Autosomal dominant – Gain of function mutations Flashcards
what is a hypermorph?
an allele that produces an increase in quantity or activity of its product
What is a Neomorph?
an allele with a novel activity or product
what is the common mechanism of GOF mutations at the cellular level?
Often a control or signalling system behaving aberrantly; signalling when it should not, or failing to switch a process off when it should
Example of a product acquiring a novel function?
BCR-ABL1 translocation in chronic myeloid leukaemia (CML)
examples of some GOF mutations:
Overexpression PMP22 CMT
Receptor permanently on GNAS McCune-Albright
Acquire New Substrate PI Alpha 1 Antitrypsin
Protein Aggregation HTT Huntington Disease
Chimeric Gene BCR-ABL CML
Where is HTT located?
4p16.3
Evidence that the CAG repeat expansion is a gain of function mutation includes:
- deletions including HD fail to manifest HD
- Phenotypically normal individuals with translocation breakpoint disrupting HTT
- Homozygotes clinically identical to heterozygotes
- The dominant phenotype suggests the mRNA or protein has acquired a new property or expressed inappropriately; HD levels of polypeptides encoded by normal and mutant allele are identical
Describe the pathogenic events in HD
Polyglutamine expansions =neuronal intranuclear inclusions containing HTT, chaperone proteins and ubiquitin.
inclusions most frequently observed in the regions of brain showing particular sensitivity to the HD mutation and more abundant in brains of juvenile onset HD with large CAG repeat.
However, inclusions do not cause the disease themselves: mouse models and human brains, location of the inclusions does not always correlate with cell toxicity.
Mutant HTT = abnormal protein structures e.g. β-sheets -truncated by caspase-6 cleavage, = toxic N-terminal frags= processing of abnormal proteins (e.g. ubiquitin pathway) altered in HD.
The toxicity of HTT is affected by post-translational modification and nuclear localisation.
Mutant HTT interferes with gene transcription (PGC1α) and may effect mitochondria= affected metabolism and oxidative stress.
Abnormal vesicle transport with decreased transport/release of brain-derived neurotrophic factor (BDNF) and increased excitotoxicity.
Nature of expanded repeats in DM1 and DM2?
(CUG)n and (CCUG)n
mechanism of parthenogenesis
- Repeat expansions form stable structures that sequestrate RNA-binding proteins e.g. muscleblind-like (MBNL) and CUG-BP1 in ribonuclear inclusions.
- Altered expression and activity of these RNA regulatory proteins affects alternative splicing e.g. downregulation of MBNL1, upregulation of CUG-BP1.
- embryonic splicing patterns of several important genes observed instead of adult splicing e.g. CIC-1 chloride channel, insulin receptor, troponin T.
Types of Spinocerebellar ataxia caused by CAG polyglutamine expansions?
1, 2, 3, 6, 7, 17
What is the mechanism of SC8 pathogencity?
both RNA and protein gain of function
• Proposed bi-directional transcription at SCA8 locus ATXN8 antisense CAG-containing translated into ataxin 8 protein and found in intranuclear inclusions in Purkinje cells and in brainstem neurons of SCA8 patients
• concomitant expression of untranslated antisense CTG mutation in the 3’UTR of the ATXN8OS =CUG repeat transcript that becomes toxic via an RNA gain of function mechanism
Gene for Achondroplasia?
FGFR3
What is FGFR3?
transmembrane TK which negatively regulates bone growth by inhibiting the proliferation of chondrocytes
Pathogenic mechanism of Achondroplasia mutations?
constitutive activation of the FGF receptor= severely limiting bone growth.
