Genetics 3 Flashcards
(28 cards)
What is the transcriptome
The functional effects of the RNA transcribed
Describe genomic imprinting
The genome carries an imprint of its parental origin
Affects expression of approx. 75 known genes in humans
Non-Mendelian inheritance
No change in genetic sequence
epigenetic modification
Describe the process of DNA methylation
Addition of a methyl group to the 5 position of the pyrimidine ring of a cytosine
Occurs at CpG dinucleotides …AGTTCGTTAG…
This process underlies imprinting and X-inactivation
SAM is S-Adenosyl Methionine (source of the methyl group) and DNMT is DNA Methyltransferase (the catalytic enzyme)
What happens to the imprinting in the germ-line cells
The imprinting is reset, new imprinting pattern will occur, which will be maintained in the somatic cells of the offspring- hence it is non-Mendelian inheritance,
Describe chromosome 15 imprinting disorders
Two distinct clinical syndromes Prader-Willi syndrome (PWS) Angelman syndrome (AS) Loss of function of a specific parental chromosome Paternal Prader-Willi Maternal Angelman
Describe the symptoms of PWS
Symptoms include: Hyperphagia obesity Mental impairment (avg. IQ 60-70) Behavioural problems Muscle hypotonia Short stature, small hands and feet Delayed/incomplete puberty, infertility
How is PWS treated
Hyperphagia managed by diet restriction
Exercise to increase muscle mass
Growth hormone treatment for short stature
Hormone replacement at puberty
Describe the symptoms of AS
Consistent
Developmental delay and speech impairment
Movement disorder (usually ataxia of gait and/or tremulous movement of limbs)
Behavioral uniqueness: happy demeanor; excitable, short attention span
Frequent (more than 80%)
Microcephaly (absolute or relative)
Seizures, onset usually <3 years of age
Associated (20–80%)
Strabismus
Tongue thrusting; suck/swallowing disorders
Feeding problems during infancy
Prominent mandible, wide mouth, wide-spaced teeth
Hypopigmented skin and eyes
Hyperactive tendon reflexes
Uplifted, flexed arms during walking
Increased sensitivity to heat
Sleep disturbance
Attraction to/fascination with water
Brachycephaly
Treatments for AS
Symptomatic – anti-convulsant, physiotherapy, communication therapy
What is PWS and AS caused by
Deletion of chromosome 15q11-q13, caused by recombination of misaligned repeats (BP1 and 2) In PWS paternal copy is deleted, in AS the maternal copy is deleted. Hence if we express the paternal copy of this deletion- PWS. If we express the maternal copy with the deletion- AS.
What is the other cause of PWS and AS
As this part of chromosome 15 is inherited, certain genes are only expressed on the maternal copy or the parental copy.
Maternal copy- UBE3A
Hence if we inherit both copies of this gene from the father ( where it is not expressed)- AS- uniparental disomy.
Parental copy- SNORD16- same scenario, but will develop PWS.
How do we diagnose PWS and AS
Methylation-specific PCR uses PRC primers specific for methylated or unmethylated DNA. Bisulfite modification is used to chemically modify unmethylated bases into uracil prior to PCR as PCR primers do not bind differently to methylated versus unmethylated DNA. Amplify both primers, obtain gene products. In normal, both bands seen. PWS, maternal band not seen. AS, paternal band not seen.
Maternal copy has more bp
How can FISH be used to diagnose PWS and AS
PML = Promyelocytic leukaemia – a gene present on chromosome 15 outside the PWS/AS region
SNRPN = Small nuclear ribonucleoprotein polypeptide N – a gene present in the PWS/AS region
Both present- no deletion
Only PML present- deletion
How is uniparental disomy caused
Most likely to be caused by trisomy rescue. Non-disjunctions that produce diploid gametes usually occur in Mothers. Hence fertilisation will result in a triploid zygote. A chance non-disjunction in early mitosis of this cell may result in the daughter cell being diploid, but the chromosomes will come from the same parent- 1 IN 3 CHANCE.UPD is therefore more common in PWS
Describe the mitochondrial genome
16.6 kb 37 genes, encoding: Respiratory complexes (13) tRNA (22) rRNA (2) 2-10 copies per mitochondrion Estimates of 2,000-2,500 mitochondria per cell Genes are 13 for respiratory chain complexes, 22 for transfer RNA and 2 for ribosomal RNA
Describe mitochondrial inheritance
Transmitted through females (via oocyte)
Passed on to all children regardless of gender
Phenotype can be variable due to heteroplasmy
Only the ovum contributes mitochondria to the zygote
Give some examples of mitochondrial disorders
MELAS
LHON
MERRF – Myoclonic epilepsy with ragged red fibres
DEAF – Non-syndromic hearing loss
NARP – Neuropathy, ataxia and retinitis pigmentosa
Describe MELAS
Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes Progressive, ultimately fatal Muscle weakness Vomiting Episodic seizures and headache, hemiparesis Dementia Hemiparesis is weakness on one side of the body. Not as severe as hemiplegia, which is paralysis on one side of the body
How is MELAS treated and diagnosed
Estimated prevalence of 1:13,000
Symptomatic treatment
Diagnosis by muscle biopsy
Genetics – single mutations in several genes
MTTL1: tRNA translates codon as Phe instead of Leu during mitochondrial protein synthesis
MTND1, MTND5: NADH dehydrogenase subunits 1 and 5
Describe LHON
Leber’s Hereditary Optic Neuropathy
More common in males (unclear why)
Degeneration of retinal ganglion cells (oxidative stress?)
Bilateral, painless, loss of central vision and optic atrophy
Average age of onset 20 (but wide range, 6-60)
Symptoms and causes of LHON
Estimated prevalence of 1:50,000
Diagnosis based on ophthalmological findings and blood test for mtDNA mutations
>90% of mutations are in:
NADH dehydrogenase subunits (MTND1, MTND4, MTND5, MTND6)
Cytochrome B (MTCYB )
How could three-parent babied prevent mitochondrial disorders
Take cytoplasm from healthy egg donor containing healthy mitochondria.
Fuse with nuclear genome in maternal egg
Fertilise with Father’s sperm
What does the newborn screening programme in the UK include
Physical exam Hearing test Blood spot test for genetic diseases (“Guthrie card”) Sickle cell disease (SCD) Cystic fibrosis (CF) Congenital hypothyroidism (CHT) Phenylketonuria (PKU) Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) Maple syrup urine disease (MSUD) Isovaleric acidaemia (IVA) Glutaric aciduria type 1 (GA1) Homocystinuria (HCU)
What is Phenylketonuria (PKU
Phenylalanine hydroxylase (PAH) deficiency
>600 genetic mutations described
1 : 14,000
Symptoms:
Blond hair/blue eyes (lack of melanin)
Eczema, musty odour (excess phenylacetate)
If untreated, seizures and severe mental retardation
