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The Pathogenesis of Diseases from Genetic and Genomic Point of View Part 3 - Nonmendelian Rácz and František Ništiar Institute of Pathological Physiology Medical School, Šafárik University 2015/2016 ©Oliver 28.9.2015 gene15c 1 NONMENDELIAN FORMS OF INHERITANCE Expansion of trinucleotide repetitions (dynamic mutations) Imprinting Mitochondrial genes and genetics Errors in alternative splicing (This chapter is NOT about the inheritance of complex diseases) 28.9.2015 gene15c 2 Expansion of trinucleotide repetitions (dynamic mutations) Increased number of triplets (not insertions) disease ??? Increase of repetition number from one generation to the next (anticipation) Does not fit into our concept of classical genetics, molecular biology and mutations More repetitions, more severe disease Only in humans ??? Mostly in noncoding regions Also in exons, but only CAG = Glu 28.9.2015 gene15c 3 DIFFERENT POSSIBILITIES 26.9.2015 gens15c.ppt 4 Expansion of trinucleotid repetitions (dynamic mutations) sy. Martin & Bell, mental retardation, X - linked (fragile X, FRAXA) men 1/1000; women 1/2500 – FRAXE, mental retardation (X) less severe – Myotonic dystrophy (m. Steinert, AD) Huntington disease (AD) ataxia & dementia – Spinal & bulbar muscular atrophy (AR), spinocerebellar atrophy type 1, Haw River sy, Machado - Joseph disease (all AD) Friedreich ataxia (AR) 28.9.2015 gene15c 5 29 29 29 29 29 29 29 29 55 75 95 120 200 325 500 28.9.2015 gene15c 6 sy. Martin & Bell, mental retardation, X - linked The second most common cause of mild mental retardation (IQ 60 – 20) Specific signs – elongated face, big ears, macrorchidism, mitral valve prolapsus 1/1550 m; 1/2500 f A fragile region of the long arm of X (incubation in special medium – without folic acid) 26.9.2015 gens15c.ppt 7 sy. Martin & Bell Xq27, gene FMR-1, chromosome breaks, hypermethylation CGC repetitions in noncoding 5’ region 6 - 53 (mostly 29) norm, stable 54 - 200 „premutation“ expansion 200 - 4000 full mutation, methylation affects the promotor region (OFF) Asymptomatic men pass the defect to their daughters, increase of triplet number, manifestation in the next generation 28.9.2015 gene15c 8 sy. Martin & Bell The coded protein is FMRP Functions of FMRP – High expression in brain and testes – Binds to ribosomes and the complex is transported through axons and dendrites near to synapses – Regulates the translation of specific proteins of nervous system Decreased expression – mental retardation 26.9.2015 gens15c.ppt 9 26.9.2015 gens15c.ppt 10 Zero generation Man, premutation, healthy First generation All daughters carriers of permutation, healthy Sons healthy 26.9.2015 gens15c.ppt 11 A daughter of first generation Change to full mutation during oogenesis Why? How? Always? SECOND AND FURTHER GENERARIONS Sons affected with 50% probability They are fertile!!! Daughters 50% mild signs 26.9.2015 gens15c.ppt 12 Group of neurodegenerative diseases - Huntington (+ 7 others) Only nervous tissue, death of a specific group of cells; manifestation in early adulthood In Hungtinton repetitions in exons - > 35 CAG = > 35 Glu in protein Gain of function mutations Lot of unanswered questions – why in adulthood ? – why a specific group of cells ? the expression of a (mutated) gene depends on a lot of other genes !!!gene15c 28.9.2015 13 28.9.2015 gene15c 14 Huntington 1872 George Huntigton in age 22 years „on chorea“ 26.9.2015 gens15c.ppt 15 Huntington Progressive ataxia (chorea) and decrease of cognitive and mental functions. Broad scale of symptoms, big individual differences Beginning typically in age 35 – 44 years, sometimes earlier – poor prognosis Heredity is formally dominant The faulty protein is prone to aggregation The diagnosis of mutated gene is possible – and thereafter??? – Positive = fate, negative = „survivor guilt“ Therapy only symptomatic 26.9.2015 gens15c.ppt 16 Epidemiology 5 – 10/100 000 (SK 300 – 400) Are they diagnosed ? (not only HD) Exceptions Lake Maracaibo, Venezuela 700/100,000 but also Tasmania and some regions in EU An example of „founder effect“ (big families) 26.9.2015 gens15c.ppt 17 Friedreich ataxia Rare AR disease (1/50 000) Multisystemic - beside symptoms of nervous system cardiomyopathy and disorders of glucose metabolism gene - frataxin repetitions GAA in the 1st intron – norm 7 - 22, disease 200 - 900 (splicing ???) Also classic mutations lead to disease 28.9.2015 gene15c 18 Imprinting - absolutely against Mendel Mendel: Homologous autosomes (mother = father) are equivalent (globin a chains) Imprinting - different expression of genes on homologous chromosomes (mother father) Oddity? Prader - Willi & Angelman sy. PWS: Muscle hypotony, mental retardation, bulimia eat everything what they find, also from garbage AS: Mental & motor retardation, agressivity, do not sleep („happy puppet syndrome“) 28.9.2015 gene15c 19 PWS & AS are different diseases Caused by deletions of the 15th ch. PWS - deletion on CH15 from father AS - deletion on CH15 from mother P 28.9.2015 M P gene15c M 20 And this is only the beginning! Uniparental disomy P P M PWS ! AS ! 28.9.2015 M gene15c 21 Different expression of genes on paternal and maternal chromosomes A B C D E P 28.9.2015 A B C D E M The same genes are present on both chromosomes For normal function we need expression of one set ABCDE gene15c 22 Different expression of genes on paternal and maternal chromosomes 28.9.2015 A B C D E A B C D E P M For normal function we need expression of one set ABCDE This can be achieved by imprinting (block) of some genes on paternal and maternal chromosome gene15c 23 Explanation for normal development gene cooperation is necessary some genes expressed only on maternal, others on paternal chromosome 28.9.2015 gene15c 24 Deletions of maternal on paternal chromosome ABCDE OK AC BDE missing BDE AC missing Uniparental disomy 28.9.2015 gene15c AACC BBDDEE 25 Explanation for normal development gene cooperation is necessary some genes expressed only on maternal, others on paternal chromosome AC m + BDE p = ABCDE (O.K.) Deletion „m“ Deletion „p“ two „p“ two „m“ 28.9.2015 expression BDE not enough expression AC not enough expression BBDDEE not enough expression AACC not enough gene15c 26 Mechanism methylation of regulatory regions of genes catch 22 - what is occuring in the next generation ? AC 28.9.2015 BDE AC gene15c BDE 27 We should something to do with it & & OVUM AC & BDE SPERMIUM AC & BDE PROBLEM WITH THEIR COMBINATION 50 % children with PWS or AS 28.9.2015 gene15c 28 We should something to do with it & & OVUM AC & BDE SPERMIUM AC & BDE Removal of the old sign introduction of new imprinting according to the sex 28.9.2015 gene15c 29 We should something to do with it & & OVUM SPERMIUM Removal of the old sign introduction of new imprinting according to the sex MOTHER FATHER 28.9.2015 gene15c 30 Parthenogenesis is not working The development of zygotes 46 XX or 46 XY is normal only when the chromosomes are from both parents Experiments on mice 46 XX from mother - teratoma 46 XY from father - mola hydatydosa 28.9.2015 gene15c 31 Is it really so rare ? About mice and men Growth, obesity, energetic metabolism gene for IGF2 is active paternal CH7 in mouse gene for IFG2 receptor is active on maternal CH17 Pathogenesis of Type 2 diabetes ??? The cooperation of paternal and maternal part of genome is not so peaceful ??? 28.9.2015 gene15c 32 Mitochondrial genetics In the cells there is one nucleus with two sets of chromosomes (= Mendel’s laws) In the cells there is a great number of mitochondria in each of them more copies of circular two-chain DNA (16569 bp) HETEROPLASMIA Maternal genetics (Eve from Bible?) 28.9.2015 gene15c 33 Functions and pathology of mitochondria Citrate cycle Steroid synthesis Terminal oxidation Damaged in hypoxia, repefusion damage (release of free radicals) Mitochondria and aging 28.9.2015 gene15c 34 The structure of mtDNA 16959 bp Heavy & Light chain and D-loop (triple) Both chains code genes (without intrones) 13 proteins 2 rRNAs (!) 22 tRNAs Small noncoding regions 28.9.2015 gene15c 35 Characteristics of mtDNA Without histones 800 – 1000 copies (up to 10 000) in a cell Maternal heredity Higher mutations rate as in nDNA (ROS, weak reparation mechanisms and also tissue specificity Replicative segregation 28.9.2015 gene15c UGA = stop (Trp) AUA = Ile (Met) AGA/AGG = Arg (stop) Ribosomes similar as in E.coli (chloramfenicol sensitivity) 36 28.9.2015 gene15c 37 28.9.2015 gene15c 38 Genes of terminal oxidation COMPLEX SUBUNBITS IN nDNA and mtDNA I. NADH dehydrogenase II. Succinate dehydrogenase III. Ubichinone: cytochrome Coxidoreductase IV. Cytochromoxidase V. ATP synthase I. 35 – 7 II. 4–0 III. IV. V. 9–1 13 – 3 12 – 2 28.9.2015 gene15c 39 Mitochondrial diseases Mutations of mtDNA - nonmendelian – Sporadic („somatic“), deletions, duplications, affecting protein coding genes or tRNAs – Maternal („gametic“), point mutations or microdeletions – The combination of both (!) Mutations in genes of nDNA coding mitochondrial proteins – mendelian Defects of intergenomic signaling 28.9.2015 gene15c 40 Mitochondrial diseases (mtDNA) Not very common with long names – – – – KSS – Kearns-Sayre sy LHON – Leber hereditary optic neuropathy MERFF – Myoclonic epilepsy, ragged red fibers MELAS – Myopathy, encephalopathy, lactic acidosis, apoplexia Mutations in the genes for tRNAs (?!) Forget it – remember only that most of the symptomes are consequences of altered energy production in tissues with high energy demand – muscles, heart, brain, senses Do not forget it – 22 y. old man with symptoms of stroke, CT negative ??? MELAS ! Accumulation of mutations – explanation of aging? 28.9.2015 gene15c 41