Mendelian Inheritance and Repeat Expansion Disorders

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.

HEAT Signup and view all the answers

What is the global prevalence of Huntington disease?

5 per 100,000 individuals Signup and view all the answers

What is the median survival after onset of Huntington disease?

15-18 years Signup and view all the answers

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

Backward slipping of new strand and loop formation Signup and view all the answers

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

An expanded polyglutamine (polyQ) tract Signup and view all the answers

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

Influences disease progression Signup and view all the answers

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

Occurs in both dividing and non-dividing cells Signup and view all the answers

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

Neurons in the cerebral cortex Signup and view all the answers

What is the mode of inheritance associated with Huntington disease?

Autosomal dominant Signup and view all the answers

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

Somatic mosaicim Signup and view all the answers

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

30-40 repeats Signup and view all the answers

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

It slips backward Signup and view all the answers

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

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

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

Toxic protein aggregation Signup and view all the answers

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

Increased repeat expansion Signup and view all the answers

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

Epigenetic modification of histone proteins Signup and view all the answers

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

Repeat expansion Signup and view all the answers

Which brain regions show a greater degree of somatic expansion?

Striatum and cortex Signup and view all the answers

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

Expansion of CGG repeats in the 5'UTR region Signup and view all the answers

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

Slipped-strand mispairing Signup and view all the answers

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

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

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

Blood Signup and view all the answers

Which type of inheritance is associated with Fragile X syndrome?

X-linked dominant Signup and view all the answers

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

Transcriptional silencing of the gene Signup and view all the answers

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

HTT Signup and view all the answers

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

Expansion of triplet repeats Signup and view all the answers

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

Formation of protein aggregates and activation of the DNA damage response Signup and view all the answers

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

Expansion of tandem repeats Signup and view all the answers

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

Cancer predisposition Signup and view all the answers

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

Toxic gain of function of the huntingtin protein Signup and view all the answers

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

Myotonic dystrophy Signup and view all the answers

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

Ability to detect expansions in non-coding regions Signup and view all the answers

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

All of the above Signup and view all the answers

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

Transport of vesicles along microtubules Signup and view all the answers

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

All of the above Signup and view all the answers

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

11-35 CAG repeats Signup and view all the answers

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

Risk of expansion to pathogenic range Signup and view all the answers

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

Size-based separation of PCR products Signup and view all the answers

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

Inverse correlation between CAG repeat size and age of onset Signup and view all the answers

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

Trinucleotide repeat expansion Signup and view all the answers

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

Earlier onset and more severe symptoms Signup and view all the answers

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

To separate PCR products based on size Signup and view all the answers

What is the significance of prenatal diagnosis in Huntington disease?

To determine risk of disease in progeny Signup and view all the answers

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

It plays a role in mucociliary clearance Signup and view all the answers

What is the effect of ivacaftor on CFTR?

It potentiates the activation of CFTR by forskolin Signup and view all the answers

What is the effect of PKA phosphorylation on CFTR?

It induces a conformational change leading to pore opening and chloride flux 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?

27°C Signup and view all the answers

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

It is normally localized on the apical membrane Signup and view all the answers

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

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

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

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

What is the activator of CFTR used in the experiment?

Forskolin Signup and view all the answers

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

It binds to PKA and activates it Signup and view all the answers

What is the effect of CFTR dysfunction on bronchial epithelium?

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

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

Chloride transport Signup and view all the answers

What is the chamber used to measure transepithelial chloride transport?

Ussing chamber Signup and view all the answers

What is the mechanism by which PKA activates CFTR?

Through phosphorylation of the regulatory domain Signup and view all the answers

What is the effect of ivacaftor on CFTR activation?

It potentiates CFTR activation by forskolin Signup and view all the answers

What is the function of CFTR correctors?

To correct defective folding and trafficking of the CFTR protein Signup and view all the answers

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

To potentiate channel activity in the CFTR protein Signup and view all the answers

What type of mutation is the G551D mutation?

Class III mutation, defective channel gating Signup and view all the answers

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

To measure the functional activity of the CFTR protein Signup and view all the answers

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

Vertex Pharmaceuticals Signup and view all the answers

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

To increase the amount of functional CFTR protein Signup and view all the answers

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

Ivacaftor (VX-770) Signup and view all the answers

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

F508del Signup and view all the answers

What is the estimated frequency of cystic fibrosis carriers?

1/25 Signup and view all the answers

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

To regulate chloride transport Signup and view all the answers

Which of the following is a CFTR-related disorder?

All of the above Signup and view all the answers

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

Good correlation Signup and view all the answers

What is the result of phosphorylation of CFTR protein?

Activation of CFTR function Signup and view all the answers

Which exocrine organ is commonly affected in cystic fibrosis?

Pancreas Signup and view all the answers

What is the mechanism of heterozygote advantage in cystic fibrosis?

Resistance to cholera Signup and view all the answers

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

Severe, residual, and minimal 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.