Unusual Molecular Pathogenesis

[edit] Unusual Molecular Pathogenesis

Know the concepts:
- Unstable repeat expansions
- Two hit phenomenon
- Alterened gene structure / dose from unusual crossover
Know the standard profile of each disease

Unstable repeat expansion refers to the phenomenon of nucleotide repeats accumulating in a certain region of the genome and causing disease.
- Repeats can be at any location in the genome: non-coding regions, regulatory regions, introns, or exons.
- The repeats are usually triplets.
Note that this is a true instability in that repeats are added with each mitosis / meiosis.
- NB: instability can also result in decreases in repeats.
- Yes, indeed, even the germline cells have instability of these repeats.
The number of repeats usually correlates with severity of disease.
Repeat expansion leads to anticipation: earlier onset of disease with each generation.
Some expansions become interrupted by a second codon sequence (like in Fragile X syndrome, CGGs are interrupted by AGGs); interrupted repeats are less likely to expand.
In this group, some bases (e.g. a CAG triplet) are repeated in tandem multiple times (e.g.: (CAG)7).

When repeats result in coding regions, they are called poly amino acid tracts.
- It is estimated that 20% of human proteins contain a poly amino acid tract.
Poly amino acid tracts tend to manifest as neurologic disorders.
Some poly amino acid tracts demonstrate anticipation.
Poly amino acids tracts include:
- Huntington disease
- Spinocerebellar ataxia
- Spinobulbar muscle atrophy
- Macado-Joseph disease
- Dentorubropallido dysplasia

The concept of the two hit phenomenon is the idea that if a pt inherits one mutant allele, it only takes one "hit" at that locus to cause dieases; whereas if a pt has not inherited a mutant allele, two hits are required at the locus (which is highly unlikely) to cause disease.
- The second hit can result from the mutation of the wild-type allele or the deletion of the wild-type allele.
Loss of heterozygosity is related to the two hit phenomenon; LOH is the case when a pt has the same alleles at both copies of a loci.
- LOH can result from uniparental disomy, abnormal crossover events, etc.

Gene duplication can lead to disease.
Gene duplication may be facilitated by homologous sequences and / or repeats flanking a loci causing misalignment during synthesis and an attempt at "repair" generating a new copy.