Lecture 15

Question 1

What is often an effect of parents are related?

Answer 1

Related parents= parental Consanguinity
Greater liklihood to reveal Autosomal recessive diseases
-as the variants which can lead to diseases on the maternal and paternal chromosomes are more likely to come together

Question 2

What is a quick way of noticing autosomal dominant inheritance?

Answer 2

almost every generation/row will have an affected individual

Question 3

When is the exception to the statement “In Autosomal dominant inheritance, if both parents are unaffected, all children are unaffected”?

Answer 3

When there is a new mutation
“incomplete penetration”
-dominant mutation does severely increase your risk of a disease, but there are other factors at play, which can alter the timing/severity of disease in individuals
-one brother and one sister each inheriting same mutation but developing mutation at different times or differing severities

Question 4

Autosomal Dominant Disorders

Answer 4

> 4000 Autosomal Dominant diseases known (most rare)
Most are uncommon (less frequent than 1/5000)
Tend to be more biologically complex than autosomal recessive (has to be dominance over wild type allele)
Gene product usually a non-enzymic and non-diffusible protein (50% levels of a diffusible protein are often adequate for normal function)
-phenotype/disease by inheriting only 1x copy of mutated allele/overwhelming/suppressing/dominating protein produced by remaining wild type allele
Examples: Achondroplasia and Marfans Syndrome (myotonic dystrophy, Hungtingtons disease and Familial hypercholestrolaemia (leads to arthlosclerosis and CDV))

Question 5

What is the typical Genetic Product of Autosomal Dominant disorders?

Answer 5

Gene product usually a non-enzymic and non-diffusible protein (50% levels of a diffusible protein are often adequate for normal function)
-e.g. building blocks of CT in Marfan’s syndrome (how cartilage ossifies into bone)

Question 6

Achondroplasia

Answer 6

“dwarfism”
Autosomal dominant
Clinical features: shortening of proximal limbs, prominent forehead, depressed nasal bridge, otitis media (susceptible as children)
The most common type of short-limbed dwarfism (1 in 15,000 to 40,000)
Achondroplasia means “without cartilage formation” - actually cartilage is okay but the pathology is altered ossification of the cartilage in bone
Mutation in the fibroblast growth factor receptor 3 (FGFR3) gene
-many members have very dominant skeletal phenotypes (other forms of dwarfism mutations on other genes and small breeds/short limbed dogs (fgfr4)- for dogs doesnt always depend on dominant as are often breeding 2 similar and related parents)
Mutation in FGFR3 gene:
-Mutations result in premature differentiation of chondrocytes into bone
-the wild type allele cannot compensate for/reduce the mutant alleles activity
-these incidence of these mutations increases with paternal age
-mutations sometimes occur during spermatogenesis
-Potential for prenatal diagnosis
4p16.3 (location of mutation)
Genetics of 20% of Achondroplasia: Autosomal dominant. 1x parent affected: 50%. 2x parents affected: 75% (the 25% of being non-affected, arises possibility of pre-natal selection (if ethically appropriate))
-If offspring have 2x mutated genes (no wild type) often so severely affected with achondroplasia that they do not survive pregnancy
Genetics of 80% of achondroplasia: 80% of people with Achondroplasia have parents of normal size. For these people, as spontaneous (de novo) mutation has occurred in the father’s germ cells (50%)

Question 7

New mutations in the male germ line are responsible for many cases of Achondroplasia

Answer 7

For a few congenital disorders, the probability of having an affected child increases exponentially with paternal age
Achondroplasia, spontaneous (de novo) mutations in FGFR3 1138 G>A (at one single position) are ten times more common in normal fathers in their fifties, than in normal fathers in their twenties
-DNA repair mechanisms become less effective with age (small point)
-Mutation seems to affect downstream signalling pathways, spermatigonial stem cells in testes may have a growth advantage if they carry this mutation in the testes, grow quicker and slowly take over the testes
In achondroplasia this may be possible due to germline selection
Male germ cells in the testes carry a FGFR3 1138 G>A mutation may have increased activation of RAS/MAPK and PI3K/AKT pathways (sometimes these pathways are turned on in cancer)
This may give cells carrying this mutation a weak proliferative advantage that compounds over time (grow a little quicker if have this mutation, receptor on surface turns pathways on a little more, shorter time between cell divisions, dividing a little faster, over lifetime 1% can occumulate and this difference can have an effect)
20% achondroplasia seems to be inherited through generation. remaining 80% de nova

Question 8

Potential therapy for Achondroplasia

Answer 8

FGFR3 protein
FLAG-sFGFR3 - make a soluble form of the receptor which doesnt signal into the cell/cell membrane. Instead soaks up, and acts as a decoy to pull away fibroblast growth factor, reducing its ability to stimulate this receptor
-mice -failure of fusion, but with this soluble treatment the normal vertebral fusion is occuring
C-type natriuretic peptide reduced the effects of FGFR3
A peptide named Vosoritide is a CNP analogue with prolonged half-life
PG-QEHPN…. (2x extra aa on amino terminal end of peptide, prolong half life)
-injected in mutation mice, results in normal formation of growing bones (forelimbs and hind limbs)
Future:
cure based on understand biology of disease
potential for prenatal selection or selection of male sperm cells during IVF

Question 9

Marfan Syndrome: another AD disorder

Answer 9

Autosomal dominant disorder due to mutation in fibrillin-1-gene
The protein encoded by the mutated gene binds to and disables normal fibrillin = a dominant negative effect
Several hundred mutant alleles (allelic heterogeneity)- lots of different points in gene which can cause same problem
Affects several organ systems (skeleton, heart, eyes) = pleiotropy
-Clinically diagnosed syndrome that can lead to a number of different outcomes
Different features may be evident in different members of the same family - variable expressivity (different members can have different phenotypes and different levels)

Question 10

When is the exception to the statement “In Autosomal dominant inheritance, the affected person has an affect parent”?

Answer 10

(vertical transmission)

unless new allele being generated in Achondroplasia

Question 11

Autosomal Recessive Disorders

Answer 11

Largest group of single gene disorders
Gene responsible in chromosomes 1-22 (on any autosome)
Disorder where the phenotype only expressed in the homozygous state; i.e. both alleles are mutant
Gene product commonly an enzyme or diffusible protein, but anything (50% protein made by remaining allele is enough/sufficient). Often isnt Phenotype in heterozygous offspring
-sometimes is phenotype (haploinsuifficency)
Phenylketonuria and Haemochromatosis
(cystic fibrosis and thalassaemia)

Question 12

Phenylketonuria (PKU)

Answer 12

Inherited autosomal recessive disorder
Inborn error of metabolism (inherited metabolic defect)
Most commonly due to mutation in Phenylalanine hydroxylase gene (PAH) that encodes an enzyme that normally converts phenylalanine to tyrosine)
-most common cuase
-block in metabolic pathway of a Dietary protein
Causes Phenylalanine and its metabolites to build up upstream, prevents manufacturing of Tyrosine and other downstream components (Melanin, proteins and Dopamine)
New metabolic screening programme
Disease frequency approximately 1/10,000 Caucasians
Carrier Frequency approximately 1/50
Homozygotes:
-typically fair headed, blue eyed
-(as builds up)vomiting, convulsions, and progressive mental retardation if unrecognised and not treated
Allelic heterogeneity (>450 alleles)-makes it hard to screen for, as there isnt a single base that is commonly mutated
Management:
- Screening programme
- Low phenylalanine diet + supplements

Question 13

New Metabolic Screening Programme

Answer 13

Heel prick blood from all newborns is analysed
28 conditions are currently screened for using biochemical assays
-amino acid disorders (14 disorders, including PKU)
-fatty acid oxidation disorders (9 disorders)
-congenital hypothyroidism
-cystic fibrosis
-congenital adrenal hyperplasia
-galactosaemia
-biotinidase deficiency

Question 14

Hereditary Haemochromatosis

Answer 14

Autosomal recessive disorder of iron metabolism (storage and absoportion)
Iron overload due to increased absorption of iron; excessive iron causes organ and tissue damage over time
Common
-1 in 10 Caucasians are carriers (asymptomatic)
-1 in 200-400 homozygous
-frequently diagnosed in general practice incidentally
increased iron absorption
excess iron accumulation
multi-organ dysfunction due to iron deposition
Late onset of clinical symptoms and signs (age usually > over 40)
M=F(same) but later presentation in females as tend to have low iron stores until post-menopausal

Question 15

Clinical features of Haemochromatosis

Answer 15

Non-specific symptoms of lethargy(tiredness)
As disease progresses, organ damage from iron overload
heptamegaly and cirrhosis
diabetes
-can affect range of organs, SKin: changes colour/tinge. Pancreas:diabetes(gold diabetes),
Joints: arthritis
Heart muscle: cardiomyopathy
Steroid hormones: hypogonadism, hypothyroidism
skin pigmentation
Liver: hepatic cirrhosis(activation of tissue repair with fibrous tissue) and increased risk of hepatocellular carcinoma
Phenotype varies
Venesection to deplete iron stores

Question 16

Locas Heterogeneity in Hereditary Haemochromatosis

Answer 16

All recessive - need both
Most common 95%:Type 1: classical HFE gene mutations (C282Y) or (H63D) (AR) (not much allelic heterogeneity)
Type 2 (arises in Childhood): non-classical (=juvenile hemochromatosis) resulting from mutations in hemojuvelin (HJV) and hepcidin (HAMP) (AR)
Type 3 (iron carrier protein): non-classical resulting from mutations in the transferrin receptor protein 2 (TFR2) (AR)
*dominant disease Type 4: Non-classical resulting from mutations in the iron exporter, ferroportin (SLC40A1 gene) (AD)

Question 17

Model of HFE protein

Answer 17

HFE binds to B2 beta 2 -microglobulin (anitgen recognition)
2x sites: 63 and 282 which ahve a common mutation
Haemochromatosis
90% Cys282Tyr Homozygous
5% compound heterozygotes Cys282Tyr and His63Asp (both mutations alter protein but in different ways. 1/2 protein carries different mutation)
^^ both HFE mutations
Others= rarer non-HFE mutations

Question 18

Impact on HFE gene discovery in clinical practice

Answer 18

Diagnosis of Haemochromatosis now based on abnormal iron studies and HFE gene testing ( easier to screen and test for as only mutated in 2x places, as not alot allelic heterogeneity, and 90% of patients only have single mutation); liver biopsy usually not required
Liver biopsy done in HFE gene testing negative or concern about cirrhosis (prognostic information including risk of hepatocellular carcinoma)-liver cell cancer
Has facilited family screening; iron studies and HFE gene testing of adult siblings and close relatives

Question 19

Clinical study

Answer 19

work though pedigree

Haemochromatosis

Question 20

What is the conparative frequency of Autosomal dominant and recessive diseases?

Answer 20

Dominant : large number known (>4000 diseases known)
-but frequency of each is low
vs Autosomal recessive which are large group (of single gene disorders) that are relatively common