Genetic Pathology Part 12 2021 PDF

Dr. Nor SyafinazYaakob Fakulti Farmasi, UKM [email protected]  Basic introduction to genetics  Genetic expression and mutation  Genetic inheritance patterns  Mendelian disorders  Study of heredity  Important components ▪ DNA ▪ Genes ▪ Chromosomes  Complete se...

Dr. Nor SyafinazYaakob Fakulti Farmasi, UKM [email protected]  Basic introduction to genetics  Genetic expression and mutation  Genetic inheritance patterns  Mendelian disorders  Study of heredity  Important components ▪ DNA ▪ Genes ▪ Chromosomes  Complete set of ALL genes present in human  Normal human karyotype: 46,XY (Male); 46, XX (Female)  Genes ▪ Coding sequence (produce proteins) ▪ Non-coding sequence (eg. promoter/enhancer sequence)  Dominant allele  Recessive allele  Codominant alleles  Critically affect homeostasis via protein expression (eg. enzymes, receptors)  How are genes expressed?  What happens if genes are expressed abnormally? Transcription Translation Folding  Mutation : permanent change in the genetic components  Mutation in germ cells → transmitted to progeny and cause inherited disease  Mutation in somatic cells → do not cause hereditary disease, but can cause other diseases such as cancer and congenital malformations  Genome mutations : involve loss or gain of whole chromosomes  Chromosome mutations : rearrangement in genetic material which leads to structural changes in chromosomes  Gene mutations : submicroscopic, alterations of DNA sequence (gene)  Mutation in one gene that can cause disease → single gene defect/Mendelian disorder  Mutation in multiple genes to cause a disease → polygenic disease  Question : Do all mutations lead to diseases?  Nonsense mutation Point mutations Missense mutation Substitution Insertion Transition Transversion Frame-shift Deletion Trinucleotide repeats Mutations in non-coding sequences Silent mutation 5’ ATG GCT CTC GCC TCA TAA 3’ DNA Met Ala Leu Ala Ser STOP AA  Disease with abnormal structure of hemoglobin (Hb)  Mutation in HBB gene affects the β-globin chain of hemoglobin → produce hemoglobin S  Premature termination of β-globin gene translation  Shorter β-globin peptide – rapidly degraded  Lack β-globin chains  Reduced functional hemoglobin -> reduced mature red blood cell  Mutation in HEXA gene which codes for enzyme β- hexosaminidase A  β-hexosaminidase A catalyse breakdown of GM2 ganglioside (fatty substance)  Disruption of β-hexosaminidase A activity → toxic accumulation of GM2 ganglioside → neuronal damage  Autosomal recessive  Autosomal dominant  X-linked recessive  X-linked dominant  Y-linked  Codominance  Mitochondrial DNA inheritance  e.g. cystic fibrosis e.g. Huntington disease e.g. Fragile X syndrome e.g. Haemophilia  e.g. Leber hereditary optic neuropathy (LHON)  Question : Why is mitochondrial DNA inheritance only passed from the mother? https://ghr.nlm.nih.gov/primer/inheritance/inheritancepatterns  Cytogenetic disorders  Multifactorial disorders  Can occur due to alterations in ▪ Number or chromosomes ▪ Structure of chromosomes What is……….  ?Haploid (n)  ?Diploid (2n)  ?Euploid (2n, 3n…..)  ?Polyploid (> 2n)  ?Aneuploid (2n -1, 2n+1, 2n+2,2n-3)  ?Monosomy (2n-1)  ?Trisomy (2n+1)  Location of genes on a chromosome is specific  Annotated by “chromosome number, arm, region, band”  Abnormality : Chromosomal breakage → loss or rearrangement  Down syndrome  22q11.2 Deletion syndrome  Klinefelter syndrome  Turner syndrome  Multigenic/polygenic/multifactorial  Disorders caused by interactions between different forms of genes and environmental factors  Collective genetic inheritance contribute to Type I diabetes  20 – 30 genes involved; 6 or 7 most important  HLA alleles contribute >50% of risk  Type 1 : childhood/young age onset – body not produced insulin  Type 2 : adult-onset – body has reduced ability to produce/utilize insulin  Nutritional/diet factors play an important contribution  Polymorphism  Reduced penetrance  Variable expressivity