Mendelian Inheritance and Repeat Expansion Disorders
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Questions and Answers

What is the genetic basis of Huntington disease?

Expansion of CAG triplet repeat in exon 1 of the HTT gene

Which type of inheritance is associated with Huntington disease?

  • Autosomal recessive
  • Autosomal dominant (correct)
  • X-linked dominant
  • X-linked recessive

    • Huntington disease has a complete penetrance over the individual's lifespan.

    True

    Huntingtin (HTT) gene contains a polyQ tract and ______________ domains.

    <p>HEAT</p> Signup and view all the answers

    What is the global prevalence of Huntington disease?

    <p>5 per 100,000 individuals</p> Signup and view all the answers

    What is the median survival after onset of Huntington disease?

    <p>15-18 years</p> Signup and view all the answers

    What is the mechanism behind the expansion of triplet repeats during gametogenesis?

    <p>Backward slipping of new strand and loop formation</p> Signup and view all the answers

    What is the characteristic feature of the Huntingtin gene in individuals affected by Huntington disease?

    <p>An expanded polyglutamine (polyQ) tract</p> Signup and view all the answers

    What is the consequence of somatic instability in triplet repeat disorders?

    <p>Influences disease progression</p> Signup and view all the answers

    Which of the following is a characteristic of somatic expansion in triplet repeat disorders?

    <p>Occurs in both dividing and non-dividing cells</p> Signup and view all the answers

    Which type of cells are most affected by the somatic expansion of triplet repeats in Huntington disease?

    <p>Neurons in the cerebral cortex</p> Signup and view all the answers

    What is the mode of inheritance associated with Huntington disease?

    <p>Autosomal dominant</p> Signup and view all the answers

    What is the term used to describe the variation in the degree of expansion among different somatic tissues?

    <p>Somatic mosaicim</p> Signup and view all the answers

    What is the typical range of repeats in the Huntingtin gene of unaffected individuals?

    <p>30-40 repeats</p> Signup and view all the answers

    During replication, what happens to the new strand in triplet repeat expansion?

    <p>It slips backward</p> Signup and view all the answers

    What is a consequence of active transcription through repeats in triplet repeat disorders?

    <p>Formation of RNA-DNA hybrids (R-loops) and exacerbation of somatic instability of repeats</p> Signup and view all the answers

    What is the consequence of the somatic expansion of triplet repeats in Huntington disease?

    <p>Toxic protein aggregation</p> Signup and view all the answers

    What is the result of inefficient mismatch repair in triplet repeat expansion?

    <p>Increased repeat expansion</p> Signup and view all the answers

    Which of the following mechanisms is NOT associated with the pathogenesis of triplet repeat disorders?

    <p>Epigenetic modification of histone proteins</p> Signup and view all the answers

    Which of the following is a characteristic feature of triplet repeat disorders?

    <p>Repeat expansion</p> Signup and view all the answers

    Which brain regions show a greater degree of somatic expansion?

    <p>Striatum and cortex</p> Signup and view all the answers

    What is the characteristic feature of the FMR1 gene in Fragile X syndrome?

    <p>Expansion of CGG repeats in the 5'UTR region</p> Signup and view all the answers

    What is the primary mechanism of repeat expansion in Huntington disease?

    <p>Slipped-strand mispairing</p> Signup and view all the answers

    What is the characteristic pattern of disease progression in triplet repeat disorders?

    <p>Earlier age-of-onset and increasing severity from one generation to the next</p> Signup and view all the answers

    Which tissue is most resistant to somatic expansion of triplet repeats in Huntington disease?

    <p>Blood</p> Signup and view all the answers

    Which type of inheritance is associated with Fragile X syndrome?

    <p>X-linked dominant</p> Signup and view all the answers

    What is the consequence of hypermethylation of DNA at gene promoter regions in triplet repeat disorders?

    <p>Transcriptional silencing of the gene</p> Signup and view all the answers

    What is the name of the gene affected in Huntington's disease?

    <p>HTT</p> Signup and view all the answers

    Which of the following is a characteristic feature of triplet repeat disorders?

    <p>Expansion of triplet repeats</p> Signup and view all the answers

    What is the mechanism by which triplet repeat expansions can lead to neurodegeneration?

    <p>Formation of protein aggregates and activation of the DNA damage response</p> Signup and view all the answers

    What is the primary characteristic that distinguishes triplet repeat disorders from other types of monogenic disorders?

    <p>Expansion of tandem repeats</p> Signup and view all the answers

    Which of the following is NOT a common feature of triplet repeat disorders?

    <p>Cancer predisposition</p> Signup and view all the answers

    What is the primary mechanism underlying the pathogenesis of Huntington disease?

    <p>Toxic gain of function of the huntingtin protein</p> Signup and view all the answers

    Which of the following is an example of a triplet repeat disorder that affects the peripheral nervous system?

    <p>Myotonic dystrophy</p> Signup and view all the answers

    What is the primary benefit of using whole-genome sequencing for the diagnosis of repeat expansion disorders?

    <p>Ability to detect expansions in non-coding regions</p> Signup and view all the answers

    Which of the following triplet repeat disorders is characterized by anticipation?

    <p>All of the above</p> Signup and view all the answers

    What is the primary function of the huntingtin protein in healthy individuals?

    <p>Transport of vesicles along microtubules</p> Signup and view all the answers

    Which of the following is a characteristic feature of the somatic instability of triplet repeat disorders?

    <p>All of the above</p> Signup and view all the answers

    What is the range of CAG triplet repeats in the normal population?

    <p>11-35 CAG repeats</p> Signup and view all the answers

    What is the risk associated with pre-mutation range during gametogenesis?

    <p>Risk of expansion to pathogenic range</p> Signup and view all the answers

    What is the principle behind PCR amplification for molecular diagnosis of Huntington disease?

    <p>Size-based separation of PCR products</p> Signup and view all the answers

    What is the correlation between CAG repeat size and age of onset?

    <p>Inverse correlation between CAG repeat size and age of onset</p> Signup and view all the answers

    What is the characteristic of CAG repeat expansion in Huntington disease?

    <p>Trinucleotide repeat expansion</p> Signup and view all the answers

    What is the typical feature of juvenile onset in Huntington disease?

    <p>Earlier onset and more severe symptoms</p> Signup and view all the answers

    What is the purpose of electrophoretic separation in molecular diagnosis of Huntington disease?

    <p>To separate PCR products based on size</p> Signup and view all the answers

    What is the significance of prenatal diagnosis in Huntington disease?

    <p>To determine risk of disease in progeny</p> Signup and view all the answers

    What is the normal function of CFTR in the respiratory tract?

    <p>It plays a role in mucociliary clearance</p> Signup and view all the answers

    What is the effect of ivacaftor on CFTR?

    <p>It potentiates the activation of CFTR by forskolin</p> Signup and view all the answers

    What is the effect of PKA phosphorylation on CFTR?

    <p>It induces a conformational change leading to pore opening and chloride flux</p> Signup and view all the answers

    What is the temperature at which the cells were incubated overnight to improve cell surface density of mutant channels?

    <p>27°C</p> Signup and view all the answers

    What is the characteristic feature of CFTR in the apical membrane of bronchial epithelium?

    <p>It is normally localized on the apical membrane</p> Signup and view all the answers

    What is the effect of ivacaftor on chloride transport in G551D-FRT cells compared to F508del-CFTR cells?

    <p>It has a greater effect on G551D-CFTR cells</p> Signup and view all the answers

    What is the consequence of impaired CFTR function in cystic fibrosis?

    <p>Enhanced Na+ reabsorption and H2O reabsorption, leading to dehydration and acidification of airway surface liquid</p> Signup and view all the answers

    What is the activator of CFTR used in the experiment?

    <p>Forskolin</p> Signup and view all the answers

    What is the role of cAMP in the activation of PKA?

    <p>It binds to PKA and activates it</p> Signup and view all the answers

    What is the effect of CFTR dysfunction on bronchial epithelium?

    <p>It results in impaired mucociliary clearance and dehydration of airway surface liquid</p> Signup and view all the answers

    What is the type of transport increased by ivacaftor in cells expressing recombinant G551D or F508del CFTR?

    <p>Chloride transport</p> Signup and view all the answers

    What is the chamber used to measure transepithelial chloride transport?

    <p>Ussing chamber</p> Signup and view all the answers

    What is the mechanism by which PKA activates CFTR?

    <p>Through phosphorylation of the regulatory domain</p> Signup and view all the answers

    What is the effect of ivacaftor on CFTR activation?

    <p>It potentiates CFTR activation by forskolin</p> Signup and view all the answers

    What is the function of CFTR correctors?

    <p>To correct defective folding and trafficking of the CFTR protein</p> Signup and view all the answers

    What is the purpose of using Ivacaftor (VX-770) in CF cell models?

    <p>To potentiate channel activity in the CFTR protein</p> Signup and view all the answers

    What type of mutation is the G551D mutation?

    <p>Class III mutation, defective channel gating</p> Signup and view all the answers

    What is the purpose of cell-based assays in the study of CF?

    <p>To measure the functional activity of the CFTR protein</p> Signup and view all the answers

    What is the name of the company that is working on CFTR modulators?

    <p>Vertex Pharmaceuticals</p> Signup and view all the answers

    What is the purpose of amplifiers in the treatment of CF?

    <p>To increase the amount of functional CFTR protein</p> Signup and view all the answers

    What is the name of the CFTR potentiator that is used to treat CF?

    <p>Ivacaftor (VX-770)</p> Signup and view all the answers

    What is the most common CFTR variant associated with cystic fibrosis?

    <p>F508del</p> Signup and view all the answers

    What is the estimated frequency of cystic fibrosis carriers?

    <p>1/25</p> Signup and view all the answers

    What is the function of the CFTR protein in normal individuals?

    <p>To regulate chloride transport</p> Signup and view all the answers

    Which of the following is a CFTR-related disorder?

    <p>All of the above</p> Signup and view all the answers

    What is the correlation between CFTR function and sweat chloride levels?

    <p>Good correlation</p> Signup and view all the answers

    What is the result of phosphorylation of CFTR protein?

    <p>Activation of CFTR function</p> Signup and view all the answers

    Which exocrine organ is commonly affected in cystic fibrosis?

    <p>Pancreas</p> Signup and view all the answers

    What is the mechanism of heterozygote advantage in cystic fibrosis?

    <p>Resistance to cholera</p> Signup and view all the answers

    What is the classification of CFTR variants based on their function?

    <p>Severe, residual, and minimal</p> Signup and view all the answers

    Study Notes

    Repeat Expansion Disorders

    • At least 50 monogenic disorders are caused by the expansion of tandem repeats, typically triplets (triplet repeat disorders)
    • Most disorders affect the CNS and neuromuscular disorders, with different genes, repeat sequences, location within genes, and molecular mechanisms

    Huntington Disease (HD)

    • Progressive neurodegenerative disease characterized by motor, cognitive, and psychiatric disturbances
    • Age-dependent penetrance, with a mean age of onset at 44 years
    • Complete penetrance over life span, with a median survival of 15-18 years after onset
    • Inheritance: autosomal dominant
    • Global prevalence: 5 per 100,000 individuals

    Clinical Findings

    • Abnormalities of movement: chorea, twisting and writhing motions, disjointed gait
    • Cognitive decline: impairment of executive functions, memory deficit, impaired visuospatial abilities
    • Psychiatric disturbances: personality changes, depression, hostility, obsessive-compulsiveness, anxiety, apathy, psychosis

    Genetics

    • Gene: HTT
    • Pathogenic variant: expansion of CAG triplet repeat in exon 1
    • Normal range: 11-35 CAG repeats
    • Pathogenic range: >36 CAG repeats
    • Pre-mutation: risk of expansion to pathogenic range during gametogenesis → risk of disease in progeny

    Molecular Diagnosis of Huntington Disease

    • PCR amplification with primers flanking repeat region
    • Electrophoretic separation by gel or capillary electrophoresis

    Anticipation

    • Earlier age-of-onset and increasing severity from one generation to the next
    • Due to expansion of triplet repeats during gametogenesis
    • Repeat expansion due to DNA slippage

    Somatic Instability

    • Triplet repeats can undergo expansion in somatic cells throughout lifetime and in different cell types → influences disease progression
    • Expansion can occur in non-dividing cells (e.g., neurons), as well as in dividing cells
    • Degree of expansion differs substantially among somatic tissues (somatic mosaicism) and in different brain regions (greater in striatum and cortex)

    Huntingtin (HTT)

    • No homology to other proteins
    • Broad tissue expression; highest levels in CNS, enriched in striatal and corticostriatal neurons
    • Wide subcellular distribution: mainly cytoplasm, also in nucleus and organelles throughout neuron
    • PolyQ tract and HEAT domains interact with other neuronal proteins

    Huntingtin Function

    • Important for development of CNS; essential for survival and function of corticostriatal network
    • Multifunctional protein → functions by interacting with other effector proteins (>400) involved in numerous neuronal processes

    Mutant Huntingtin (mHTT)

    • Expansion of polyQ tract
    • Change in conformation: transformation of α-helices into β-folded chains leading to cross-linking & missfolding
    • Aberrant interaction with other proteins
    • Aberrant cleavage into toxic fragments
    • Formation of insoluble protein aggregates (inclusions) in cytoplasm and nucleus
    • Gain-of-function: neurotoxicity

    Pathogenesis

    • Involves BDNF, ROS, and NMDAR
    • Hypermethylation of DNA at gene promoter regions → transcriptional silencing of gene harbouring repeats
    • Active transcription through repeats triggers formation of RNA–DNA hybrids (R-loops) → DNA damage response, potentially exacerbating somatic instability of repeats

    Repeat Expansion Disorders

    • At least 50 monogenic disorders are caused by the expansion of tandem repeats, typically triplets.
    • These disorders are mostly neurologic disorders of the CNS and neuromuscular disorders, with different genes, repeat sequences, location within the gene, and molecular mechanisms.
    • Examples include Huntington disease, spinocerebellar ataxia (SCA), and Fragile X syndrome.

    Huntington Disease (HD)

    • HD is a progressive neurodegenerative disease with motor, cognitive, and psychiatric disturbances that increase in severity with age.
    • The mean age of onset is 44 years, with 5-20% of patients having onset at age 50 years.
    • HD has complete penetrance over a lifetime, with a median survival of 15-18 years after onset.
    • Inheritance is autosomal dominant, with a global prevalence of 5 per 100,000 individuals.

    Clinical Findings

    • Abnormalities of movement, including chorea, irregular jerking of limbs, face, or trunk, twisting and writhing motions, and disjointed gait.
    • Cognitive decline, including impairment of executive functions, memory deficit, and impaired visuospatial abilities.
    • Psychiatric disturbances.

    Genetics

    • The gene responsible for HD is HTT.
    • The pathogenic variant is the expansion of the CAG triplet repeat in exon 1.
    • The normal range is 11-35 CAG repeats, while the pathogenic range is >36 CAG repeats, with full penetrance.
    • Pre-mutations are at risk of expanding to a pathogenic range during gametogenesis, increasing the risk of disease in progeny.

    Molecular Diagnosis of Huntington Disease

    • PCR amplification with primers flanking the repeat region.
    • Electrophoretic separation by gel or capillary electrophoresis.
    • Prenatal diagnosis is possible using these methods.

    Anticipation

    • Earlier age of onset and increasing severity from one generation to the next due to the expansion of triplet repeats during gametogenesis.
    • Triplet repeats can expand during gametogenesis due to slippage of DNA strands during replication and inefficient mismatch repair.

    Somatic Instability

    • Triplet repeats can undergo expansion in somatic cells throughout a lifetime and in different cell types, influencing disease progression.
    • Expansion can occur in non-dividing cells (e.g., neurons) and dividing cells, suggesting a replication-independent mechanism for somatic expansion.
    • The degree of expansion differs substantially among somatic tissues (somatic mosaicism) and in different brain regions (greater in striatum and cortex).

    Molecular Mechanisms of Nucleotide Repeat Expansion Pathogenesis

    • Hypermethylation of DNA at gene promoter regions → transcriptional silencing of the gene harboring repeats.
    • Active transcription through repeats triggers the formation of RNA-DNA hybrids (R-loops) → DNA damage response, potentially exacerbating somatic instability of repeats.

    CFTR (Cystic Fibrosis Transmembrane Conductance Regulator)

    • CFTR is a protein that regulates chloride transport in cells
    • It is normally closed, but opens following activation via cAMP signaling pathway
    • Activation occurs through ligand binding to membrane receptor, adenylate cyclase activation, and protein kinase A (PKA) phosphorylation of CFTR regulatory domain

    CFTR in the Respiratory Tract

    • In bronchial epithelium, normal CFTR is localized on apical membrane and mediates Cl- efflux
    • In cystic fibrosis, mutant CFTR is absent or dysfunctional, leading to no Cl- efflux, enhanced Na+ and H2O reabsorption, dehydration and acidification of airway surface liquid, and impaired mucociliary clearance

    Pathophysiological Cascade of Respiratory Disorder in Cystic Fibrosis

    • Dehydration and acidification of airway surface liquid lead to impaired mucociliary clearance, which in turn leads to recurrent respiratory infections, bronchiectasis, and eventual respiratory failure

    Ivacaftor (VX-770)

    • Acts as a CFTR potentiator to increase Cl- transport
    • Does not directly activate CFTR, but potentiates activation by forskolin
    • Has a greater effect against G551D versus F508del CFTR

    Correctors and Amplifiers

    • Correctors facilitate the processing of mutated CFTR protein, leading to improved delivery to the cell membrane
    • Amplifiers increase the amount of functional CFTR, e.g., read-through agents to promote read-through of premature stop codons in CFTR mRNA

    CFTR Variants

    • >2000 variants, of which ~380 are CF-causing variants
    • Most frequent variant is F508del (a.k.a. ΔF508), a deletion of Phe at aa 508, which accounts for 50-70% of all CF alleles

    Global Distribution of CF Patients and F508del Allele

    • CF patients: prevalence per 100,000 inhabitants varies by region
    • F508del allele: % of CF patients bearing at least one allele varies by region

    CFTR Modifiers and Phenotypic Variability

    • Genetic factors contributing to phenotypic variability include combination of CFTR variants in trans and in cis
    • Other genetic and environmental factors also contribute to variability in disease severity and age of onset
    • Congenital bilateral absence of the vas deferens (CBAVD): male infertility, alone or with mild CF features, associated with CFTR variants
    • Recurrent idiopathic pancreatitis: 10-20% present CFTR variants, distinct from those affecting respiratory disease
    • Bronchiectasis: rare presentation in carriers, unclear correlation with CFTR genotype

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    Description

    This quiz covers the complications of Mendelian inheritance patterns, repeat expansion disorders, and their clinical findings, genetics, and molecular mechanisms. It also explores the role of whole-genome sequencing in diagnosis.

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