Single Gene Disorders II Flashcards
Why is diagnostic criteria important? What is an example?
Helps determine if a disorder is inherited in a dominant or a recessive pattern.
A heterozygous individual may show some loss of physiologic function and it is up to the medical community to define if reduced activity can still be considered normal
Example. Familial Hypercholesteremia, heterozygous individual will present twice the elevation of LDLs so disorder is dominant. Disorder is dominant because threshold is set low
What is heterogeneity?
One disorder can be caused by different mutations, in different chromosomal loci
What is pleiotrophy?
One mutation can cause more than one disorder
What is locus heterogeneity? Where does it often occur?
Mutations in different chromosomal loci cause the same disorder
Often observed in proteins that require processing and trafficking like extracellular matrix proteins (collagen)
Defects of the protein processing have the same outcome as defects of protein itself
What is allelic heterogeneity?
Different mutations in the same gene (same locus) cause the same disorder or different subtypes of disease
Null mutations may cause disease via haploinsufficiency
Missense mutations may cause disease via dominant negative effect
May complicate molecule disease since one does not know which mutation to look for in a large gene
In regards to pleiotropy, what needs to be taken into consideration?
Often a mutation affects more than one system and can cause seemingly separate disorders
Produces more than one trait and same mutation might present differently in different patients
Traits might overlap for different mutations
What are examples of pleiotropy?
Phenylketonuria affects the nervous system development and the integumentary system (form of albinism)
Overlaps with disorders like tyrosinase mutation which also causes albinism
What is osteogenesis imperfecta?
A disorder of type I collagen
Causes deficiency in bone formation
Caused by mutations in COL1A1 and COL1A2 collagen genes
What is osteogenesis imperfect an example of? What heterogeneity does it have?
Genetic Heterogeneity
Allele heterogeneity
Type I: Caused by null mutation in COL1A1 gene due to haploinsufficiency and will reduce amount of collagen in tissue
Type II: Caused by missense mutations in COL1A1 gene via dominant negative effect - assembly of nonfunctional fibers
Locus heterogeneity:
Type VIII: Caused by loss of function mutations in prolyl-hydroxylase (P3H1) gene via recessive inheritance - impair collagen processing
What is collagen made from? and what occurs to it to make collagen?
Collagen is made from procollagen alpha1 and alpha2 proteins
Both proteins need post-translational modifications via hydroxylation of proline and lysine and N-linked glycosylation
What mutations can occur in collagen assembly in OI?
Mutations in collagen processing enzymes cause recessive forms of OI
Mutations in collagen genes cause dominant forms of OI
Dominant negative mutations can be more severe than null mutations
What is NF1?
Neurofibromatosis type 1
Physical exam shows multiple neurofibromas and cafe au lait macules on abdomen
Eye exam shows Lisch nodules
What is penetrance?
Percentage of people with mutation who develop symptoms
Penetrance has to be factored into risk and disorder can skip generation when penetrance is low.
Reduced penetrance means individuals with mutation have no signs of disease
What is expressivity?
Differences in presentation
Disorders can present differently even in the same family
Variable expressivity means individuals with the mutations have different phenotypes and diagnosis may be missed
In relation to NF1, what is its penetrance and expressivity?
NF1 has complete penetrance (everyone with mutation shows symptoms) and variable expressivity (cafe au lait spots to severe neurofibromas)
