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Name the 4 genetic disorders related to DNA structure.
What gene is affected in each disorder?
DNA/Nucleotide modification
- ICF (DNMT3B gene)
- Rett Syndrome (MeCP2 gene)
Histone modification
- Coffin–Lowry syndroms (RSK gene)
- Rubinstein–Taybi Syndrome (CBP gene)
Describe the phenotype associated with ICF.
What is ICF caused by?
DNMT3b dna methyl transferase
––>people are born with it, VERY RARE AUTOSOMAL RECESSIVE
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While immunodeficiency (defects in B cell function such as reduced immunoglobulin production), facial anomalies (epicanthic folds and flat nasal bridge) and mental retardation/developmental delay constitute common phenotypic abnormalities among ICF patients, one of the disease’s most defining features is loss of DNA methylation from centromeric and pericentromeric repeat regions (alpha satellite
and satellite 2/satellite 3 repeats, respectively) and marked loss of chromosomal condensation during mitosis (6,7). Chromosome 1 and to a lesser extent chromosomes 9 and 16 are the most affected by DNA hypomethylation in ICF patients. h 5 nucleotide repeats found in 1, 9, 16, and half of Y chromosome.
Fmr excessive methylation interferes also with condensation
Rett Syndrome (RTT)
X linked. Males usually die.
Apraxia is a disorder caused by damage to specific areas of the cerebrum, characterized by loss of the ability to execute or carry out learned purposeful movements
Occurs in 1/10,000
XLINKED DOMINANT
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Normal pathway:
––>MECP 2 binds to methyl cytosine.
Pathway with mutation:
––>you don’t have repression of genes that should be repressed (just as bad as turning on genes that should be repressed) and so it affects neurotransmitters, growth factors, see slide for symptoms.
**This is out of the ARTICLE that you should read.It’s X dominant, which is unusual. See ARTICLE.
Human diseases with underlying defects in chromatin structure and modification”
Describe the molecular basis of ICF and RTT
ICF: problem with DMNT 3b
Rett syndrom: problem with MECP2
––>for the ones that turn things ON, like rsk which phoshorylates and CBP which is a histone acetyl transferase
––>there is this phosphorylation of serine 10, that’s what this RSK2 does
––>when serine 10 is phosphorylated, these two things are acetylated. Acetylation in general tends to turn on genes, moving it from 30 nm ––> 10 nm form
Coffin–Lowry Syndrome
Coffin–Lowry syndrome, mutations in RSK
–means it can’t phosphorylate serine 10
–facial dysmorphism, skeletal deformation, abnormal digits
Rubenstein–Taybi Syndrome
–downstream of that, mutations in CBP, which is a histone acetyl transferase, called Rubenstein–Taybi Syndrome
–review tries to explain some of these things, but its hard because there are pleiotropic effects
––>in the review they say why is it T cells, why the nervous system, they give different reasons for it, one might be bone morphogenetic proteins (BMPs) if there is a mutation maybe for the facial abnormalities
1/125,000 AUTOSOMAL DOMINANT
Charcot–Marie–Tooth disease (CMT)
–Heterogeneous inherited disorder of nerves (neuropathy)
–Characterized by loss of muscle tissues and touch, predominantly feet and legs
––>This high arch is the characteristic of it
–Incurable, so far
–One of most common inherited nerve disorders, 37 in 100,000
–prokaryotes use the same mechanism for aminoacyl tRNA synthetase as do eukaryotes
–what about the mutations you see in the human population?
You see a couple that can become mutated and give rise to Charcot–Marie–Tooth disease (CMT) :
–glycyl–tRNA synthetase gene (GARS –pronounced like cars with a g) mutations– CMT2D
–tyrosyl–tRNA synthetase gene (YARS – pronounced pirate style :) )– intermediate CMT type C.
There is Localization of aa–tRNA synthetase in granules of neuronal cells
–For some reason it ends up in the cytoplasm of axons because of the site of the mutation.
–Not all mutations are on or off completely, some will change the localization, some will change the activity, some will be a gain of function
**So, everything that we talked about is the normal process, using the 20 aa synthetase genes, including the GARS and YARS genes. Charcot–Marie Tooth 2D and CMTC are the syndromes that result if all the processes can’t occur normally, because the tRNA synthetases don’t function correctly, or at all.
Mutations in aa–tRNA synthetases
- CMT1–demyelinating polyneuropathies,
- CMT2 – axonal polyneuropathies;
- intermediate CMT
glycyl–tRNA synthetase gene (GARS) mutations– CMT2D
tyrosyl–tRNA synthetase gene (YARS)– intermediate CMT type C.
**Localization of aa–tRNA synthetase in granules of neuronal cells
Mutations of Ribosomal Proteins in the SMALL subunit of eukaryotes:
Mutations of Ribosomal Proteins in the SMALL subunit of eukaryotes:
RPS19, RPS24 mutations
- required for the maturation of 40S ribosomal subunits
- Required for binding of eIF2
–Both mutations lead to Diamond–Blackfan anemia
–DBA: abnormal thumb; short; dys heart, kidney, glaucoma
–RPS19 required for the maturation of 40S ribosomal subunits, decrease in ribosome levels
OR
RPS19 and RPS24 might be involved in binding eiF2 ––> Impairment of mRNA translation initiation.
Diamond–Blackfan anemia
DBA: –abnormal thumb –short –dys heart –kidney –glaucoma
RPS19, RPS24 mutations
**small ribosomal subunit
Human Mutations associated with initiation
- Vanishing white matter ––> eiF2b
VWM is characterized by ataxia with CNS hypomyelination
–Not enough myelination acting as insulators for main nerves
–Normally myelin is produced in the oligodendrocytes
–The ER is important in oligodendrocytes because it produces lots of myelin proteins
–If there is a problem activating protein synthesis, then you don’t produce enough
- Wolcott–Rallison Syndrome
All known WRS mutations either impair or abolish PERK activity. PERK is supposed to shut things down but because of the mutation it can no longer do that.
characterized by: –Childhood diabetes; –dys kidney, liver, pancreas, –mental retardation, – central hypothyroidism
Vanishing White Matter (VWM)
–eIF2B is supposed to activate
–People with a mutation in subunits α–ε or eIF2B won’t active as well, leading to
Vanishing white matter (VWM)
In VWM, you’re not making enough myelin because it’s not churning it out fast enough. See the article…
VWM is characterized by ataxia with CNS hypomyelination
–Not enough myelination acting as insulators for main nerves
–Normally myelin is produced in the oligodendrocytes
–The ER is important in oligodendrocytes because it produces lots of myelin proteins
–If there is a problem activating protein synthesis, then you don’t produce enough
Wolcott–Rallison Syndrome
–mutation in a protein (PERK eIF2α kinase) that is supposed to shut things down but because of a mutation it cannot anymore.
This can result in Wolcott–Rallison syndrome.
Wolcott–Rallison Syndrome is characterized by: –Childhood diabetes; –dys kidney, liver, pancreas, –mental retardation, – central hypothyroidism
Highest expression of PERK in secretory cells including β–cells,
WRS patients suffer from infantile onset diabetes mellitus.
––>Get infantile onset diabetes mellitus because it makes so much insulin and it can’t shut it down.
––>Normally it regulates, but in this case in these individuals the beta cells just overload with unfolded insulin and the beta cells die and these patients get type I diabetes as a result
All known WRS mutations either impair or abolish PERK activity
Might allow overproduction of insulin beyond the capacity of the ER UPR activation and β–cell apoptosis
Mutations in elongation factors
No human inherited diseases of elongation factors are known.
Termination–Mutations
eRF3
––>GGC expansion gastric cancer.
––>Most common allele encodes 10 glycines
––>12–glycine allele has been detected exclusively in cancer patients that can lead to a 20–fold increase in gastric cancer but scientists are sure why this is so
eRF3
–Has a GGC expansion in gastric cancer
––>codes for glycine
Apparently we will learn much more about triplet expansion in later courses
––> happens in huntington’s disease
––>The longer the expansion, the bigger of a chance of earlier onset of huntingtons disease
