Principles of Genetic disease Flashcards
What are frameshift mutations?
Occurs when nucleotides are added or subtracted in non-multiples of three
Results in subsequent codons specifying the wrong amino acid or termination signal
What is Waardenburg syndrome?
Truncation, splicing abnormalities and inactivation of the DNA binding region
Autosomal dominant
Pigmentary disturbance, wide nasal bridge and cochlear deafness
What is Huntington disease caused by?
Tandem repeat expansion
What are some possible mutations in regulation and RNA processing?
Promoter mutations
Splicing mutations
Mutations in transcription factors
Transposons
Tandem repeat expansion
What is Loss-of-function?
A change in a gene negatively affecting the amount or function of a gene product
What is haploinsufficiency?
50% of the normal gene product is not sufficient for normal function
Usually caused by loss of function mutations
What is gain-of-function?
A change in a gene, resulting in a gene product that is usually biologically harmful
Most commonly, overexpression or inappropriate expression.
What does it mean to be Dominant negative?
When a defective protein is not only nonfunctional but it inhibits function of normal counterparts
E.g. Osteogenesis imperfecta
What is a mutation?
any permanent change in the nucleotide sequence of a genome
What is a polymorphism?
A mutation that is relatively abundant in a population.
Many are silent mutations
E.g. Rh +/-
What is a silent mutation?
A gene mutation that has no consequence at the phenotypic level
Functionally equivalent AAs, and redundancy in the genetic code are responsible for these
I.e. protein product of this mutation functions just as well
What is Dosage sensitivity
The level of protein product produced by a gene can produce different phenotypes at various levels, rather than one phenotype in the presence and one in the absence of a protein.
E.g. different types of Charcot-Marie-Tooth disease
What is Charcot-Marie-Tooth disease?
Demyelination is the hallmark
Loss of PNS motor and sensory neurons
Many phenotypes depending on mutation
What causes CMT Disease Type 1A?
Duplications in PMP22
Autosomal dominant
What causes hereditary neuropathy with liability to pressure palsies (HNPP) or CMT1B?
Deletions in PMP22
Affected nerves have focal regions with tomaculous changes or sausage shaped figures
Less severe phenotype than CMT
Autosomal dominant
What causes Dejerine-Sottas syndrome (DSS) or CMT3?
Point mutations in PMP22
Autosomal recessive
Clinically similar to CMT, but less severe and occurs in infancy
What is a germline mutation?
A mutation that occurs in every cell in an individual and that was therefore inherited from a parent
What is a somatic mutation?
A mutation occurring only in a subset of somatic cells
What does the phenotype of a somatic mutation depend on?
Which cells and tissues are affected
Nature of the gene product
What is allelic heterogeneity?
the occurence of more than one disease causing allele at a locus
E.g. mitochondrial depletion syndromes, CMT
What is locus heterogeneity?
The association of more than one locus with a specific clinical phenotype
E.g. hearing loss where it is common for two affected people to produce normal children
What is Clinical heterogeneity?
Variability in relation to presentation or treatment of a disease
What are modifier genes?
genes that affect the occurrence or severity of a phenotype associated with mutations in a non-allelic gene
What is an epiallele?
Alleles of genes containing epigenetic marks
What is gene silencing?
Inactivation of a gene
What is imprinting?
determination of the expression of a gene by its parental origin
sub-type of gene silencing
What is Angelman Syndrome?
Unusual facial appearance, short stature, spasticity, seizures
Caused by maternal inheritancy of 15 deletions
Paternal is imprinted
What is Prader-Willi Syndrome?
Obesity, small hands and feet, short stature, hypogonadism
Paternal inheritance of 15 deletions
Mother is imprinted
