Class 11A: Single gene disorders: defects in structural proteins Flashcards
(38 cards)
Define a mutation.
Mutation - a hereditary change
-process by which genes change from one allelic form to another
What are the 2 different levels of mutations?
GENE MUTATIONS –> point mutations (ex) –> typically map to one chromosomal locus –> changes an allele
CHROMOSOME MUTATIONS –> segments, whole or entire sets of chromosomes change –> can involve gene mutations as a result
What is the reference point for mutations?
the wildtype allele
What are mutations away from the wildtype called?
forward mutations
How can mutations be classified?
Mutations can be classified:
- Somatic versus germinal mutations
- Dominant versus recessive mutations
- Loss of function versus gain of function mutations
- -> dominant-negative mutations
Compare a dominant versus recessive mutation.
dominant mutation - only one of the 2 alleles of the gene needs to be mutant in order for the mutant phenotype to manifest
= heterozygous for mutation = mutant phenotype
recessive mutation - both alleles need to be mutant alleles in order fro the phenotype to manifest
= homozygous for the mutation = mutant phenotype
What is a loss of function mutation?
- the mutant allele leads to decreased or no function of the product generated –> ex: null allele
- most often are recessive mutations
-BUT if amount of normal protein synthesized from the normal
(unmutated) allele is not sufficient for normal phenotype, then NOT
recessive = dominant
= haploinsufficiency
= heterozygote shows phenotype
What is a gain of function mutation?
- mutant allele changes the gene product such that it now has a new and abnormal function in the cell
- usually are dominant mutations
-a dominant negative mutation results in a gene product that
antagonizes the normal gene product
What are single gene disorders? What are some examples?
Caused by mutation of a specific gene in the affected individuals
Examples:
- Cystic fibrosis
- Sickle cell anemia
- Duchenne muscular dystrophy
Single gene disorders: ECM proteins
Defects in structural proteins = proteins of the _____
ECM
collagen, fibrillin, elastin
Defects in structural proteins
________ make lots of extracellular matrix
Connective tissue cells make lots of extracellular matrix
- carry the mechanical load of these tissues
- composed of fibrous proteins
- collagen is the main member of this family
Connective tissue cells go by various names.
_____ in skin
_____ in bone
fibroblasts in skin
osteoblasts in bone
How are ECM proteins synthesized?
All ECM proteins are synthesized intracellularly (precursor form),
secreted by exocytosis and are then processed and assembled into large
aggregates (mature form) in the extracellular space
Single gene disorders: Collagen
Defects in structural proteins: Collagen
Mammals have ___ diff collagen genes
Chief protein in?
These diseases affect what?
Mammals have 20 different collagen genes
-chief protein in bone, skin & tendons
-~ 25% of our total protein mass
-mutations in any of the many genes that encode the different types of
collagens lead to severe genetic diseases
These diseases affect connective tissues!
Single gene disorders: Collagen
Describe the structure of collagen.
Three coiled subunits (two α1 (I) chains and one α2(I) chain= heterotrimer)
- form right-handed triple helix
- unusual abundance of amino acids glycine and proline in repeating units Gly-Pro-X
- Gly present at every 3rd position = crucial for helix formation
- collagen molecules formed can make side-by-side interactions to
form fibrils
The three coiled subunits in ______ form what is referred to as a _____________.
The three coiled subunits in collagen form what is referred to as a right-handed triple helix.
Single gene disorders: Collagen
What is crucial to normal collagen fibril formation?
POST-TRANSLATIONAL MODIFICATIONS are crucial to normal collagen fibril
formation.
Ex: lack of proline hydroxylation results in unstable triple helices and
lack of collagen fibrils –> defect in prolyl hydroxylase
-Scurvy caused by lack of ascorbic acid (Vit C) –> necessary cofactor for prolyl hydroxylases
Defects in structural proteins: Type I Collagen
Mutations in the α1 or α2 genes encoding Type I collagen leads to a
brittle-bone disease known as?
osteogenesis imperfecta (OI)
What is osteogenesis imperfecta (OI)?
Mutations in the α1 or α2 genes encoding Type I collagen leads to a
brittle-bone disease
What are two important genes when discussing OI?
COL1A1 or COL1A2
What can cause the disease OI?
single amino acid change can cause disease
- recall that every 3rd amino acid must be glycine!
How is OI mostly inherited?
Mostly autosomal dominant inheritance
- more than 1500 mutations in COL1A1 & COL1A2 identified!
- affect approx. 1 in every 20,000 births
Single gene disorders: OI
What are some features of OI?
Clinically heterogeneous connective tissue disorder
-can affect structure, quantity, modification or assembly into ECM
-low bone mass
-reduced bone material strength
= bone fragility
- fractures, growth deficiency, bone deformities
-range in severity from lethal to subclinical
Single gene disorders: OI
What are the OI types? (classification)
Most often deal with the OI classifications I through IV.
OI type I is a haploinsufficiency situation due to a null COL1A1 allele
- premature termination codon –> nonsense mediated decay
- autosomal dominant
Classification evolving. Clinical phenotype and type of mutation taken
into consideration.
