The Egyptian Journal of Medical Human Genetics (2013) 14, 209–21

Zaghloul Salem, Mohammad Saad

English

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The Egyptian Journal of Medical Human Genetics (2013) 14, 209–212Ain Shams UniversityThe Egyptian Journal of Medical Human Geneticswww.ejmhg.eg.netwww.sciencedirect.comEDUCATIONAL CORNER OF THE ISSUEBasic concepts of medical genetics, pathogenetics, part 3Mohammad Saad Zaghloul Salem *Medical Genetics, Faculty of Medicine, Ain-Shams University, Cairo, EgyptReceived 14 December 2012; accepted 23 December 2012Available online 30 January 20131. Pathogenetic mechanisms of genetic diseasesThe genetic material controls life activities of the cell throughregulating the synthesis of proteins which directly mediatethese activities. Regulatory genes, in addition, control the tran-scription of many classes of small RNAs that have fundamen-tal roles in direct and feed-back regulation of most aspects ofthe genetic material [1].Mutations cause structural alterations of the genetic mate-rial. Depending on the site, nature, magnitude and effects ofthe mutational event as well as on the functions and importanceof the mutated genes, pathogenetic mechanisms that result indeficient synthesis of gene products, synthesis of defective geneproducts or disturbed regulation of cellular activities will leadto the development of genetic disorders, secondary to the ensu-ing pathophysiological alterations of cellular functions.Maintaining the stability, integrity and species-specific iden-tity of the genome represents a prerequisite, not only for exe-cuting cell functions properly, but more fundamentally forthe beginning, continuation and conservation of life. It is thepreservation of the collaborative and integrated intimate rela-tionship of these three aspects of the genome that represent thereal kernel and true essence of existence of all forms of life.Many pathogenetic mechanisms that drastically affect genomestability and genome integrity have been defined. These partic-ular groups of mutations constitute important detrimentalevents that act via different pathways, e.g. defective genetic re-* Tel.: +20 1225874345/33354379.E-mail addresses: mszsalem@hotmail.com, mszsalem@yahoo.comPeer review under responsibility of Ain Shams University.Production and hosting by Elsevier1110-8630  2013 Ain Shams University. Production and hosting by Elsevhttp://dx.doi.org/10.1016/j.ejmhg.2012.12.001pair mechanisms or the premature induction of apoptosis,leading ultimately to the loss of genome stability, integrityand induction of cell death. On molecular or cellular level,these mutations might be considered as life-ending mutations.These mutations might also act in a different way throughthe total loss of reproductive fitness and the disappearanceof individual genomes from the gene pool of certain species [2].The spectrum of pathogenetic mechanisms and the resultingpathophysiological disturbances that underlie the developmentof genetic disorders is quite wide in view of the complexity ofthe structural organization of the genome and the strict func-tional specialization that characterizes each of its components.Additionally, the obscure nature and unclear functions of manycomponents of the genetic material, undoubtedly, concealmany, still unknown, pathogenetic mechanisms and hinderproper understanding of their exact pathways. It is hoped thatthe final completion of the human genome project might dis-close the exact and complete structural organization of the hu-man genome. However, a parallel human genome functionproject aiming at defining the complete functional spectrumof the genome seems to be an indispensable and imperative taskin order to finalize the knowledge of our genetic material [3].Currently defined pathogenetic mechanisms and patho-physiological alterations implicated in the pathogenesis of ge-netic disorders include the following:1. Loss/damage/duplication/inactivation of nuclear genes2. Mutation of mitochondrial genes (mitDNA)3. Deficient/defective DNA replication/repair4. Triplet repeat expansion disorders5. Loss/acquisition/damage of chromosomes6. Deficient transcription of mRNA7. Transcription of defective mRNA8. Deficient/defective post-transcription mRNA repairier B.V. All rights reserved.210 M.S.Z. Salem9. Deficient/defective post-transcription modifications ofmRNA10. Deficient translation of proteins11. Translation of defective proteins12. Deficient/defective post-translation modification ofproteins13. Deficient/defective post-translation repair of misfoldedproteins14. Deficient/defective post-translation targeting and traf-ficking of proteins15. Deficient/defective regulation of cell growth16. Deficient/defective regulation of cell division17. Deficient/defective regulation of cell differentiation18. Deficient/defective regulation of cell migration19. Deficient/defective regulation of intercellular contactand cell movement20. Deficient/defective apoptosis/selection repair21. Deficient/defective regulation of cell architecture andcytoskeleton: e.g. ciliary dyskinesia disorders (bronchi-ectasis, dextrocardia and situs-inversus, hydronephrosis,hydrocephaly, male infertility and repeated abortions),hereditary spherocytosis, Wiskott-Aldrich syndromeand neural tube defects.22. Imprinting disorders: genomic imprinting disorders, e.g.ovarian teratomas and hydatidiform moles, and genicimprinting diseases, e.g. Prader-Willi syndrome, Angel-man syndrome, Silver-Russell syndrome and Beckwith-Wiedemann syndrome.23. Deficient/defective regulation of cellular functions:a. Deficient/defective transport across cell mem-brane or membranes of cell organelles (transportdefects)Table 1 Anti-mutation mechanisms of the human genome.Anti-mutation mechanisms of the human genomeMechanism Types & pathways & com1. Structural organization of the genome 1. Nuclear genome2. Mitochondrial genome2. Structural features of DNA Complementary strand sto3. Degeneracy of the genetic code Multiple point mutations4. Nuclear localization of DNA Physical protection of nuc5. DNA-associated proteins 1. Physical barriers2. Biochemical buffers3. Deactivating biomolecu4. Modulation of charge t5. Limitation of DNA hel6. Replication proofreading system Prophylactic pathway dur7. Genetic repair systems A. Nuclear DNA repair1. Base excision repair2. Nucleotide excision rep3. Direct reversal repair4. Mismatch repair5. Recombination repairB. RNA repair/editing sysPost-transcription repair/ecomplexC. Mitochondrial DNA (m8. Protein repair systems Correction of post-transla9. Silencing of transposons by piwiRNA Reduces transposon-induc10. Antioxidant enzyme systems11. Apoptosis Prophylactic pathway agadaughter cells12. Melatonin Anti-clastogenic, anti-mutb. Deficient/defective transport across cell pores, nuclearpores or pores of cell organelles (chanellopathies)c. Deficient/defective secretion of gene products (pro-tein/enzyme deficiency disorders)d. Deficient/defective excretion of metabolic wasteproducts (storage disorders)e. Deficient/defective regulation of intra and inter net-work reactions and interactions: signal transductiondisorders: e.g. neurodegeneration, diabetes mellitus,schizophrenia and Noonan syndrome.f. Deficient/defective positioning of structural proteins(cell cytoskeleton disorders)g. Deficient/defective regulation of intracellulartrafficking.h. Deficient/defective production of cellular energy:oxidative-phosphorylation disorders.i. Ubiquitination/proteasome degradation defects: e.g.Friedreich ataxia, Huntington disease, Parkinsondisease, Alzheimer disease, Angelman syndrome,motor neurone disease and immunodeficiency.j. Apoptosis defects: e.g. congenital malformations,autoimmune disorders, cancer and neurodegenera-tion [4,5].2. Anti-mutation mechanisms of the human genome and humanproteomeThe human genome develops, persists and works in a hostileenvironment full of existing, and continuously generated,mutagens. Mutational events induced by external factors,which include physical, chemical and biological mutagens,mentsres genetic informationmight occur without affecting synthesized proteinlear genomelesransportix distortioning DNA replicationairtemditing of some mRNA defects via guide RNA (gRNA)/editosometDNA) repairtion protein misfolding/aggregation by chaperonesed mutations during developmentinst spread of mutations of heavily or lethally mutated genomes toagenic, anti-carcinogenic and anti-oxidant compound.Basic concepts of medical genetics, pathogenetics, part 3 211have widespread detrimental effects on the stability and integ-rity of the genome as well as on the stability and integrity of theproteome. Additionally, further and considerable damage ofthe structural organization and functional capabilities of boththe genome and the proteome regularly occurs on continuousand progressive basis due to the continuously generated bur-den of internal mutagens that result from the diverse metabolicactivities of the exceedingly large number of metabolic net-works of the cell. Unless a powerful and effective protectiveand repair system actively participates in protecting the gen-ome and proteome of the cell against the deleterious effectsof mutations, and in efficient repair of resulting damage, main-taining the stability and integrity of both of these bio-systemsthat constitute the framework of life activities within the cellwould have been impossible [2].The human genome is endowed with a spectacular multifac-eted strong anti-mutation system responsible for maintainingstability and integrity of the genome and preserving its iden-tity. It acts by protecting the genome from the detrimental ef-fects of mutation and by repairing mutation-induced damage.Obviously, the balance between the pathological effects ofmutation and the ability of the anti-mutation system to coun-teract and to reduce the consequences of these effects repre-sents the main factor that determines the likelihood ofhaving a mutation-induced genetic disease. The human anti-mutation system comprises both innate mechanisms commonto, and shared by, all individuals, e.g. degeneracy of the geneticcode, and acquired aspects determined by the inherited geneticbackground of each human being, e.g. DNA repair system [6].The human transcriptome, being subjected to the samemutational events that can affect, alter and damage theDNA, seems to have efficient anti-mutation mechanisms toguard against occurrence of errors during RNA transcriptionand to correct and repair some post-transcription defects ofmRNA that can cause errors during protein translation. A sep-arate RNA-proofreading system seems to exist and it probablyacts during transcription by relying on the sequence comple-mentarity information or database stored within the comple-mentary silent or non-transcribing strand of DNA.Depending on the sequence of the active strand to ensure accu-rate transcription might result in improper transcription if mis-match errors occur due to, e.g. polymerase dysfunction. Thisassumption might, partly, explain the still un-understandablebehavior of gene function which involves, seemingly needless,indirect and energy consuming mechanisms by transcribing acomplementary mRNA molecule, rather than an identicalmRNA, that has to be decoded again by rRNA and tRNAin the ribosome during translation [Table 1].Appendix A. Part II: MCQsA.1. Choose the best answer1- FISH stands for:a- fluorescent in situ hybridizationb- first induced strand hybrid.c- F1 insertion segment homolog.d- flanking insertion sequence hybrid.e- fluorescent insertion segment hybrid2- Lod score measures:a- the relatedness of two individuals.b- the length of genetic distances.c- how often double crossovers occur.d- the length of a linkage group.e- the likelihood of linkage between genes3- Crossing over occurs during:a- interphase.b- prophase.c- metaphase.d- anaphase.e- telophase.4- Inheritance of both chromosomes from the same parentis a condition called:a- displaced duplicationb- uniparental disomyc- tandem duplicationd- unbalanced polymorphisme- nondisjunction5- Enzyme assay can be used to identify carriers of:a- Cystic fibrosisb- Fragile X syndromec- Oculocutaneous albinismd- Tay-sachs diseasee- b-thalssemia6- Maternal serum level of alpha-fetoprotein (AFP) islower than average in:a- Neural tube defectsb- Exomphalosc- Down syndromed- Twin preganancye- Spina bifida7- The risk for miscarriage associated with amniocentesis isapproximately:a- 1 in 10b- 1 in 50c- 1 in 100–200d- 1 in 1000e- 1 in 100008- Which of the following karyotypes is NOT compatiblewith survival to birth:a- 47, XY, +13b- 47, XX, +18c- 47, XY, +21d- 47, XX, +16e- 48, XXY9- The DiGeorge/Shprintzen syndrome is caused by a dele-tion in:a- chromosome 4b- chromosome 7c- chromosome 15d- chromosome 21e- chromosome 22212 M.S.Z. Salem10- Which of the following is NOT a chromosome instabil-ity syndrome:a- Poikiloderma of Civatteb- Ataxia telangectasiac- Bloom syndromed- Fanconi anemiae- Xeroderma pigmentosum11- Polyploidy refers to:a- extra copies of a genes adjacent to each other on achromosomeb- complete extra sets of haploid genomec- chromosome which has replicated but not dividedd- multiple ribosomes present on a single mRNAe- inversion which does not include the centromere12- Choose the correct statement about the genetic code:a- includes 61 codons for amino acids and 3 stopcodonsb- is almost universal; exactly the same in most ge-netic systemsc- consists of three bases per codond- some amino acids are coded by multiple codonse- all of the above13- X-chromosome inactivation:a- normally takes place in males but not females:b- is the cause of the Y chromosome being geneti-cally inactivec- the same X chromosome is inactive in all of thecells of a femaled- occurs in fruit flies but not in mammalse- results in genetically turning off one of the two Xchromosomes in female mammals14- Chromosome duplication denotes:a- reciprocal exchange between non-homologouschromosomes.b- loss of genes in part of a chromosomec- extra copies of genes on part of a chromosomed- a reversal of order of genes on a chromosomee- extra sets of chromosomes in an organism15- Male to male transmission is a key feature of:a- Autosomal dominant inheritanceb- Autosomal recessive inheritancec- X-linked dominant inheritanced- X-linked recessive inheritancee- None of the aboveAnswers:1 A 6 C 11 B2 E 7 C 12 E3 B 8 D 13 E4 B 9 E 14 E5 D 10 A 15 AReferences[1] Rédei GP. Encyclopedia of genetics, genomics, proteomics andinformatics. 3rd ed. New York, USA: Springer; 2008.[2] Dale Jeremy W, Park Simon F. Molecular genetics of bacteria. 4thed. John Wiley & Sons Ltd.; 2004.[3] Pierce Benjamin A. Genetics: a conceptual approach. 2nd ed.Gordonsville, VA, USA: W.H. Freeman & Company; 2005.[4] Pasternak JJ. An introduction to human molecular genetics. 2nded. Hoboken, NJ, USA: Wiley-Liss, John Wiley & Sons, Inc.; 2005.[5] James Watson D et al. Molecular biology of the gene. 5th ed.Menlo Park, California, USA: Benjamin Cummings; 2004.[6] Passarge Eberhard. Color atlas of genetics. 3rd ed. Stuttgart, NewYork: Thieme; 2007.

Educational corner of the issueBasic concepts of medical genetics, pathogenetics, part 3

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Educational corner of the issueBasic concepts of medical genetics, pathogenetics, part 3

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