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Biochem Exam V > Single Gene Disorders > Flashcards

Single Gene Disorders Flashcards

1
Q

In General what type of proteins show recessive mode of inheritance?

A
  • -enzymes

- -proteins involved in transport and storage

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2
Q

in general, what types of proteins show dominant mode of inheritance?

A
  • -proteins w/ structural functions
  • -proteins involved in growth, differentiation and development
  • -receptor and signalling proteins
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3
Q

Null Mutation

A

–completely destroys a protein

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4
Q

Loss of Function Mutation

A

–reduces proteins activity

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5
Q

gain of function mutation

A

–alters proteins activity (maybe even a new function altogether)

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6
Q

Compound heterozygote

A

–has two defective recessive alleles but they are not identical (might be mutated in different place on gene)

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7
Q

Dominant Inheritance

A

–characteristic of heterozygote who shows signs of disease

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8
Q

Explanations for Dominant mode of inheritance?

A
  • -haploinsufficiency
  • -dominant negative effect
  • -gain of function mutation
  • -lack of backup
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9
Q

Haploinsufficiency

A
  • -half of gene dosage is NOT sufficient for cell to carry out its normal function
  • -think structural proteins, eg. collagen
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10
Q

Dominant Negative Effect

A
  • -mutant protein competes w/ wild type form

- -ex. of protein complex, if one protein is defective maybe it will inactivate the entire complex

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11
Q

Gain of Function Mutation

A
  • -mutated protein may have different functions from its wildtype variant
  • -few proteins w/ this “new” function will have an effect no matter how much normal protein is present
  • -think constituitively active ligand receptor
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12
Q

Lack of Back up

A
  • -two hit model
  • -certain kinds of cancer can develop after the inactivation of both alleles of a cell cycle protein
  • -person who already lacks one Rb gene is more likely to have somatic mutation knock out other Rb and is more likely to get cancer
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13
Q

Sex is determined by?

A

presence or absence of functional Y chromosome

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14
Q

SRY

A

-sex determining region of Y chromo

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15
Q

Pseudoautsomal Region of Y Chromosome

A

–Y chromosome has extensive homology to X chromo and is required for proper alignment w/ X-chromo in meiosis

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16
Q

Inactivation of X Chromosome

A
  • -random but fixed manner
  • -means females are mosaics for X chromo, with some cells using maternal and others using paternal homolog of X
  • -all progeny of cell will have same X chromo inactivated
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17
Q

Development of Disease from Mutation in one X homolog depends on?

A
  • -if “good” or “bad” X chromo is inactivated

- - and whether neighboring cells w/ normal copy of X active can take over function of mutant cells

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18
Q

Mitochondrial gene defects follow? and show?

A
  • -NOT mendelian inheritance

- -variable expression (since cells have many mito with many copies of chromosome)

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19
Q

Pedigree useful for (2 things)?

A
  • -making an accurate estimate of risk for a person to be a carrier of a recessive disease
  • -estimate likelihood that a couple will have an affected child
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20
Q

The parents of a child who has a recessive disease are?

A

–both carriers (Aa)

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21
Q

Genetic markers are?

A
  • -well defined DNA sequence polymorphisms

- -used to trace possible inheritance to child

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22
Q

Compensation of Recessive Defect of Enzyme?

A
  • -increased gene expression of functional enzyme from good allele
  • -increased workload of functional enzymes
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23
Q

Main Characteristics of Autosomal Recessive Pedigrees?

A
  • -affected children usually have normal parents
  • -both sexes affected equally
  • -consanguinity is often present
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24
Q

Coefficient of Inbreeding

A
  • -describes degree of homozgosity of a child
  • -ex. since siblings share 50% of their genes, if they have a kid together, it will be homozygous for 25% of its genes
  • -cousins: 1/16
  • -refer back to page slide if needed
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25
Q

Allele Heterogeneity

A

–different mutations in same gene cause different phenotypes

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26
Q

Locus Heterogeneity

A

–mutations in different gene cause same phenotype

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27
Q

Modifier Genes

A
  • -individual genetic background modifies the phenotype

- -ex. some people had a particular mutation better than others

28
Q

Pleiotropy

A
  • -mutation causes multiple phenotypes

- -not all carriers of same mutation display the same set of phenotypes

29
Q

Inborn Errors or Metabolism (IEM)

A
  • -class of hundreds of autosomal recessive disorders caused by defects in metabolic enzymes
  • -can be acute or chronic
30
Q

Acute IEM’s

A
  • -start in neonatal period
  • -defective metabolism of small molecules such as AA’s or sugars
  • -non-specific symptoms: lethargy, poor feeding, seizures
31
Q

Chronic IEM’s

A

–defects in storage and metabolism of large molecules such as glycogen

32
Q

PKU

A
  • -auto-recessive and most prevalent IEM (1/2,900)
  • -defect in Phe hydroxylase gene on Chromo 12
  • -accumulation of Phe in body
  • -impairs nerve and brain development
  • -Phe free diet
33
Q

Cystic Fibrosis

A
  • -auto recessive and 1/2,000 (of northern euro descent)
  • -defect in gene CFTR (chloride channel) on chromo 7
  • -ineffective resorption and excretion of salt
  • -severity varies: pancreatic insufficient/sufficient: due to allele heterogeneity possibly (mutation on one CFTR gene might differ some other CFTR gene–different domain–maybe one is more functional)
34
Q

Why will a Pt. suffering from an autosomal dominant disease likely be heterozygous instead of homozygous?

A
  • -homozygotes are so severely affected that they do not usually survive into adulthood
  • -probability for homozygote much lower
35
Q

Characteristics of Dominant Disease Pedigree

A
  • -an affected child has at least one affected parent
  • -both sexes equally affected
  • -disease can be transmitted from father to son
  • -vertical pattern of transmission
36
Q

Penetrance

A
  • -sometimes people w/ disease genotype dont develop the phenotype
  • -phenomena found in many dominant diseases
  • -incomplete penetrance must be factored in when calculating occurrence and recurrence risks
37
Q

Expressivity

A
  • -how severe the Pt. with the disease symptoms are

- -some diseases have variable expression (some have worse symptoms than others)

38
Q

Incomplete penetrance and low expressivity can?

A

–mask a true carrier of a mutant allele

39
Q

Neurofibromatosis (NF1)

A
  • -nervous system disorder (1/3,500)
  • -mutations in NF1 on chromo 17
  • -very large gene and easy target for new mutations
  • -multiple benign skin tumors, benign eye tumors, cafe-au-lait spots, mental retardation
  • -highly variable expressivity (diagnosis only made if Pt. shows 2 or more of symptoms above)
  • -shows complete penetrance (so affected person WILL at some point show symptoms of disease)
40
Q

Recurrence Risk of NF1

A
  • -complicated by variable expressivity
  • -if disease were caused by new mutation, then parents would not have it (low recurrence)
  • -if disease were due to inherited NF1 defect, one would predict 50% recurrence risk (hence, one parent would be affected)
  • -NOTE: if parent mildly expresses it, does NOT mean child will mildly express it as well (could be worse or even more mild)
41
Q

Huntington Disease

A
  • -complications of CAG triplet expansions
  • -late-onset (risk of having kids before people know they have it)
  • -5/100,000 persons and caused by defect of huntingtin gene on chromo 4
  • -auto dominant (gain of function)
  • -normal individuals: 9-35 CAG repeats; >40 = HD; 35-40=premutation
  • -non-mendelian element: asymptomatic person w/ premutation can have offspring w/ penetrant new mutations leading to HD full on
    • once HD is established it is inherited as an auto dominant trait
  • -severity of HD increases as # of CAG repeats increases (earlier onset w/ more repeats)
  • -severity increases when transmitted through a pedigree (anticipation)
42
Q

Why do genetic diseases that do not allow for reproduction not become extinct altogether?

A
  • -new mutations compensate for loss of mutant alleles due to reduced fitness
  • –frequency of dominant disease alleles remains constant in populations
43
Q

Achondroplasia

A
  • -dominant mutation in fibroblast growth factor receptor gene (FGFR3–which is a transmembrane tyrosine kinase) on chromo 4
  • -FGF binds and triggers signal cascade which inhibits chondrocyte proliferation
  • -mutations cause constituitively active receptor so bone growth constantly inhibited
  • -20% fertility but prevelance remains constant so 80% are attributed to new mutations at HOTSPOT
44
Q

Mutational Hotspot

A
  • -achondroplasia
  • -chromo region where mutations occur frequently
  • -CG diNT repeat and C is often methylated and then spontaneous deamination of C gives Thymine
45
Q

Problems w/ Collagen Scaffold? (2 things)

A
  • -problems w/ primary structure
  • -problems w/ enzymes that process the collagen molecules
  • -therefore collagen disorders show a typical genetic heterogeneity
46
Q

Ehlers Danlos Syndrome: Recessive vs. Dominant

A
  • -dominant form of EDS caused by mutations in collagen genes and misfolded collagen molecules exert dominant negative effect
  • -recessive form of EDS caused by mutations in enzymes required for collagen processing
47
Q

New Mutations occur frequently in which disorders?

A
  • -duchenne muscular dystrophy
  • -neurofibromatosis
  • -achondroplasia
  • -because these genes are large, complex and contain mutation hotspots
48
Q

Major source of maternal vs paternal mutations

A
  • -nondisjunction: maternal

- -paternal: replication errors (since sperm are generated by continuous cell divisions)

49
Q

Osteogenesis Imperfecta (Type 1)

A
  • -Type I: null, procollagen-alpha1 gene, all collagen made is normal but amount is reduced by half, no bone deformities but brittle bones, haploinsufficiency (one copy of gene not enough to satisfy cellular demands)
  • -Type II: perinatal lethal, missense mutation in
50
Q

Osteogenesis Imperfecta (Type 2)

A

–Type II: perinatal lethal, missense mutation in glycine codons in genes for alpha1 and alpha2 chains, abnormal collagen produced, dominant negative effect,

51
Q

Osteogenesis Imperfecta Type 3

A
  • -Progressive deforming
  • -missense mutation in glycine codons of genes for alpha-1 and alpha-2
  • -abnormal collagen formed
  • -similar to type II but not as severe
52
Q

Osteogensis Imperfecta Type 4

A
  • -missense mutations in glycine codons of gene for alpha-1 and alpha-2
  • -abnormal collagen produced
  • -mildest of OI’s, only moderate bone deformities
53
Q

Severity of Osteogenesis Imperfecta Disease depends on?

A
  • -position of mutated glycine residue within the procollagen chains and on the type of amino acid replacement that results from mutations
  • -Type I which doesnt produce any protein is less severe than Types II-IV since the abnormal protein messes up the entire scaffold (dominant negative effect)
54
Q

Familial Hypercholesterolemia

A
  • -displays dominant inheritance
  • -defect in LDL receptors (could be any part of LDL receptor uptake, utilization, etc.)
  • -you see a phenotype w/ just one allele defect (2x as much cholesterol levels; both alleles defective = 4x as much cholesterol levels)
  • -greater risk of heart attack
55
Q

Diagnosis of a disorder can affect?

A
  • -if a certain disorder is dominant or recessive
  • -think of familial hypercholesterolemia (one bad allele = 2x cholesterol and two bad alleles in 4x cholesterol; 2x cholesterol is bad enough)
56
Q

Why are diseases involving growth, development and differentiation proteins usually inherited in a dominant fashion?

A
  • -b/c the cell needs exactly the right amount of these proteins to function properly and develop
  • -gene dosage effect
  • -and to control the cell cycle in a very defined way
57
Q

RET Gene Function and Disorder

A
  • -must transmit a signal when stimulated but remain silent when not needed
  • -two mutations: gain of function or loss of function
  • -RET gene encodes tyrosine kinase receptor
  • -loss of function: Hirschsprung disease, problem w/ neuronal cell development to colon
  • -gain of function: multiple endocrine neplasia, renders Ret protein constitutively active causing proliferation of neuroendocrine cells
  • -both diseases are dominant due to haploinsufficiency
58
Q

X-Linked Recessive Pedigree Characteristics

A
  • -no father-son transmission
  • -affected boys usually have unaffected parents
  • -males are affected more frequently than girls
  • -will typically skip a generation by transmission through female carriers
59
Q

X-Linked Recessive Diseases (general)

A
  • -affect mostly males
  • -half of a carrier female’s cells will also have mutant phenotype
  • -if protein is diffusible, it wont matter for carrier female because the normal cells can supply the disease cells
60
Q

Duchenne Muscular Dystrophy

A
  • -most common X-linked recessive (1/3,000)
  • -defect in dystrophin gene
  • -Becker MD is milder version
  • -very large gene so it is target for new mutations
  • -fitness is low so new mutations big cause of it
61
Q

X-Linked Dominant Disease Pedigree Characteristics

A
  • -affected male transmits the disease to ALL of his daughters but none of his sons
  • -affected female transmits to disease to half of her children regardless of sex
  • -often lethal in males
  • -very rare
62
Q

Incontinentia Pigmenti

A
  • -defect in NF-kappaB essential modulator
  • -skin erythema, vesicles and pustules progress to scarring, hyperpigmentation
  • -mental retardation, microcephaly
  • -lethal in male embryos
63
Q

2 Types of Mitochondrial Disorders

A
  • -one caused by defects of mito genome (typically will see affecting energy metabolism [ox. phospho pathway] and function of energy-hungry cells such as nerve and muscle cells)
  • -other that are caused by nuclear mutation which are trasmitted in mendalian fashion
64
Q

Difference of Mito genome from nuclear genome (also define heteroplasmy)

A
  • -much higher mutation rate of mito DNA (10x)
  • -mito DNA is present in multiple copies, >1000 copies of mtDNA in a cell
  • -new mutation will affect 1/1000 of mtDNA molecules and will be distributed statistically at cell division, therefore, in a Pt. w/ a mito disorder will have cells w/ varying fractions of defective mtDNA molecules (Heteroplasmy)
65
Q

Leber’s Optical Neuropathy

A
  • -LHON is most prevalent mito disorder (still rare: 1/50,000)
  • -mutation of ND1 gene
  • -protein part of complex I of electron transport chain
  • -rapid deterioration of optic nerve
  • -early adulthood blindness
66
Q

When trying to determine mode of inheritance…?

A
  • -first determine if mito inheritance is seen (inheritance from mother exclusively)
  • -next determine if there is father-son transmission (yes= autosomal and no=X-linked)

Biochem Exam V (8 decks)

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