T2: Single Gene Pathology 1 Flashcards
What is locus heterogeneity?
Pathogenic variants in multiple different genes can cause one specific phenotype e.g. Retinitis pigmentosa (deposition of pigments in the retina leading to early vision loss and loss of night vision). Many genes are associated with this syndrome.
What is allele heterogeneity?
Different pathogenic variants in a single gene lead to multiple different phenotypes.
E.g. F2FR3 gene is associated with a number of mendelian diseases and cancers such as Achondroplasia (a type of dwarfism), Thanatophrohic dysplasia (lethal embryonic condition - severe bony abnormalities), Crouzon syndrome with acanthosis nigricans(Abnormal fusion of the skull an da skin condition) and Camptodactyly (Tall stature)
What is a point mutation?
A point mutation a mutation that affects a single nucleotide. This includes a substitution or insertions or deletions. This is far the most common type of mutation and the most common cause of disease.
What are the potential consequences variants can have on a gene?
- It can have no affect due to the redundancy of amino acids. This is known as a Synonymous change.
- Exchange of reference amino acid for an alternate. This is known as a Missense change. This can range from little effect to a significant damaging effect.
- Null effect - complete absence of the gene’s protein product. It leads to a truncated protein.
Give examples of null variants.
Null variants:
- Nonsense change - leads to truncated protein
- Frameshift
- Canonical ±1 or 2 splice site variants
- Loss of start codon
- Single exon or multiexon deletion
How is a reading frame established?
The reading frame begins at the start codon - ATG which codes for methionine.
What are canonical splice sites?
Variants that occurs at the boundary of an exon and an intron (canonical splice site) can impact splicing. Boundaries between exons and introns are called canonical splice sites (this is one or two nucleotides into the intron). Alteration of the first or second nucleotide into the intron has a damaging effect on spicing and will lead to translation of a damaged protein.
What are gain of function variants?
Some variants lead to the gain in function. This is variant leads to an altered gene product that processes a new molecular function or pattern of gene expression. These are almost dominate e.g. achondroplasia.
Normal function of FGFR3: slow down the formation of bone by inhibiting the proliferation of chondrocytes
FGFR3:c.1138G>C (p.Gly380Arg)
This mutation Increases the activity of FGFR3, severely limiting bone growth.
This is a gain of function affect.
What are loss of function variants?
Variants associated with reduced or abolished gene function. These are more commonly recessive.
This is as if you 1 copy of the variant, the normal copy usually produces enough functional protein to allow the gene to work e.g. cystic fibrosis and beta thalassaemia.
What are the two types of missense changes?
Conservative missesnse: Amino acid substitution within the same group.
Non-conservative missense: Amino acid substitution to one in a different group.
A non-conservative missense is much more likely to cause more damage as the amino acid is likely to interact in a different way and affect the structure and function of the protein.
What is a frameshift mutation?
A frameshift mutation is the insertion or deletion of a number of nucleotides not divisible by 3. Leads to disruption of the reading frame. Subsequent sequence will be read incorrectly. Eventually leads to reading of a premature stop codon and truncation of the protein.
