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Genetics 2017 > 9LP. Monogenic inheritance > Flashcards

9LP. Monogenic inheritance Flashcards

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1
Q

Construction of pedigree: main symbols that are used in pedigrees

A

See notes practical 24.02.17

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2
Q

Pedigree analysis (characteristics pedigree patterns of monogenic inheritances: AD, AR, XD, XR, Y-linked, mitochondrial)

A

Pedigree analysis
Autosomal dominant
- Vertical pedigree: trait seen in every generation
- 1:1 female to male ratio

Autosomal recessive

  • Horizontal pedigree: trait NOT in every generation
  • 1:1 female to male ratio

X-linked dominant

  • Vertical pedigree
  • Sick father (XY): all daughters sick, all sons healthy
  • Sick mother (XX): depends if homo- or heterozygote
  • 2:1 female to male ratio

X-linked recessive

  • Horizontal pedigree -or-
  • Criss-cross pattern: sick-carrier-sick
  • 0:1 female to male ratio (usually lethal to females)

Mitochondrial
- Maternal inheritance - all offspring of affected females gets affected, but only the daughters pass it on to 3rd generation

Y-linked

  • Vertical pedigree
  • Ex: SRY gene
  • Azoospermia on Y chr, but NOT inherited
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3
Q

Multiple allelism definition

A

More than one mutant allele at one locus can give the same traits/disease (e.g cystic fibrosis with several hundreds mutations)

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4
Q

Complex heterozygote definition

A

Also called genetic compound

  • Is an individual who has 2 mutant alleles at a locus
  • Wiki: when an organism has two recessive alleles for the same gene, but with those two alleles being different from each other (for example, both alleles might be mutated but at different locations)
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5
Q

Codominant phenotype definition

A

A form of dominance in which the alleles of a gene pair in a heterozygote are fully expressed thereby resulting in offspring with a phenotype that is neither dominant nor recessive

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6
Q

Factors affecting pedigree patterns

A

1) Reduced penetrance
2) Variable expressivity
3) Pleiotropy
4) Heterogeneity (locus and allelic)
5) Phenocopy
6) Anticipation

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7
Q

Factors affecting pedigree: reduced penetrance

A

Wiki: Penetrance refers to the proportion of people with a particular genetic change (such as a mutation in a specific gene) who exhibit signs and symptoms of a genetic disorder.
If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance

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8
Q

Factors affecting pedigree: variable expressivity

A

Wiki: Variable expressivity refers to the range of signs and symptoms that can occur in different people with the same genetic condition

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9
Q

Factors affecting pedigree: pleiotropy

A

Wiki: The phenomenon of one gene being responsible for or affecting more than one phenotypic characteristic

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10
Q

Factors affecting pedigree: heterogeneity (locus and allelic)

A

Wiki:
Heterogeneity definition: Many conditions have different genetic causes

Locus heterogeneity is a single disorder, trait, or pattern of traits caused by mutations in genes at different chromosomal loci

Allelic heterogeneity is the phenomenon in which different mutations at the same locus cause the same phenotype

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11
Q

Factors affecting pedigree: phenocopy

A

Wiki: A phenocopy is a variation in phenotype (generally referring to a single trait) which is caused by environmental conditions

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12
Q

Factors affecting pedigree: anticipation

A

Wiki: Anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase of severity of symptoms is also noted

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13
Q

Autosomal inheritance: AD diseases/syndromes

A

1) Osteogenesis imperfecta
2) Acondroplasia
3) Marphan syndrome
4) Familial hypercholesterolemia
5) Huntington disease

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14
Q

Osteogenesis imperfecta

A
  • AD inheritance
  • Gene: COL1A1, COL1A2 (CRTAP, and P3H1 genes)
  • Mutation: most common = substitutions of glycine residues
  • Protein: Collagen type I
  • Main symptoms: blue sclera, brittle bones, deafness (variable symptom expression)
  • Pleiotropy
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15
Q

Achondroplasia

A
  • AD inheritance
  • Gene: FGFR3 gene
  • Mutation: point mutation -> missense mutation (Gly380Arg) - gain-of-function mutation
  • Protein: Fibroblast growth factor receptor 3
  • Main symptoms: disproportionate dwarfism, macrocephaly
  • Thanatophoric dwarfism similar to achondroplasia
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16
Q

Marfan syndrome

A
  • AD inheritance
  • Gene: FBN1 gene
  • Mutation: reduce amount, alter structure or impair transport of protein
  • Protein: Fibrillin 1
  • Main symptoms: Long limbs and fingers, tall, flexible joints, chest protrudes out or dips in
  • Complications: Lens dislocation, aortic aneurysm due to fragmented elastin fibres (TGFβ-associated)
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17
Q

Familial hypercholesterolemia

A
  • AD inheritance (one of the most common)
  • Gene: LDLR gene (multiple allelism)
  • Mutation: deletion, insertion, missense or nonsense
  • Protein: LDL receptor (either no receptor or no LDL binding as result)
  • Main symptoms: Higher level of plasma cholesterol, atherosclerosis/MI, xanthomata
  • Pleiotropy
  • *Environmental factors strong impact on severity
  • **Locus heterogeneity: mutation in other genes can lead to high blood cholesterol level (e.g ApoB mut)
18
Q

Huntington disease

A
  • AD inheritance
  • Gene: HTT gene
  • Mutation: triplet repeats of CAG (11-34 repeats)
  • Protein: Huntingtin
  • Main symptoms: dilated ventricles, uncontrolled movements, emotional problems, and loss of cognition.
19
Q

Autosomal inheritance: AR diseases/syndromes

A

1) Albinism
2) Phenylketonuria
3) Xeroderma pigmentosum
4) Deafness
5) Cystic fibrosis
6) Sickle cell anemia
7) Thalassemias
8) Tay-Sachs disease
9) CAH
10) Arthrogryposis

20
Q

Albinism

A
  • AR inheritance
  • Gene: TRP-1 gene
  • Mutation: Ser166Ter and 368delA
  • Protein: tyrosine 3-monooxygenase (tyrosinase): tyrosine -> melanin
  • Main symptoms: white skin, red eyes (oculocutaneous albinism)
21
Q

Phenylketonuria

A
  • AR inheritance
  • Gene: PAH gene
  • Mutation:
  • Protein: Phenylalanine hydroxylase
  • Main symptoms: mental retardation, light skin and blue eyes (less melanin)
  • Guthrie test (blood)
22
Q

Xeroderma pigmentosum

A
  • AR inheritance
  • Gene: XPC, ERCC2, or POLH (?)
  • Mutation: p53 (?)
  • Protein: problem w/nucleotide excision repair (NER) enzymes
  • Main symptoms: unable to repair UV damage
23
Q

Deafness

A
  • AR inheritance
  • Gene: Connexin 26 gene (potassium homeostasis cochlea)
  • Mutation: GJB2 mutation
  • Protein: connexon
  • Main symptoms: deaf
24
Q

Cystic fibrosis

A
  • AR inheritance
  • Gene: CF gene on chromosome 7
  • Mutation: in-frame del, nonsense, splicing error, missense, frame-shift
  • Protein: CFTR protein -> CL- channels
  • Main symptoms: thick bronchial secretions, blocked bile ducts and/or pancreatic duct, intestinal obstruction, infertility, more salt sweat and saliva, obstructive azoospermia (!)
  • Pleiotropy
    • Treatment: chest percussion
  • ** Can get congenitsl bilateral absence of vas deference (CBAVD) - in 95 % of males w/CF
  • Noncoding region of CFTR gene involved: intron 8 with thymidine tracts (5T/7T/9T), 5T reduces number of functional Cl- channels
25
Q

Sickle cell anemia

A
  • AR inheritance
  • Gene
  • Mutation: Substitution (Glu->Val on 6th AA)
  • Protein: beta globin (mutation leads to aggregation)
  • Main symptoms: Hb crystalizes when oxygen content of blood is low, anemia, weakness, organ damage
  • Protect against malaria
  • *Pleiotropy
26
Q

Thalassemias

A
  • AR inheritance
  • Gene: HBB (beta)
  • Mutation: deletion in HBA1 and 2
  • Protein: beta globin
  • Main symptoms: hemoglobinopathy
27
Q

Tay-Sachs disease

A
  • AR inheritance
  • Gene
  • Mutation
  • Protein: alpha subunit of hexosamidase
  • Main symptoms: Toxic build-up of GM2 ganglioside in lysosome
28
Q

CAH

A
  • Congenital adrenal hyperplasia (AR)
  • Mutations of genes for enzymes mediating the biochemical steps of production of mineralocorticoids, glucocorticoids or sex steroids from cholesterol by the adrenal glands (steroidogenesis)
  • Altered development of primary and secondary sex characteristics
29
Q

Heterozygote advantage

A

Heterozygote advantage: in AR diseases which gives a selective advantage for carriers against:

  • Cholera - cystic fibrosis
  • Malaria - sickle cell anemia, β-thalassemia
  • Tuberculosis - Tay Sachs disease
  • A recessive allele is kept in population, though harmful as homozygote, because provides advantage as heterzygote

Example of selection for monogenic disorders
- Selection can alter gene frequencies of monogenic disorders and reduce (neg. selection) or increase (pos. selection a particular phenotype and its genotype

30
Q

Ecogenetic diseases

A

Gene-environment interactions

  • Manifestation of several genes, and hence phenotype, can be influenced by environmental factors
    1) Porphyria
    2) Malignant hyperthermia
31
Q

Porphyria

A

Acute intermittent prophyria

  • Ecogenetic disease, AD inheritance
  • Protein: Porphobilinogen deaminase (heme production)
  • Main symptoms: acute attacks, porphyrin acummulates -> Red urine, abd. pain + constipation, mad behaviour
  • Triggering factors: hormones (steroids), drugs, dietary changes

Variegate porphyria (AD)

  • Protein: Protporphyrinogen oxidase (heme production)
  • Symptoms: acute, affect skin, abdominal symptoms
  • Triggering factors same as above
32
Q

Malignant hyperthermia

A
  • Ecogenetic disease (AD)
  • Gene: RYR1 gene
  • Protein: ryanodine receptor
  • Triggers: certain drugs used for general anesthesia -> drastic and uncontrolled increase in oxidative metabolism in skeletal muscle which overwhelms the body’s capacity to supply oxygen, remove carbon dioxide, and regulate body temperature, eventually leading to circulatory collapse and death if not immediately treated.
33
Q

Example mitochondrial inherited disease

A

Leber type optic neuropathy

34
Q

Monogenic vs multifactorial diseases

A

Monogenic diseases

  • Large families
  • 1 disease-causing gene per family
  • Genes with high penetrance (disease manifests in majority of carriers)

Multifactorial (complex) diseases

  • Small families
  • Several disease-causing genes per patient
  • Genes with small penetrance (disease cannot manifest in majority of carriers)
35
Q

Important features of AD inheritance

A
  • Disease expressed even in heterozygotes
  • Homozygosity can lead to more severe or often lethal symptoms
  • On average half of offspring affected
  • 1:1 severity and frequency in each sex
  • Vertical pedigree
  • Variable expressivity and penetrance
  • Often alter structural, carrier or receptor proteins
36
Q

Polyglutamine pathogenesis

A
  • Nuclear inclusions
  • Activation of apoptotic pathways
  • Alteration of expression profiles
  • Downregulation of survival pathways
  • Interference with axonal transport
  • Example: CAG repeats in Huntington
37
Q

Potential therapeutic targets of Huntington’s disease

A

1) Caspase: Hsps, Congo Red, Antibodies as therapeutic agents
2) Apoptosis: caspase antagonists
3) Excitotoxicity: NMDA antagonists
4) Mitochondrial dysfunction: Antioxidants
5) Transcriptional dysregulation: HDAC inhibitors

38
Q

Important features of autosomal recessive disorders

A
  • Disease only in homozygotes
  • Frequency and severity equal in each sex
  • Horizontal pedigree
  • Importance of consanguinity (!) - close rel. marriage
  • Tend to be more severe than AD diseases
  • Usually cause defective enzymes or hemoglobin
39
Q

Examples of human oligogenic disorders

A

1) Cystic fibrosis
2) Bardet-Biedl syndrome
- Several (16) BBS genes (7 of them are major cause), locus heterogeneity
- Main symptoms: ciliopathy (!),
- wiki: obesity, retinitis pigmentosa, polydactyly, hypogonadism, and renal failure

40
Q

Polycystic kidney disease

A

Autosomal recessive
- Mutation of fibrocystin (PKHD1)

Autosomal dominant

  • Mutations of polycystin 1 or 2 (PKD1 or 2)
  • Locus heterogeneity

Primary factor in both: tubular cell proliferation

41
Q

Obesity and leptin

A

Obesity associated with lack of leptin
Congenital leptin deficiency exist, but is rare!
Everyday obesity is not monogenic, but complex disease

42
Q

Aging diseases

A

Werner disease

  • Premature aging
  • Caused by helicase mutation

Hutchison-Guilford progeria

  • Premature aging
  • Lamin A mutation

Genetics 2017 (19 decks)

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