classic pattern of inheritance in most large kindreds 3) parents and sibs are at some increased risk 4) the sicker the index patient, the greater the risk to the near-kin 5) the more sibs that are affected, the greater the risk to the next baby 6) diseases are of variable severity, and minor or even trivial cases can be found 7) because the disease is caused by piling up of several abnormalities, environment modifies the full expression of most of these diseases, and identical twins of patients, while at high risk, are not variably affected Genetic Diseases that are Never Inherited 1) fertilized egg with the disease in non-viable 2) all patients with these diseases are mosaics, and express their conditions variably depending on where affected cells may be - McCune Albright's polystotic dysplasia - Creutzfeldt-Jakob's is a disease that produces an infectious particle that can be propagated to healthy people - neoplasms are the great acquired genetic disease