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Pathology lectures > 12th lecture (genetics 1) > Flashcards

12th lecture (genetics 1) Flashcards

1
Q

how many base pairs are there in the human genome?

A

3 billion

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2
Q

how many genes are there in the genome?

A

25 thousand protein coding genes (1-2% of the genome)

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3
Q

how much of the genome is transcribed?

A

75-90% is transcribed (many regulatory RNA molecules = regulatory molecules)

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4
Q

what are some types of ncRNA (non-coding RNA)

A 
miRNA
lncRNA
piRNA
snoRNA
tiRNA
T-UCR
TERRA
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5
Q

what is epigenetics?

A

regulation of genetic expression without altering the genetic code.

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6
Q

how can epigenetic regulation (altering gene expression with no change in the actual DNA)

A

via the use of micro-RNA molecules:

  • 22 nucleotide long
  • post-transcriptional regulation
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7
Q

what is the process for post-transcriptional regulation?

A
  • miRNA gene (nucleus)
  • Pre-miRNA
  • pre-miRNA goes into the DICER complex, will form the single stranded mRNA.
  • the single stranded RNA will bind to the RISC complex and then bind to target mRNA (messenger RNA) and prevents the translation of the mRNA or performs cleavage of that mRNA.

A given miRNA can silence multiple target genes, binding determined by the 3’ untranslated region sequence.

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8
Q

what was so significant about the miRNAs in terms of treatment?

A

cancers have certain miRNA patterns (microRNA) since some miRNA may be missing. (today this is not entirely true)

Targeting RNA interference can be used for therapeutic reasons.

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9
Q

describe the long non-coding RNAs?

A 
the only difference between miRNA and lncRNA is their length;
200 nucleotide vs 100kb long RNAs
Function:
- regulate transcription, splicing
- chromatin regulation
- binding to histone proteins

they have been linked to various disorders

They also help inactivate one of the X-chromosomes.

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10
Q

name some of the disease that long non-coding RNAs (lncRNA).

A

XIST: X-chromosome inactivation
FMR4: fragile X-syndrome
BACE1: Alzheimer’s disease

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11
Q

what methods (in terms of epigenetics) are used to regulated DNA?

A
  • DNA methylation: silencing DNA segments.
  • Histone modifications (methylation and acetylation, Phosphorylation) They change the amount which the DNA code is accessible.

mutations in these regulation proteins can cause cancers as unnecessary proteins can be expressed without regulation.

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12
Q

what does it mean if a mutation is germline?

A

inherited and is transferred to offspring.

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13
Q

what does it mean if the mutation is somatic?

A

the mutation is no transferred to offspring.

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14
Q

name the types of protein coding mutation?

A

AA = amino acids

  • missense mutation (one AA to another AA) such as sickle cell anemia, a Hg mutation.
  • Nonsence mutation (a protein coding codon is converted to a STOP codon)
  • Frameshift mutation: (insertion or deletion of a single nucleotide, altered reading frame)
  • Trinucleotide repeat mutations (excessive number of trinucleotide repeats.
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15
Q

what are some types of mutation present at the nucleotide level?
Chromosomal aberrations that can be detected on a large scale.

A
  • structural alterations: (deletion, amplifications, inversion, translocation)
  • Numerical alterations (aneuploidy, monosomy, trisomy)
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16
Q

what are natural variations in the genome (polymorphisms)

A

SNP (single nucelotide polymorphism)

  • There is about 99.5% similarity between 2 humans.
  • potentially 15 million nucleotide differences
  • 6 million known SNPs. (some can causes diseases) its hard to know how many of these could potentially cause harm. It could contribute to increases risk to other diseases.
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17
Q

what is the mendelian disorders?

A

a disease caused by a single gene.

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18
Q

what are some types of inheritance?

A
  • Autosomal dominant
  • Autosomal recessive (need to copies)
  • X-linked
  • Y-linked (not so common)
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19
Q

define the following:

  • pleiotropy:
  • Genetic heterogeneity:
  • Modified genes:
A
  • pleiotropy: single gene mutation with many phenotypic effects
  • Genetic heterogeneity: mutation of different loci leading to the same bait
  • Modified genes: at other loci.
20
Q

Describe how an autosomal DOMINANT inheritance affects generations of a family?

A
  • at least one parent affected
  • manifested in heterozygous state (AA, Aa)
  • Both males and females are affected
  • 1:2 chance in the offspring to have the disease
  • Delayed age of onset (huntington’s)
21
Q

why are mutations to the receptors , transport proteins (regulators of metabolic processes, LDL rec) Almost always dominant?

Structural proteins are also affected. (collagen)

A

because the mutated receptor allele will repress the healthy normal allele and thus only the mutated allele will be present. Mutated regulatory proteins and alter the structure of the recessive allele.

50% reduction > symptoms > DOMINANT negative effect

22
Q

why are enzymes rarely affected by autosomal dominant inheritance?

they are autosomal recessive.

A

because a mutated enzymes will be compensated by the other enzyme. The healthy allele will compensate for the lack of the mutated enzymes. Thus both alleles must be mutated to affect an enzymes.

23
Q

Describe how an autosomal RECESSIVE inheritance affects generations of a family?

A
  • Both alleles are mutated (aa)
  • the disease can skip generations (parents may not be affected)
  • offspring have 25% chance for having the disease.
  • Enzymes are affected.
24
Q

Describe how an X-linked inheritance affects generations of a family?

A
  • heterozygous females (carriers) transmit to sons only)
  • Affected males are hemizygous for the trait. (since they have only on X-chromosome)
  • Rarely heterozygous females may be affected (x-inactivation)
  • all daughters of an affected male will be carriers
  • offspring of carrier females have a 50% chance for inheriting the mutated allele.
25
Q

what kindof inheritance is hemophilia?

A

X-linked recessive.

26
Q

Describe Marfan Syndrome?

structural protein mutation

A
  • Autosomal dominant connective tissue disorder.
  • Fibrillin gene (FBN1) mutations
  • microfibrils (ECM) aorta, ligaments affected)
  • they often die from valve dissection.
  • skeletal abnormalities (arachnodactyly, spinal deformities)
  • overgrowth of bones (dislocation of the lens (ectopia lentis)
  • floppy valve syndrome
  • Cardiovascular symptoms: aortic dissection, predisposition to aneurisms
  • Most common cause of death: aortic rupture
  • Clinical heterogeneity
  • TGFb inhibition as experimental therapy
27
Q

Describe the Ehlers-Danlos syndrome (EDS)

structural protein mutation.

A
  • autosomal dominant (autosomal recessive is also possible)
  • At least 6 variants caused by different mutations
  • collagen gene mutations
  • strechable skin, hypermobile joints
  • ruptures involving large arteries, colon
  • impaired wound healing.
28
Q

what are the main types of ehlers-Danlos syndrome?

A
  • Lack of lysyl hydroxylase (AR)
  • COL3A1 mutations (AD)
  • COL5A1, COL5A2 mutations (AD)
AR = autosomal recessive
AD = autosomal dominant
29
Q

Describe familial hypercholesterolemia?

A
  • LDL receptor mutations, impaired LDL uptake > hypercholesterolemia
  • increase cholesterol uptake by the monocytes and macrophages
  • Xanthomas, premature atherosclerosis > myocardial infraction
  • increased risk in homozygous patients (MI before age 20)
  • 5 different types of mutations.
30
Q

Describe cystic fibrosis? (receptor mutations)

A
  • most common lethal genetic disease (caucasian population)
  • Autosomal recessive, CFTR gene mutations, impaired Cl- transport
  • Sweat: high NaCl concentration
  • Abnormally viscous mucus: recurrent pulmonary infections, pancreatic insufficiency.

NOTE: know the difference between what occurs in the sweat glands vs the respiratory epithelium.

31
Q

what are some of the consequences of cystic fibrosis? what causes it?

A
  • severe and mild CFTR mutations
  • F508 (deletion of phenylalanine 508)
  • pulmonary changes (obstruction and infection)
  • cardiopulmonary complications (frequent cause of death)
  • pancreatic insufficiency, liver involvement
  • viscous mucus in small intestine of infants (meconium ileus)
  • infertility (bilateral absence of the vas deferens)
  • Median life expectancy (36 years)
32
Q

Describe phenylketonuria (PKU)

A
  • Autosomal recessive pattern
  • Lack of Phenylalanine hydroxylase (PAH) > hyperphenylalaninemia
  • Phenylalanine – Tyrosine conversion inability
  • Impaired brain development, mental retardation apparent by 6 months of life
  • Dietary restriction of phenylalanine
  • Lack of tyrosine > decreased pigmentation of hair and skin
33
Q

Describe Galactosemia enzyme protein mutations).

A
  • Autosomal recessive pattern
  • Mutations of GALT: systemic accumulation of galactose-1-phosphate, galactitol
  • Vomiting, diarrhea within few days of milk ingestion
  • Liver, brain and eye damage (jaundice, hepatomegaly, cataracts, mental retardation)
  • Dietary restriction of lactose
34
Q

What are the main characteristics for lysosomal storage disease?

A
  • Autosomal recessive inheritance (predominantly)
  • Symptoms in infants and young children
  • Deficiency of the catabolism of complex substrates, (enzyme defects)
  • Storage of insoluble intermediates in phagocytes> hepatomegaly
  • Frequent CNS involvement with neuronal damage
  • Cascade of secondary events triggered (macrophage activation)
35
Q

Lysosomal storage disease:

Tay-Sachs disease?

A
  • GM2 gangliosidosis, mutation of hexose-aminidase-A b subunit
  • Brain is principally involved (neurons, glial cells)
  • Motor weakness, neurologic impairment, severe progressive neurological dysfunction
36
Q

Lysosomal storage disease:

NIEMANN-PICK DISEASE, TYPES A and B?

A
  • Accumulason of sphingomyelin (SM-ase deficiency) in phagocytes and neurons
  • Spleen, liver, bone marrow, lymph nodes, lungs most severely affected
  • Severe neurological dysfunction, death within the first 3 years
37
Q

Lysosomal storage disease:

NIEMANN-PICK DISEASE, TYPE C

A
  • NPC1 and NPC2 mutations
  • Primary defect of lipid transport, cholesterol and ganglioside accumulation
  • Ataxia, dystonia, psychomotor regression
38
Q

Lysosomal storage disease:

GAUCHER DISEASE

A
  • Glucocerebrosidase mutations (cleaves glucose from ceramide)
  • Glucocerebroside accumulation in macrophages&raquo_space; Gaucher cells
  • Type I.: (chronic, non-neuropathic): bone involvement, hepatosplenomegaly (99%)
  • Type II and III.: characterized by neurological symptoms
  • Therapy: Enzyme replacement
39
Q

Lysosomal storage disease:

MUCOPOLYSACCHARIDOSES (MPS)

A
  • Mucopolisaccharide accumulation
  • Depending on the enzyme error types I-VII
  • Hepatosplenomegaly, Skeletal deformities, brain lesions, arterial deposits
  • Myocardial infarction as important cause of death
  • Type I (Hurler syndrome): dermatan and heparan-sulfate, cardial involvement
  • Type II (Hunter syndrome), X-linked recessive, milder clinical course
40
Q

Glycogen Storage Diseases:

HEPATIC TYPE

A
  • von-Gierke disease: lack of glucose-6-phosphatase
  • Enlargement of the liver due to the stored glycogen
  • Hypoglycemia (failure of glucose production)
41
Q

Glycogen storage disease:

MYOPATHIC TYPE

A
  • McArdle disease: lack of muscle phosphorilase
  • Impaired energy production, muscle weakness
  • Cramps, myoglobinuria
42
Q 
Glycogen storage disease:
POMPE DISEASE (Type II glycogenosis)
A
  • Lysosomal storage disease (lack of acid maltase/glucosidase)
  • Glycogen deposition in every organ, cardiomegaly is the most prominent, early death
43
Q

what are single-gene disorders with atypical patterns of inheritance?

A
  • Diseases caused by triplet repeat mutations
  • Fragile X-syndrome,
  • Huntington’s disease
  • Diseases caused by mitochondrial gene mutations
  • Diseases associated with genomic imprinting
  • Angleman and Prader-Willi syndrome
44
Q

What are complex multigenic disorders?

Multifactorial or poligenic traits/diseases.

A

Polygenic: cannot find a single gene that would be responsible for the trait.
Complex: The environment can have a role
- Skin color, height, intelligence
- Type-2 diabetes, hypertension
- Wide range, continuous traits
- Role of environmental factors („Nature-Nurture”)

45
Q

Diseases caused by triplet repeat mutations.

A

Fragile X-syndrome

  • CGG repeat in the FMR1 gene
  • Mental retardation
  • Macroorchydism
46
Q

Disease associated with genomic imprinting:

A

Parader-Willi and Angelman Syndrome

  • Chr15 microdeletion
  • AS: maternal, PWS: paternal, (deletion)

Pathology lectures (24 decks)

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