Genetics (Day 1) Flashcards
What are some causes of complete loss of function mutations (null mutations)?
- Nonsense
- Splice-site
- Frameshift
- Some missense and regulatory sites
- Large deletions or insertions
What are some causes of partial loss of function mutations?
Most missense and some regulatory site
What are the common mutations involved with DMD?
- Deletions
- Frameshift
- Nonsense
What are the common mutations involved with BMD?
- In frame deletions
What happens to the exon length in DMD?
It is NOT a multiple of 3, so there is a frameshift mutation (which leads to no protein due to premature termination codons).
What happens to the exon length of BMD?
It IS a multiple of 3, so there is no frameshift mutation, which results in a protein with reduced function.
Enzyme diseases are almost always ____?
Recessive
What are the three clinical variant forms of PKU and what is their degree of severity?
- Classical PKU (most severe)
- Variant PKU (intermediate form)
- Non-PKU Hyperphenylalaninemia (mildest form)
What are normal plasma phenylalanine levels?
< 0.12 mM
The enzyme phenylalanine hydroxylase (PAH) requires what cofactor for activity? What other enzymes require this cofactor?
- Tetrahydrobiopterin (BH4)
- Tyrosine Hydroxylase and Tryptophan Hydroxylase
What are three mechanisms of dominance?
- Haploinsufficiency
- Gain of Function Mutations
- Dominant Negative Mutations
What are two explanations for variable expressivity?
- Variation at other genes (effect of modifier genes)
2. Stochastic events in development (random chance)
With NPS, where are the missense mutations clustered?
In the “LIM” and “HD” domains.
What are some enzymes that when deficient, can cause hepatic porphyrias?
- Porphobilinogen demaminase
- Protoporphyrinogen oxidase
- Coproporphyrinogen oxidase
- Uroporphyrinogen decarboxylase
What are some effects of a gain of function mutation?
- Increased gene function
- New gene function
- Mutant protein synthesis (usually missense, gene duplications, and chromosomal translocations)
What kind of mutation is never present in gain of function mutations?
Null Mutations
The mutant gene product interferes with the function of the normal gene product.
Dominant Negative Mutations
What are some causes of Dominant Negative Mutations?
- Usually missense mutations
- NEVER null mutations
Osteogenesis Imperfecta has clinical heterogeneity. Why is it’s null mutation unique?
The null mutation has a milder phenotype and missense mutations are more severe (opposite of most types of manifestations).
What are common clinical manifestations of OI Type II?
- Perinatal Lethal
- Multiple in utero fractures
- Dominant negative glycine substitutions
Explain the details of the mechanism of Osteogenesis Imperfecta.
In this disease, the glycine substitutions introduce bulkier amino acids that alter the helical structure of the alpha chain (thus altering the triple helix)
This ⍺1-AT allele is associated with relatively mild disease. Homozygotes of this allele have 60% of their normal ⍺1-AT levels.
S (Slow) Allele
This ⍺1-AT allele is associated with more severe disease, and 15% of people with this allele have normal ⍺1-AT levels.
Z (Very Slow) Allele
This a1-AT allele is prone to aggregation and polymerization, associated with inclusions in hepatocytes, and increased inflammation in lungs following infection.
Z (Very Slow) Allele
What disease has complete penetrance and variable expressivity?
Nail Patella Syndrome (NPS)
What are the different mutations that can cause NPS?
Missense, Nonsense, Frameshift, and Splice Mutations
What are the types of Gain of Function Mutations?
- Usually missense
- Gene duplications and chromosomal translocations
For regulatory region mutations, mutations in the proximal promotor region are usually?
Null Mutations
For regulatory region mutations, mutations in the enhancer region may?
Prevent transcription or change specificity
What are the haplosufficiency (loss of function) diseases?
- Duchenne Muscular Dystrophy (DMD)
- Becker Muscular Dystrophy (BWD)
- Phenylketonuria (PKU)
- Tetrahydrobiopterin Deficiency (BH4)
- Oculocutaneous Albinism
- Maple Syrup Urine Disease
What are the haploinsufficiency (loss of function) diseases?
- Nail Patella Syndrome (NPS)
- Cleidocranial Dystosis/Dysplasia
- Acute Hepatic Porphyria
- Acute Intermittent Porphyria (AIP)
- Variegate Porphyria (VP)
What are the two dominant (gain of function) diseases?
- Thanatophoric Dysplasia (TD)
- Achondroplasia
What is the dominant negative disease?
Osteogenesis Imperfecta (OI)
What is the codominance disease?
Alpha 1-Antitrypsin Deficiency
What are the regulatory site mutations?
- Polydactyly
- Campomelic Dysplasia
- Lactose Intolerance
Explain the symptoms of WBS duplication.
- Short philtrum, thin lips
- Large teeth, arched palate
- Narrow forehead, normal periorbital area
- Severe language delay
- Relative spatial skills
Explain the symptoms of WBS deletion.
- Long philtrum, full lips
- Small teeth, normal palate
- Broad forehead, full periorbital area
- Relative language
- Poor spatial skills
