X-Chromosome Inactivation and X-Linked Diseases
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X-Chromosome Inactivation and X-Linked Diseases

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Questions and Answers

What is the term for the process where one of the two X-chromosomes in female cells is inactivated?

  • Chromosome segregation
  • X-chromosome inactivation (correct)
  • X-linked disease
  • Randommutation

    • What do we call the inactive X chromosome that appears as a dark-staining mass?

  • X-chromosome marker
  • Barr body (correct)
  • Inactivopy
  • Chromatin body

    • Which of the following statements is true regarding X-linked diseases?

  • X-linked diseases show male to male transmission.
  • X-linked diseases can be either dominant or recessive. (correct)
  • Males can inherit X-linked diseases from their fathers.
  • Females have only one X chromosome, so they express X-linked diseases completely.

    • What characterizes a disorder classified as X-linked recessive in females?

    <p>It is rarely expressed clinically in females.</p> Signup and view all the answers

    What term is used to describe females who carry an X-linked disease but do not show clinical symptoms?

    <p>Manifesting heterozygote</p> Signup and view all the answers

    What happens during the random X-chromosome inactivation process in females?

    <p>Either the paternal or maternal X can be inactivated.</p> Signup and view all the answers

    What is the implication of males being hemizygous for the X chromosome?

    <p>X-linked mutant traits are expressed in full.</p> Signup and view all the answers

    What is the significance of skewed X-inactivation in females?

    <p>One of the X chromosomes is preferentially inactivated.</p> Signup and view all the answers

    What is the primary genetic defect associated with Fragile X syndrome?

    <p>CGG triplet repeat in the 5' UTR</p> Signup and view all the answers

    What range of CGG repeats is considered a premutation in Fragile X syndrome?

    <p>50 – 100 CGG repeats</p> Signup and view all the answers

    Which statement about the anticipation phenomenon in genetic disorders like Fragile X and Huntington's disease is true?

    <p>Anticipation results in unstable expansion of mutations</p> Signup and view all the answers

    What is the impact of having more than 200 CGG repeats in Fragile X syndrome?

    <p>Prevention of FMR1 protein translation</p> Signup and view all the answers

    In which region does the CAG triplet repeat occur in Huntington's disease?

    <p>Coding region</p> Signup and view all the answers

    What is the characteristic break observed on the chromosome associated with Fragile X syndrome?

    <p>Fragile site on the X chromosome</p> Signup and view all the answers

    Which effect is described as the reason a premutation only expands when inherited from the mother in Fragile X syndrome?

    <p>Maternal parent of origin effect</p> Signup and view all the answers

    What is the typical range of CAG repeats that leads to the expression of protein causing neuronal damage in Huntington's disease?

    <p>More than 28 repeats</p> Signup and view all the answers

    What is a characteristic of X-linked recessive diseases?

    <p>Females can be carriers without showing symptoms.</p> Signup and view all the answers

    Which of the following is an example of an X-linked dominant disorder?

    <p>Vitamin-D resistant rickets</p> Signup and view all the answers

    What distinguishes mitochondrial inheritance from other inheritance patterns?

    <p>It is maternally inherited.</p> Signup and view all the answers

    What defines heteroplasmy in mitochondrial inheritance?

    <p>A mixture of normal and mutated mitochondrial genomes exists.</p> Signup and view all the answers

    In X-linked recessive mating types, what is the expected outcome for female offspring?

    <p>Half of the females are carriers.</p> Signup and view all the answers

    How is a triplet repeat disorder characterized?

    <p>It results from an unstable expansion of DNA repeats.</p> Signup and view all the answers

    Which of the following diseases is associated with a deficiency of factor VIII?

    <p>Haemophilia A</p> Signup and view all the answers

    What is the male-to-female inheritance pattern of X-linked dominant diseases?

    <p>All daughters of affected males may be affected.</p> Signup and view all the answers

    What is a potential result of triplet repeat expansion in genetic disorders?

    <p>Variable number of repeats between individuals.</p> Signup and view all the answers

    What type of inheritance mechanism is associated with Leber’s hereditary optic atrophy?

    <p>Mitochondrial inheritance</p> Signup and view all the answers

    What is the range of CGG repeats classified as a full mutation in Fragile X syndrome?

    <p>200 - 2000 repeats</p> Signup and view all the answers

    What consequence occurs when CGG repeats exceed 200 in Fragile X syndrome?

    <p>Prevention of FMR1 protein translation</p> Signup and view all the answers

    In the context of Huntington's disease, which factor leads to the expression of a damaging protein?

    <p>Expansion beyond 36-40 CAG repeats</p> Signup and view all the answers

    Which inheritance pattern is associated with the expansion of the CAG repeat in Huntington's disease?

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

    What is the primary role of the FMR1 gene in Fragile X syndrome?

    <p>RNA binding and synaptic function</p> Signup and view all the answers

    What term describes the phenomenon where the age of onset or severity of a genetic disorder increases from one generation to the next?

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

    What is the diagnostic significance of a 'normal transmitting male' in Fragile X syndrome?

    <p>They exhibit no symptoms but carry a premutation.</p> Signup and view all the answers

    Which aspect of premutation expansion is unique to Fragile X syndrome?

    <p>It expands only when inherited maternally.</p> Signup and view all the answers

    What is the main mechanism by which females achieve equal expression of X-linked genes despite having two X chromosomes?

    <p>X chromosome inactivation</p> Signup and view all the answers

    How does X chromosome inactivation occur in females?

    <p>It occurs randomly and permanently</p> Signup and view all the answers

    What differentiates X-linked recessive diseases from X-linked dominant diseases in terms of expression in females?

    <p>Recessive diseases may not be expressed clinically in females</p> Signup and view all the answers

    Which of the following best describes the phenomenon of mosaicism as it relates to X chromosome inactivation?

    <p>Random inactivation of X chromosomes leading to varied cell expression</p> Signup and view all the answers

    What effect does skewed X-inactivation have on the expression of X-linked traits in females?

    <p>It leads to the manifestation of one X-linked trait over another</p> Signup and view all the answers

    What is the role of mitochondrial DNA in the context of genetic disorders?

    <p>It is inherited solely from the mother</p> Signup and view all the answers

    What characterizes anticipation in triplet repeat disorders?

    <p>Symptoms worsen in future generations due to repeat expansion</p> Signup and view all the answers

    Which of the following diseases is categorized as an X-linked dominant disorder?

    <p>Fragile X syndrome</p> Signup and view all the answers

    What is a characteristic feature of X-linked dominant disorders in terms of male-to-female transmission?

    <p>Daughters of affected males may be affected</p> Signup and view all the answers

    Which of the following statements is true regarding mitochondrial inheritance?

    <p>All children of an affected mother are affected</p> Signup and view all the answers

    What effect does heteroplasmy have on the severity of mitochondrial diseases?

    <p>It introduces variation in disease severity</p> Signup and view all the answers

    Which disease is associated with a deficiency of factor VIII?

    <p>Haemophilia A</p> Signup and view all the answers

    How does the inheritance pattern of triplet repeat disorders primarily vary?

    <p>By the base sequence of the repeat</p> Signup and view all the answers

    What is the primary consequence of unstable expansion in triplet repeat disorders?

    <p>It leads to increased severity of symptoms</p> Signup and view all the answers

    What characterizes X-linked recessive diseases in terms of carrier females?

    <p>They do not show any symptoms</p> Signup and view all the answers

    What is a distinguishing factor of triplet repeat diseases like Huntington's disease?

    <p>They involve specific sequences of triplet repeats</p> Signup and view all the answers

    In the context of X-linked recessive mating types, what is the expected genetic outcome for female offspring?

    <p>All females will be carriers</p> Signup and view all the answers

    Which of the following features is unique to X-linked dominant inheritance?

    <p>It can be passed unchanged from fathers to daughters</p> Signup and view all the answers

    What is the classification of a male who carries a premutation of the FMR1 gene?

    <p>Normal transmitting male</p> Signup and view all the answers

    Which phenomenon describes the increased severity of symptoms in subsequent generations for certain genetic disorders?

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

    How does the parent of origin effect influence the inheritance of Huntington's disease?

    <p>Expansion occurs in males only</p> Signup and view all the answers

    What occurs when the CGG repeat in the FMR1 gene exceeds 200 copies?

    <p>Prevention of transcription</p> Signup and view all the answers

    Which range of CAG repeats is identified as a critical threshold for expression of damaging protein associated with Huntington's disease?

    <p>36-40 repeats</p> Signup and view all the answers

    What is the primary role of the FMR1 gene product in the context of Fragile X syndrome?

    <p>Formation of synapses</p> Signup and view all the answers

    In Fragile X syndrome, what triggers the instability of the CGG triplet repeat during female meiosis?

    <p>Maternal parent of origin effect</p> Signup and view all the answers

    What does a length of 10-50 CGG repeats signify in terms of Fragile X syndrome classification?

    <p>Normal range</p> Signup and view all the answers

    What is the main outcome of X-chromosome inactivation in females?

    <p>One X chromosome is permanently inactivated, creating a Barr body.</p> Signup and view all the answers

    What distinguishes X-linked dominant diseases from X-linked recessive diseases in females?

    <p>X-linked dominant diseases are expressed more frequently in heterozygous females.</p> Signup and view all the answers

    Which statement accurately describes the inheritance pattern of X-linked diseases?

    <p>They exhibit a characteristic pattern with no male-to-male transmission.</p> Signup and view all the answers

    What is a key feature of mitochondrial DNA disorders?

    <p>They display a characteristic maternal inheritance pattern.</p> Signup and view all the answers

    In the context of triplet repeat disorders, what role do parent of origin effects play?

    <p>They contribute to variations in symptom severity and age of onset.</p> Signup and view all the answers

    Which of the following best describes skewed X-inactivation?

    <p>It can lead to the expression of a mutant X chromosome in females.</p> Signup and view all the answers

    What does anticipation refer to in the context of triplet repeat disorders?

    <p>An increase in the number of repeats with maternal inheritance.</p> Signup and view all the answers

    What is the significance of a Barr body in female cells?

    <p>It represents the inactivated X chromosome that does not contribute to protein production.</p> Signup and view all the answers

    What is a key characteristic of X-linked dominant disorders in terms of male inheritance?

    <p>All daughters of an affected father are guaranteed to inherit the disorder.</p> Signup and view all the answers

    Which of the following disorders is primarily associated with mitochondrial inheritance?

    <p>Leber's hereditary optic atrophy</p> Signup and view all the answers

    What does heteroplasmy indicate in terms of mitochondrial conditions?

    <p>A mixture of normal and mutant mitochondrial genomes exists.</p> Signup and view all the answers

    Which is true regarding the inheritance pattern of triplet repeat expansion disorders?

    <p>Symptoms vary based on the number of repeats present.</p> Signup and view all the answers

    What is a common outcome in offspring of an affected mother with a mitochondrial disorder?

    <p>All children have a chance of being affected.</p> Signup and view all the answers

    In X-linked recessive diseases, which statement is accurate about female carriers?

    <p>Carriers have a 50% chance of passing on the affected allele to each child.</p> Signup and view all the answers

    What is an important factor in how X-linked dominant disorders present in males compared to females?

    <p>Males often display more severe and constant symptoms than females.</p> Signup and view all the answers

    What distinguishes triplet repeat disorders like Huntington's disease from other genetic disorders?

    <p>Their expression is typically influenced by the number of repeats inherited.</p> Signup and view all the answers

    What best describes the transmission of X-linked recessive diseases?

    <p>Sons of carrier females have a 50% chance of being affected.</p> Signup and view all the answers

    Study Notes

    X-Chromosome Inactivation

    • In females, one X chromosome is randomly inactivated early in embryonic development.
    • This inactivation is permanent and clonally propagated.
    • The inactive X chromosome appears as a Barr body.
    • Inactivation can lead to mosaicism, with different cell lineages expressing different X-linked alleles.

    X-Linked Diseases

    • Genes located on the X chromosome are called X-linked genes.
    • X-linked diseases have a characteristic pattern of inheritance, with males being hemizygous for the X chromosome and females being heterozygous.
    • X-linked diseases can be dominant or recessive, with different severity and expression patterns between males and females.
    • X-linked recessive diseases are often observed in males due to hemizygosity, while females may have a milder phenotype due to random X inactivation.
    • X-linked dominant diseases can affect both males and females, with males usually exhibiting more severe symptoms.

    X-Linked Recessive (XLR) Diseases

    • Males are more likely to be affected.
    • Females are usually carriers but may exhibit symptoms due to skewed X inactivation.
    • Examples include Hemophilia A and Duchenne Muscular Dystrophy.

    X-Linked Dominant (XLD) Diseases

    • Both males and females can be affected.
    • Males usually have more severe symptoms.
    • Fathers cannot transmit the disease to their sons.
    • Example: Vitamin-D resistant rickets (hypophosphatemic rickets).

    Extra-Nuclear Inheritance (Mitochondrial DNA Disorders)

    • Mitochondria contain their own circular DNA (mtDNA), which is maternally inherited.
    • Some diseases are caused by mutations in mtDNA, often affecting skeletal/cardiac muscle and neurological function.
    • Examples: Leber's Hereditary Optic Atrophy.

    Triplet Repeat Disorders

    • Sequences of three base pair (bp) repeats are common in the genome.
    • Triplet repeat disorders are caused by unstable expansion of these repeats.
    • The number of repeats can influence disease severity and age of onset.
    • There are over 30 known diseases caused by triplet repeat expansion, with varying inheritance patterns and repeat sequences.

    Fragile X Syndrome

    • This is the most common inherited cause of intellectual disability.
    • Caused by expansion of a CGG repeat in the 5' UTR of the FMR1 gene.
    • The gene encodes an RNA-binding protein involved in synapse formation.
    • Premutations (50-100 repeats) are clinically normal but can expand to full mutations during female meiosis, leading to a maternal parent of origin effect.
    • Full mutations (>200 repeats) lead to silencing of the FMR1 gene, resulting in the syndrome.

    Huntington's Disease

    • Caused by expansion of a CAG repeat in the coding region of the huntingtin gene.
    • The repeat expansion leads to an altered protein that causes neuronal damage.
    • Over 36-40 repeats are associated with disease.
    • Expansion primarily occurs during male meiosis, indicating a paternal parent of origin effect.
    • This is an autosomal dominant disorder.

    Anticipation in Triplet Repeat Disorders

    • Expansion of the repeat during transmission can lead to earlier onset and increased severity of the disease in subsequent generations.
    • This phenomenon is known as anticipation.
    • The Sherman paradox describes a specific case of anticipation where a father transmits a premutation to his daughter, who later expands the repeat and gives birth to a child with a full mutation.

    Parent of Origin Effects

    • The identity of the parent transmitting the mutated gene can influence the expansion of the repeat and the severity of the disease.
    • In Fragile X, premutation expansion occurs during female meiosis, making it a maternally transmitted disorder.
    • In Huntington's Disease, premutation expansion occurs during male meiosis, making it a paternally transmitted disorder.

    X-chromosome inactivation

    • In female cells, one of the two X-chromosomes is inactivated, this can occur on the maternal or paternal chromosome
    • X-chromosome inactivation occurs early in embryonic life, the inactivation is random and permanent and is clonally propagated
    • The inactive X chromosome appears as a dark-staining mass known as a Barr body

    X-Linked Diseases

    • Genes carried on the X chromosome are “X-Linked”
    • May be dominant or recessive
    • Males are hemizygous for X
    • Random X inactivation occurs in females – X-linked traits are variably expressed
      • Balanced X-inactivation
      • Skewed X-inactivation
        • ‘Manifesting heterozygote’ – the normal X chromosome is preferentially inactivated
        • Unbalanced inactivation -- the mutant X chromosome is preferentially inactivated: clinically unaffected

    X-Linked Recessive

    • XLR diseases are rarely expressed clinically in females
    • Males are affected in half the offspring from a carrier female and all carrier females
    • Females are carriers in half the offspring from a carrier female

    X-Linked Recessive Diseases: Examples

    • Haemophilia A:
      • Deficiency of factor VIII
      • Haemophilia A is characterised by soft-tissue bleeding
    • Duchenne Muscular Dystrophy
      • A form of muscular dystrophy; onset at ~5 years, progressive muscle weakness, death in early 20s
      • death occurs due to respiratory or cardiac complications

    X-Linked Dominant

    • Example: vitamin-D resistant rickets
      • Low blood and high urinary phosphate
      • Short stature and bony deformities
      • Absence of male-to-male transmission
      • Daughters of affected males may be affected
    • Expression of XLD symptoms are more severe and constant in males than in females

    Extra-nuclear inheritance

    • The mitochondrion contains a ~16kb circular DNA genome – mtDNA
    • mtDNA is maternally inherited
    • Some human diseases are characterised by abnormal mtDNA
    • Mitochondrial diseases often involve skeletal/cardiac muscle impairment and neurological problems

    Triplet Repeat Disorders

    • Sequences of three bp repeats are found throughout the genome
    • Repeat sequences may be polymorphic
    • Triplet repeat disorders are due to unstable expansion in number of repeats

    Triplet Repeat Expansion Diseases

    • At least 30 diseases are known to result from triplet repeat expansion
    • Characteristics/differences
      • Inheritance : AD, AR, X-linked
      • Base sequence of repeat
        • eg CGG in Fragile-X; CAG Huntingtons
      • Number of repeats, presymptomatic vs. affected

    Fragile X Syndrome

    • Most common form of inherited mental retardation
    • ~ 1/2000 - 1/4000 individuals are affected
      • Females are also affected
    • Fragile X is responsible for 4-8% of males with mental retardation
    • Named for a characteristic break observed on the X chromosome (cytogenetics)
    • Molecular defect in FMR1 (Fragile X Mental Retardation 1) gene
    • FMR1 is an RNA binding protein involved in formation of synapses
    • FMR1 has CGG ‘triplet repeat’ in the 5’ UTR
    • During meiosis in the female, the repeat is unstable and can increase in length – expansion
    • Expansion beyond 200 copies prevents translation of FMR1 protein

    Fragile X Syndrome: Repeat Number Ranges

    • 10 – 50 CGG repeats - normal
      • 50 – 100 repeats - premutation
      • 200 – 2000 repeats - full mutation

    Fragile X: Inheritance

    • Grandfather (I-1) has premutation -- is a ‘normal transmitting male’
    • Expansion of repeats during meiosis in the Mother (II-2) results in a full mutant gene being transmitted to the son (III-1)
    • ‘modified’ X-linked inheritance
    • Premutation : upper limit of normal, but capable of expanding to disease

    Anticipation, the Sherman paradox and parent of origin effects

    • Anticipation & the Sherman paradox:

      • Expansion of mutation from one generation to the next
      • Sometimes seen clinically as: reduced age of onset and / or increased severity down the pedigree

      Parent of origin effect

      • Premutation – expansion occurs:
        • in fragile X, premutation only expands in female : risk
      • only if inherited from mother  sometimes described as being “maternally transmitted “

    Huntington’s disease

    • CAG triplet repeat in protein coding region  polyQ region in protein
    • Over 28 repeats leads to unstable expansion
    • Expansion beyond ~ 36 -40 repeats leads to expression of a protein that causes neuronal damage
    • Paternal parent of origin effect (Expansion of repeat number occurs in males)
    • Autosomal dominant

    Other resources

    • Reading
      • Thompson & Thompson ch 5,12
      • ABC of clinical genetics Ch 6

    Learning Objectives

    • Explain X-chromosome inactivation in females
    • Describe extra-nuclear inheritance (mitochondrial DNA disorders)
    • Discuss triplet repeat disorders, parent of origin effects and anticipation (with examples: Huntington disease and Fragile X Syndrome)

    Sex Determining Chromosomes

    • Sex determined at fertilization
    • Male: XY
    • Female: XX
    • Males are "hemizygous" for the X chromosome
    • Equal amounts of proteins encoded by genes on the X chromosome are produced in males and females, despite females having twice the number of chromosomes

    X-Chromosome Inactivation

    • One X-chromosome is inactivated in female cells
    • Occurs early in embryonic development
    • Inactivation is random (either maternal or paternal X can be inactivated)
    • Complete inactivation is permanent and clonally propagated
    • Inactive X chromosome appears as a dark-staining mass (Barr body)

    X-Linked Diseases

    • X-linked genes are carried on the X chromosome
    • Lack of male to male transmission
    • X-linked disorders can be dominant or recessive
    • Males are hemizygous for X, leading to full expression of mutant traits
    • Random X inactivation occurs in females, causing variable expression of X-linked traits
      • Balanced: Equal inactivation of X chromosomes
      • Skewed: Preferential inactivation of either normal or mutant X chromosome
      • Manifesting heterozygote: The normal X chromosome is preferentially inactivated, leading to clinical expression of the trait
      • Unbalanced inactivation: The mutant X chromosome is preferentially inactivated, leading to clinically unaffected individuals

    X-Linked Recessive Inheritance

    • X-linked diseases are rarely expressed in heterozygous females and are therefore labelled as X-linked recessive (XLR).

    X-Linked Dominant Inheritance

    • X-linked dominant (XLD) disorders are expressed clinically in many females.
    • XLD disorders are characterized relative to XLR disorders by the proportion of males and females who are affected.

    Mitochondrial Inheritance

    • Mitochondria have a circular DNA genome (~16kb) - mtDNA
    • Mitochondrial inheritance is maternal
    • Some diseases involve abnormal mtDNA, often affecting skeletal/cardiac muscles and neurological function
      • Leber’s Hereditary Optic Atrophy

    Triplet Repeat Disorders

    • Sequences of three base pair (bp) repeats are found throughout the genome
    • These repeats can be polymorphic (variable number of repeats between individuals)
    • Triplet repeat disorders are caused by unstable expansion in the number of repeats
    • At least 30 diseases are known to arise from triplet repeat expansion
    • Characteristics of Triplet Repeat Expansion:
      • Different inheritance patterns: Autosomal dominant (AD), Autosomal recessive (AR), X-linked
      • Variable base sequence of repeat
      • Variable number of repeats (presymptomatic vs. affected)

    Fragile X Syndrome

    • Most common form of inherited mental retardation
    • Affects ~1/2000 - 1/4000 individuals
    • Accounts for 4-8% of males with mental retardation
    • Named for a characteristic break observed on the X chromosome (cytogenetics)
    • Molecular defect in the FMR1 (Fragile X Mental Retardation 1) gene
      • FMR1 encodes an RNA binding protein involved in synapse formation
    • FMR1 has a CGG triplet repeat in the 5’ UTR
    • Expansion of the repeat during meiosis in females leads to a maternal parent of origin effect
    • Expansion beyond 200 copies prevents translation of the FMR1 protein
    • Repeats:
      • 10 - 50: Normal
      • 50 - 100: Premutation (can expand to disease)
      • 200 - 2000: Full mutation

    Huntington's Disease

    • CAG triplet repeat in the protein coding region
    • PolyQ region in protein
    • Over 28 repeats leads to unstable expansion
    • Expansion beyond 36-40 repeats causes neuronal damage
    • Paternal parent of origin effect (expansion occurs in males)
    • Autosomal dominant inheritance pattern

    Anticipation

    • Expansion of the mutation from one generation to the next
    • Can result in:
      • Reduced age of onset
      • Increased severity
    • Parent of origin effect:
      • Fragile X premutation only expands in females
      • Huntington's expansion occurs in males

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