CCFC 513 Lecture Notes - Lecture 6: Friability, Alanine, Hydroxylation
25 Jun 2018
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Genetic diseases caused by mutations in collagen genes
• COL15,16,20 and 21,23,24 and 28 do not cause any disorders in human beings
• Each COL gene is related to a different disorder
• There is no need to need to memorize all the genes
• Mutations in collagen genes coding for collagenopathies affect many organ systems with
overlapping clinical features
• If you mutate a single gene in collagen, multiple tissues can get affected
Gene disorder
There are two types of inheritance:
• Dominant- even one mutant allele is enough to develop a gene
• Dominant negative effect- production of abnormal protein that can impair function of normal
protein-Very common for structural proteins like collagen
• Recessive – Only if both your parents contribute a mutant allele to a gene, you will develop the
disease-Very common for enzymes
• You need to be either homozygous for the mutant allele or compound heterozygous to develop
recessive disorder (because of lack of normal protein)
• De novo mutations- completely new mutation in individual which is not present in the parental
units- if it occurs at the conception stage, all the cells will be affected, if it occurs after the 8 celled
stage, only some cells will affected and some cells wont.
• Variable mutations (mosaicism)- if you do not inherit mutation from the gene cells, it may be
present only in a fraction of cells and not all your cells-this results in mosaicism
Mutant Collagen trimers
• Collagen alpha chains associate as trimers
• Mutations are usually due to glycine residues-only amino acid small enough to come to the centre
of the triple helix- mutations in glycine disrupt the triple helix and is detrimental to function
• If you have a mutation in the alpha 2 chains, 50 % will be normal and 50% of the collagen will be
mutated
• If one of the chains is mutant , again 50% wild protein and 50% mutant
Collagen-gene disorders
• All autosomal dominant
• EDS Type VII- Ligament laxity (extreme flexibility of ligaments)
• Chondrodysplasia- abnormal cartilage
• Type IV- Alport syndrome- affects the basement membrane of kidney- basement membrane
needed for glomeruli
• Type V- Associating with Type I triple helix-
• Bethlem myotraphy-muscle dystrophy syndrome- begins progressively after birth-they will rarely
live beyond 30-40 years of age
• Type VII- Epidermolysis bullosa- Skin blisters over entire body- responsible for anchoring fibrils
Ehlers-Danlos Syndrome
• It is usually not very easy to diagnose without sequencing for the mutation
• Ehlers and Danlos recognized this disorder
• Physical symptoms- joint dislocation, skin extensibility and tissue friability
• There are other disorders that cause the symptoms but are a result of different other mutations
Polymorphisms-Mutations or not?
• The difference between the two is very subtle
• Mutations CAN HAPPEN in the binding sites of the DNA Polymerase in the promoter and CAN
promote gene expression
• Intron mutations may/may not influence splicing
• Exon mutations-most damaging
• Variations in intergenic regions that can cause lower expression of the gene
• Enhancer regions can get mutation (sequences present at a distance from the gene which bind to
transcription factors and regulate activity of the promoter)
Consequences of Exon Mutations
• Most damaging type of mutation
• Can be a substitution (Missense, Nonsense, Polymorphic), Insertion (In-frame or frameshift),
deletion (In-frame and frameshift)
Glycine and Nonsense Mutations
• GGU, GGC, GGA, GGG- code for glycine
• Mutations in any of these codons can result in mutated glycine and mutated collagen triple helix
• Can result in substitution mutations and nonsense mutations
Intron Mutations
Mutations in the splice donor or splice acceptor site
Splice donor site mutation-retention of intron, exclusion of exon, can result in cryptic splice sites (where
the wrong gt sites are included resulting in extra intron and result in stop codons down the line)
Splice donor acceptor sites- splice machinery will try to look for another splice acceptor site if the original
one is mutated (for e.g if AG is the splice acceptor site and it is mutated to TG, the splice machinery will
look for another AG, the AG might be between another exon and might splice the intron +some part of
the exon resulting in truncation or it might be after the next exon and cleave off the next exon, it varies)
Osteogenesis Imperfecta- Clinical manifestations
• Association with dentinogenesis imperfecta
• Dentine is heavily loaded with collagen Type I
• Vertebral compression fractures (very painful)
Document Summary
If you mutate a single gene in collagen, multiple tissues can get affected. If you have a mutation in the alpha 2 chains, 50 % will be normal and 50% of the collagen will be mutated. If one of the chains is mutant , again 50% wild protein and 50% mutant. Polymorphisms-mutations or not: the difference between the two is very subtle, mutations can happen in the binding sites of the dna polymerase in the promoter and can promote gene expression. Consequences of exon mutations: most damaging type of mutation, can be a substitution (missense, nonsense, polymorphic), insertion (in-frame or frameshift), deletion (in-frame and frameshift) Glycine and nonsense mutations: ggu, ggc, gga, ggg- code for glycine, mutations in any of these codons can result in mutated glycine and mutated collagen triple helix, can result in substitution mutations and nonsense mutations. Mutations in the splice donor or splice acceptor site.
