Unusual Molecular Pathogenesis

From Iusmgenetics

Contents 1 Unusual Molecular Pathogenesis 1.1 Objectives 1.2 Unstable repeat expansion 1.2.1 Myotonic Dystrophy 1.2.2 Fragile-X Syndrome 1.2.3 Huntington Disease 1.3 Two Hit Phenomenon 1.3.1 Polycystic Kidney Disease 1.3.2 Neurofibromatosis 1.3.3 Hemophilia A 1.4 Gene duplication 1.4.1 Charcot-Marie-Tooth Disease

Unusual Molecular Pathogenesis

Objectives

• 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

• 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

Myotonic Dystrophy

Fragile-X Syndrome

Huntington Disease

Two Hit Phenomenon

• 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.

Polycystic Kidney Disease

Neurofibromatosis

Hemophilia A

Gene duplication

• 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.

Charcot-Marie-Tooth Disease