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Terms in this set (148)

-Most common trisomy
-Chromosomal Karyotype: 47, XY +21 or 47, XX +21
-Prevalence: 1 in 850 live births
-Most of the conceptions are spontaneously aborted, thus risk of producing affected live child is considerably lower
-Only 20 - 25% of trisomy 21 conceptuses survive to birth
-Phenotypic Features:
*Characteristic appearance of Face (MONGOLOID appearance), Slanting eyes, small open mouth with a protruding tongue, Flat nasal bridge
-Hypotonia (Decreased muscle tone)
-Short stature
-Single transverse crease in the palm of the hand
-Wide gap between 1st & 2nd toes
-Incurved fifth digits (clinodactyly)
-Moderate to severe intellectual disability
-Several patients have structural heart defects
-Increased risk for hypothyroidism
-Increased risk for leukemia
-Characteristic neurological complications of Alzheimer disease appear much earlier in life in Down syndrome patients compared to general population
-Survival rates of Down syndrome children are significantly lower- possibly due to CONGENITAL HEART DEFECTS
-However, the survival rate is better in recent years because of medical care
-Approx. 95% of Down Syndrome cases are caused by nondisjunction, 47, XX/XY + 21
-In more than 90% of cases nondisjunction occurs in the mother (predominantly during meiosis I) & 10% cases paternal nondisjunction (mostly during meiosis II)
-Risk for having a child with trisomy 21 increases with maternal age, especially >30 yrs of age
-Amyloid precursor protein gene is located on chromosome 21
-Congenital malformations such as duodenal atresia and tracheoesophageal fistula are more common in Down syndrome than in other disorders
-About 4% of DS patients exhibit Robertsonian translocation (usually involving Chr.14 & 21) - they are trisomic with respect to the genes present in q arm of chr.21
-Translocation Down syndrome shows no relation to maternal age but has a relatively high recurrence rate in families, when a parent, especially the mother, is a carrier of the translocation
-MOSAICISM is seen in approx. 2% of trisomy 21 live births
-These individuals have some normal & some trisomy 21 somatic cells
-Karyotype: 47 XX +21/46 XX, or 47 XY +21/46 XY
-Here clinical manifestations are milder, comparatively
-The most common cause of mosaicism in trisomy is - trisomic conception followed by loss of extra chromosome in some cells during embryonic development
-A small % of patients with Down syndrome have a 21q21q translocation chromosome, in which the q arm of chromosome 21 is present in duplicate (thought to originate as an isochromosome) and along with a normal chromosome 21 results in trisomy for the genes present in q arm of chromosome 21.
-Partial trisomy 21: rarely, Down syndrome is diagnosed in a patient in whom only a part of the long arm of chromosome 21 is present in triplicate.
- Fatal neurodegenerative disease
- Most common adult onset neurodegenerative disorder
- Affects 1.4% of individuals in developed countries
- Presents typically in 6th -9th decade
- Clinical features include
- Progressive deterioration of
Higher cognitive functions
- Behavioral changes
- Cause: Degeneration of neurons in specific regions of cerebral cortex and hippocampus
- Most important pathological abnormalities
-Amyloid /senile plaques
- Extracellular depositions of mainly Aβ42 and apoE
Neurofibrillary tangles -> intracellular (intraneuronal)
- Hyperphosphorylated Tau protein
- Tau protein
promotes assembly and stability of microtubules . Hyperphosphorylation impairs microtubule stability
Note: Mutations are not associated with AD
-Amyloid Precursor Protein (βAPP)
- βAPP
- Single pass transmembrane protein
- 10% by β-secretase and γ-secretase
- Production of either nontoxic Aβ40 or neurotoxic Aβ42
- Normally little Aβ42 is produced
- Mutations in secretase genes lead to
- Increased production of Aβ42 peptide
- Accumulation -> neurotoxicity
- Patients with Down syndrome
- Early onset of AD by age 40
- 3 copies of βAPP gene
- Aβ42 increased in serum of individuals with mutations in βAPP
- Four genes are associated with Alzheimer disease (AD)
- Mutations in 3 of these lead to AD
- APP -> encoding βAPP
- PSEN1 -> presenilin 1
- PSEN 2 -> presenilin 2
- The more common late-onset form (after age 60) shows
familial aggregation and relative risk of complex inheritance
- Role of ε4 Allele of apoE -> predisposes to early onset of
AD when homozygous
- ε4 allele is a major risk factor for development of AD
- 40% of patients with AD have the allele
- Associated with earlier age of onset 10-15 years earlier
- Relationship between ε4 allele and disease is dose dependent
- Carriers of ε4 allele also have poor outcomes after
- Head injury
- Stroke
- Other neuronal insults
- No role for screening for apoE ε4
- Poor positive and negative predictive values
-Mutations in coding region -> Novel properties of the encoded protein
-Mode of inheritance -> AD
- Heterozygous and homozygous individuals equal severity
- Homozygotes may have a more rapid progress of the disease
- Paternal transmission bias
- Juvenile form of HD (70-121 repeats) almost always inherited from an affected father
-The expression of mHTT has global effects on the transcriptome suggesting that transcriptional dysregulation is a key feature of HD pathogenesis. mHTT interacts with, and disrupts, major components of the general transcriptional machinery, affecting both general promoter accessibility and recruitment of RNA polymerase II. Studies in pre-symptomatic HD brains have shown that soluble mHTT oligomers interact with and impede the function of specificity protein 1 (SP1), TATA box binding protein (TBP), the TFIID subunit TAFII130, the RAP30 subunit of the TFIIF complex, and the CAAT box transcription factor NF-Y, all of which are important mediators of general promoter accessibility and transcription initiation.
-The expression of mHTT also disrupts the activity of histone acetyl transferases (HATs), such as CBP/p300 and p300/CBP associated factor (PCAF), which results in histone hypoacetylation and increased heterochromatin formation. Strategies that utilise histone deacetylase (HDAC) inhibitors to correct transcriptional dysregulation by restoring or enhancing histone acetylation have been shown to ameliorate mHTT toxicity in flies and mice, thereby supporting a central role for transcriptional dysregulation in HD . However, because of the broad action of many HDAC inhibitors and the promiscuous nature of HDAC activity, the precise mechanisms by which these molecules influence mHTT toxicity remain unclear .Yet, genetic studies in flies and worms suggest HDACs 1 and 3 are required for mHTT toxicity and could be the primary targets of HDAC inhibitors .function
- Mutational mechanism:
]- CAG nucleotide repeat expansion in the coding region of the huntingtin gene
- Normal gene product -> Huntingtin.
- Widely expressed
- Carries polyglutamine tract
- Abnormal gene product (mutant Huntingtin protein/mHTT)
- CAG repeat translated into stretch of glutamine residues
- When expanded
- Increased interaction with transcriptional regulators including TATA box binding protein
- Changes transcription of many proteins
- Huntington Disease
-Clinical Features
-Age dependent penetration, depending on repeat size
- Mean age of onset is about 40
- Early signs and symptoms -> Minor motor abnormalities
- Clumsiness
- Hyperreflexia
- Eye movement disturbances
- Gradually progression to:
- Involuntary movements
- Chorea (most prominent)
- Parkinsonism
- Dystonia
- Involuntary motor impairment
- Progressive dementia
- Psychological disturbances
- Mood disorder and personality changes
- Cellular hallmark of disease
- Insoluble aggregates of mutant proteins (inactive) and other polypeptides clustered in nuclear inclusions
- Normal cellular response to misfolding of huntingtin
- Soluble nonaggregated form of mutant huntingtin (active) is responsible for pathogenesis
- Neuropathological hallmark -> degeneration of striatum and cortex
-Specification, Determination and Fate
-Axis Specification and Pattern Formation
-Undifferentiated Cells -> Specification -> Determination -> Fate

- Acquires specific characteristics
- Reversible
- Influenced by environmental cues
- Responsible for Regulative Development

- Acquires attributes (environmental cues)
- Irreversible
- Responsible for Mosaic Development

- Ultimate destination
- Specific functions
-Specific fate -> a region of the embryo that regularly gives rise to same structure
-Fate map -> A collection of how all the different regions of an embryo develop

-Gene expression profile for differentiated cells normally not the result of permanent changes to DNA
*Epigenic gene regulation
*Stable transcription complexes
*Modification of histones in chromatin
*DNA methylation
-Epigenetic control of gene expression is responsible for the loss of developmental plasticity

-Exception to this rule
*Lymphocyte precursor cells -> rearrangements in T-cell Receptor
-Immunoglobulin genes -> somatic rearrangements to increase antibody diversity

-Regulative and Mosaic Development
-Regulative Development
*Ability to compensate for loss or injury of cells
*Early human embryogenesis is regulative
*Exposure to teratogens in the 2 weeks after conception carries low risk of causing birth defects
*Evidence: Prenatal diagnosis by biopsy of pre implantation embryo is possible

- Male and female gametes
collected -> IVF
- Biopsy at 8 cell stage
- Remaining seven cells ->

-Mosaic Development
-Inability to compensate for loss or injury of cells
-Fate of particular cells specified independently of environment
-Eg: Rubella virus induced congenital cataracts and microphthalmia from loss of fetal lens cells
-Exception: Regeneration in adult salamanders (Limb, Heart, Spinal cord, Retina, Tail)
-Inability to compensate for loss or injury of cells
-Fate of particular cells specified independently of environment
-Eg: Rubella virus induced congenital cataracts and microphthalmia from loss of fetal lens cells
-Exception: Regeneration in adult salamanders (Limb, Heart, Spinal cord, Retina, Tail)
-Cell-to-cell communication through signaling mechanisms
-Cell surface receptor and ligand
*Ligands -> e.g., growth factors (FGF, etc.)
*Ligand binding -> activates receptor -> signal transmission
-Abnormalities can lead to

- Hedgehog
-Gene originally discovered in Drosophila
-Ability to alter orientation of epidermal bristles
-Human homolog -> Sonic hedgehog (SHH)
-Diffusion of hedgehog protein -> gradient in concentrations of protein -> surrounding cells assume different fates
-Secretion of SHH by notochord and floor plate of the developing neural tube -> development of brain and spinal cord
-By cells in the limb bud -> zone of polarizing activity -> responsible for the asymmetrical pattern of digits within individuals

-SHH in limb development
-Morphogenetic action of the Sonic hedgehog protein during limb bud formation. SHH is released from the
zone of polarizing activity (labeled polarizing region in B) in the posterior limb bud to produce a gradient
(shown with its highest levels as 4 declining to 2).

-Dominant mutation in SHH gene
-Failure of the midface and forebrain to develop
-Cleft lip and palate
-Hypotelorism (closely spaced eyes)
-Variable expressivity common
*Mild/subtle: single central incisor or partial absence of the corpus callosum
*Role of modifier factors suspected

Variable expressivity of an SHH mutation. The mother and her daughter carry
the same missense mutation in SHH, but the daughter is severely affected with
microcephaly, abnormal brain development, hypotelorism, and a cleft palate,
whereas the only manifestation in the mother is a single central upper incisor