MBG Block 4 Exam Review PDF

An individual inherits a pathogenic variant of a gene: - If the pathogenicity is inherited in an autosomal dominant manner, what are the possible genotypes of the parents? AA or Aa for at least 1 - If the pathogenicity is inherited in an autosomal recessive manner, what are...

An individual inherits a pathogenic variant of a gene: - If the pathogenicity is inherited in an autosomal dominant manner, what are the possible genotypes of the parents? AA or Aa for at least 1 - If the pathogenicity is inherited in an autosomal recessive manner, what are the possible genotypes of the parents? aa or Aa for both. Affected parents MUST be aa. Unaffected parents MUST be Aa. Draw the pedigree adding in the following features: the individual is male, neither parent is affected, there are 3 siblings as follows: male with, male without, female without. The maternal grandfather was affected but the maternal grandmother was not (no additional relatives on the maternal side). Neither paternal grandparent was affected and one additional child was also not affected. - Condition is most likely recessive. There does appear to be a discrepancy between males and females so it is most likely x-linked though there is insufficient information to confirm. Details on mom’s siblings as well as on any offspring from the two affected sons would be necessary to clarify. What would you expect for manifestation of a genetic disorder if disease phenotype is influenced by environment and no environmental triggers are present? - No phenotype without trigger OR very mild or low presentation - If the environmental trigger merely increases severity (i.e. XP tumor presentation) then I would expect a later timeline for onset of the phenotype or less severe phenotypes compared to those who experienced the environmental exposures. Which operon example is turned on when needed? - Lac operon Which operon example also has significant translational regulation? - Trp operon Translational regulation in eukaryotes can be thought of as a method that affects the level of translation and/or _________? - Location; affects timing and location What is the role of mRNA higher order structures in regulation? - Folding or 3D conformations affect access to both transcriptional and translational machinery High levels of glucose are available in the environment along with high levels of lactose. What is the most likely consequence for the lac operon in terms of relative activity? - Can be on due to presence of lactose but will be suppressed as utilization of glucose eliminates cAMP What is the expected consequence in terms of gene expression for the following changes: constitutive binding of repressor to operator? - Operon OFF constitutive binding of cAMP to operon? - Operon ON; cAMP available to promote operon A change in sequence prevents mRNA folding. If folding was necessary to enable full transcription of the mRNA, what is the consequence in terms of functional product? - Shortened transcripts (premature termination) or lower level of transcription BOTH have the potential to cause lower function of product Presence of GLUCOSE shuts OFF operon because GLUCOSE is a preferred fuel When lots of glucose metabolism = low cAMP and lac operon is OFF (even in absence of repressor) When glucose metabolism is absent = high cAMP and lac operon can be ON (unless repressor is present) A protein that does not spontaneously fold and is no longer capable of interacting with folding machinery would not be capable of what level(s) of protein structure? - Both tertiary and quaternary; loss of molecular interactions A structurally abnormal protein that is capable of inducing altered structure of normal protein variants would be classified as what and would most likely cause what? - Prion or prion-like; if capable of causing that change in folding when placed in a new cell or system, then it would be infectious as well The genetic sequence of a protein whose active site is made available via conformational changes induced via phosphorylation is altered, turning all serine sites to threonine. What is the potential consequence of this change? - As serine/threonine kinases can often simply phosphorylate both residues, this molecule may still retain function provided all other factors are equal - If this was a complete loss in the ability to be phosphorylated, then this could result in a loss of function A pathogenic variant in the RYR1 gene is observed. 1. What condition is this associated with? - congenital myopathies; specifically central core myopathies 2. If this variant is a biallelic change that causes a nonsense mutation, which inheritance pattern is expected? - Autosomal recessive 3. Severe forms of this mutation are linked with which clinical features in addition to the myopathy? - Facial dysmorphisms and severe respiratory involvement Disorder Gene(s) Onset and Noteworthy or Expected Presentation Fructosemia ALDOB Cross-over with other pathways; correlates with hepatosplenomegaly Galatosemia GALT, GALK1, GALT = most severe; disorder generates galacitol GALE (toxic) PKU PAH Loss of enzyme function can be variable; impacts during pregnancy MSUD BCKDHA, BCKDHB, Multi-subunit complex needed for breakdown of and DBT branched chain amino acids; Branched-chain-α-keto acid dehydrogenase What is the relationship between metabolic disorders and clinical presentation based on tissues? - Tissue specificity based on pathway expression; tissues that do not utilize the pathway are not affected A disorder that affects catabolic breakdown of amino acids is most likely to result in what? - Toxic build-up of the amino acid and/or disruption of downstream pathways Milder PKU could also be thought of as what? - non-PKU hyperphenylalaninemia Condition/Syndrome Genes Implicated Description of Consequences/Disease Features Fructosemia ALDOB Cannot breakdown fructose connections to pentose phosphate pathway Galactosemia Type I = GALT Type I = galacitol, most severe TYPE II = GALK1 Type II and III = more mild with TYPEIII = GALE fewer long-term consequences PKU PAH Toxic build-up of phenylalanine MSUD BCKDHA, Reduced ability to process amino BCKDHB, DBT acids CONDITION Lac operon activity Trp operon activity High levels of trp Depends; not enough Formation of aporepressor information and reduced transcription Lower free trp but high Depends; not enough Unlikely to form levels of trp-tRNA information aporepressor so may still have transcription but will undergo attenuation and block translation via trp-tRNAs Low glucose, high trp, low Low levels due to low Formation of aporepressor lactose lactose and reduced transcription High glucose; high Lower than maximum lac Formation of aporepressor lactose; high trp activity due to loss of and reduced transcription cAMP Disorder Associated Details Genes Alzheimer’s APP, PSEN1, All of the genes are correlated with disease PSEN2, APOE autosomal dominant inheritance and disease severity APOE-ε4 (pathogenic variant) is correlated with increasing severity and risk in absence of the others Wolfram WFS1 DIDMOAD presentation with autosomal Syndrome recessive inheritance Huntington’s HTT expansion 27-35 repeats = next generation at risk but disease (CAG repeats) no risk to parent >35 repeats = at risk for disease presentation with increasing probability and severity with increasing number of repeats Spina bifida and MTHFR and many Closure of the neural tube during Myelomeningoce others development is HIGHLY correlated with le folic acid metabolism and multiple genes Syndactyly HOXD13 Loss in apoptosis; failure to properly develop structure Congenital See other more detailed charts! Be able to myopathies differentiate the 4 we discussed based on genes and clinical presentation!! Condition Inheritance Most Most Common change and Pattern Common additional information Gene Implicate d Central core Autosomal RYR1 Missense Myopathy Dominant Central core Autosomal RYR1 Biallelic mutations; variable myopathy Recessive missense and nonsense Nemaline Autosomal ACTA1 Missense (often Myopathy Dominant heterozygous) Nemaline Autosomal NEB Splice site mutations, Myopathy recessive frameshifts (+ or -