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?
Huntington disease has a complete penetrance over the individual's lifespan.
True
Huntingtin (HTT) gene contains a polyQ tract and ______________ domains.
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What is the global prevalence of Huntington disease?
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What is the median survival after onset of Huntington disease?
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What is the mechanism behind the expansion of triplet repeats during gametogenesis?
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What is the characteristic feature of the Huntingtin gene in individuals affected by Huntington disease?
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What is the consequence of somatic instability in triplet repeat disorders?
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Which of the following is a characteristic of somatic expansion in triplet repeat disorders?
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Which type of cells are most affected by the somatic expansion of triplet repeats in Huntington disease?
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What is the mode of inheritance associated with Huntington disease?
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What is the term used to describe the variation in the degree of expansion among different somatic tissues?
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What is the typical range of repeats in the Huntingtin gene of unaffected individuals?
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During replication, what happens to the new strand in triplet repeat expansion?
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What is a consequence of active transcription through repeats in triplet repeat disorders?
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What is the consequence of the somatic expansion of triplet repeats in Huntington disease?
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What is the result of inefficient mismatch repair in triplet repeat expansion?
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Which of the following mechanisms is NOT associated with the pathogenesis of triplet repeat disorders?
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Which of the following is a characteristic feature of triplet repeat disorders?
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Which brain regions show a greater degree of somatic expansion?
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What is the characteristic feature of the FMR1 gene in Fragile X syndrome?
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What is the primary mechanism of repeat expansion in Huntington disease?
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What is the characteristic pattern of disease progression in triplet repeat disorders?
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Which tissue is most resistant to somatic expansion of triplet repeats in Huntington disease?
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Which type of inheritance is associated with Fragile X syndrome?
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What is the consequence of hypermethylation of DNA at gene promoter regions in triplet repeat disorders?
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What is the name of the gene affected in Huntington's disease?
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Which of the following is a characteristic feature of triplet repeat disorders?
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What is the mechanism by which triplet repeat expansions can lead to neurodegeneration?
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What is the primary characteristic that distinguishes triplet repeat disorders from other types of monogenic disorders?
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Which of the following is NOT a common feature of triplet repeat disorders?
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What is the primary mechanism underlying the pathogenesis of Huntington disease?
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Which of the following is an example of a triplet repeat disorder that affects the peripheral nervous system?
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What is the primary benefit of using whole-genome sequencing for the diagnosis of repeat expansion disorders?
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Which of the following triplet repeat disorders is characterized by anticipation?
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What is the primary function of the huntingtin protein in healthy individuals?
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Which of the following is a characteristic feature of the somatic instability of triplet repeat disorders?
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What is the range of CAG triplet repeats in the normal population?
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What is the risk associated with pre-mutation range during gametogenesis?
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What is the principle behind PCR amplification for molecular diagnosis of Huntington disease?
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What is the correlation between CAG repeat size and age of onset?
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What is the characteristic of CAG repeat expansion in Huntington disease?
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What is the typical feature of juvenile onset in Huntington disease?
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What is the purpose of electrophoretic separation in molecular diagnosis of Huntington disease?
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What is the significance of prenatal diagnosis in Huntington disease?
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What is the normal function of CFTR in the respiratory tract?
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What is the effect of ivacaftor on CFTR?
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What is the effect of PKA phosphorylation on CFTR?
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What is the temperature at which the cells were incubated overnight to improve cell surface density of mutant channels?
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What is the characteristic feature of CFTR in the apical membrane of bronchial epithelium?
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What is the effect of ivacaftor on chloride transport in G551D-FRT cells compared to F508del-CFTR cells?
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What is the consequence of impaired CFTR function in cystic fibrosis?
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What is the activator of CFTR used in the experiment?
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What is the role of cAMP in the activation of PKA?
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What is the effect of CFTR dysfunction on bronchial epithelium?
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What is the type of transport increased by ivacaftor in cells expressing recombinant G551D or F508del CFTR?
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What is the chamber used to measure transepithelial chloride transport?
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What is the mechanism by which PKA activates CFTR?
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What is the effect of ivacaftor on CFTR activation?
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What is the function of CFTR correctors?
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What is the purpose of using Ivacaftor (VX-770) in CF cell models?
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What type of mutation is the G551D mutation?
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What is the purpose of cell-based assays in the study of CF?
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What is the name of the company that is working on CFTR modulators?
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What is the purpose of amplifiers in the treatment of CF?
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What is the name of the CFTR potentiator that is used to treat CF?
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What is the most common CFTR variant associated with cystic fibrosis?
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What is the estimated frequency of cystic fibrosis carriers?
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What is the function of the CFTR protein in normal individuals?
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Which of the following is a CFTR-related disorder?
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What is the correlation between CFTR function and sweat chloride levels?
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What is the result of phosphorylation of CFTR protein?
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Which exocrine organ is commonly affected in cystic fibrosis?
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What is the mechanism of heterozygote advantage in cystic fibrosis?
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What is the classification of CFTR variants based on their function?
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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
CFTR-Related Disorders
- 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.