Patterns of Inheritance: Autosomal Dominant - dominant negative effect Flashcards
Examples of conditions exhibiting a dominant negative effect (6)
1 Non-syndromic sensorineural hearing loss GJB2
2 Osteogenesis Imperfecta (OI) COL1A1 or COL1A2
3 Osteopetrosis CLCN7
4 Myotonia Congenita CLCN1
5 Tumour suppressor TP53
6 Marfan Syndrome FBN1
How do dominant pathogenic variants in GJB2 cause non-syndromic sensorineural hearing loss?
DFNB1 locus 13q11–12 contains the Gap Junction Beta 2 and 6 genes (GJB2 and GJB6)
produce connexins 26 and 30
Cx26 and Cx30 involved in K+ recycling in the ear; required for neurotransmitters release from the hair cell in the cochlea
Most pathogenic variants in connexin 26 (GJB2) are recessive
Dominant missense connexin 26 (GJB2) pathogenic variants produce full-length structurally abnormal connexin 26 (GJB2) molecules. Form gap junction plaques with WT connexion 26+30 = connexons with impaired permeability to K+ ions and other small molecules
What are connexins 26 and 30?
Major Gap Junction protein expressed in the human cochlea
What are Fibrillar collagens?
major structural proteins of connective tissue
What is a Preprocollagen?
mature collagen precurosr
what is cleaved from Preprocollagen in the process of mature collagen formation?
C and N terminal fragments. This process is disrupted in Osteogensis imperfecta.
what type of patho mechanism is involved in OI type I?
HI. null variants- < mRNA
what type of patho mechanism is involved in OI type 2,3 and 4?
dom negative. 80% of pathogenic variants replace glycine residues in triple helical domain of COL1A1 or COL1A2= Production of abnormal type I preprocollagen=Disrupt triple helix formation=Severe disease
What is Osteopetrosis?
bone disorder caused by ineffective osteoclast-mediated bone reabsorption
Gene involved in Osteopetrosis
CLCN7. chloride channel protein 7 (CIC-7)
What is the funciton of chloride channel protein 7 (CIC-7) ?
Regulate the pH of osteoclasts-pH control is vital for osteoclast function – balances the acidic environment that osteoclasts use to dissolve bone tissue
Explain variants involved in AR and AD Osteopetrosis
Autosomal recessive osteopetrosis (ARO) o LOF (majority nonsense) in CLCN7 = loss of chloride channel function of varying degree. In the most severe cases(ClC-7) is absent. Autosomal dominant osteopetrosis (ADO) Less severe. Incomplete inactivation of ClC-7 = altered electrophysiological properties of the channel and reduced chloride conductance. Dominant-negative effect.
What gene is involved in Myotonia congenita
CLCN1 CIC-1 chloride channel protein 1
CIC-1 function
exists as a homodimer, each forming a protopore- channel to stabilize cells’ electrical charge, preventing muscles from contracting abnormally
Phenotypic features of Myotonia congenita
characterised by muscle stiffness and inability to contract after voluntary contraction. ‘warm up effect’
What are the two types of Myotonia congentia?
Autosomal dominant (Thomsen-type) myotonia: Autosomal recessive (Becker-type) myotonia
mechanism of autosomal dominant (Thomsen-type) myotonia
Inactive channel dimers contain both WT and variant ClC-1- Less common and less severe than AR myotonia congenitia
mechanism of Autosomal recessive (Becker-type) myotonia
Nonsense or missense LOF-Loss of function through NMD, impaired transport to the membrane or inability to form dimers.
What is the function of P53 (TP53)?
transcription factor p53 mediates changes in gene expression that promote apoptosis= eliminating damaged cells and suppressing tumorigenesis.
Role of dominant negative mutations in P53 pathogenesis?
o p53 binds DNA as a tetramer consisting of a dimer of dimers.
o Wild-type and pathogenic p53 forms heterooligomers with impaired DNA association and transcriptional activity.
What is the nature of the majority of p53 pathogenic mutations ?
• 74% of p53 pathogenic variants are missense within the DNA-binding domain (either sequence-specific recognition of DNA or alter protein conformation).
what is Marfan syndrome?
connective tissue disorder caused by mutations in FBN1
what important role does fibrillin-1 have?
maintaining arterial wall.
How does morbidity and mortality usually result from Marfan syndrome?
aortic aneurysm and dissection
Role of dominant negative mutations in Marfan syndrome?
o Missense and exon skipping variants that result in a stable but altered variant protein.
o Disturbed interaction between variant and wild type fibrillin-1 and other proteins result in a disorganized extracellular matrix.
Role of haploinsufficient FBN1 pathogenic variantsin Marfan syndrome?
o Nonsense and frameshift variants that lead to nonsense-mediated decay.
o Decreased amount of fibrillin-1 leads to a thinner fibrillin-1 matrix in the vasculature with a consequent decrease in aortic wall strength-more severe
o Increased risk of cardiovascular death compared with dominant negative variants.
o Potentially more responsive to losartan therapy for inhibition of aortic root dilatation.
Role of haploinsufficient FBN1 pathogenic variants in Marfan syndrome?
o Nonsense and frameshift variants that lead to nonsense-mediated decay.
o Decreased amount of fibrillin-1 leads to a thinner fibrillin-1 matrix in the vasculature with a consequent decrease in aortic wall strength-more severe
o Increased risk of cardiovascular death compared with dominant negative variants.
o Potentially more responsive to losartan therapy for inhibition of aortic root dilatation.
