Abnormal receptors Flashcards
Difference between somatic and germline mutations?
Somatic - sporadic
Germline - hereditary
State some different types of genetic mutations
- Substitution
- deletion
- inversion
- reciprocal translocation
- chromosomal rearrangement
What effect can mutations have?
Loss of function
- Complete loss of protein (null, amorph)
- Reduction of proteins ability to work (hypomorph, reduction of function)
Gain of function ()
- increasing in protein function (hypermorph, gain of function)
- Protein interfere with WT protein function (antimorph, dominant negative)
- acquistion of a new function (or ectopic expression of the function)
How are the GPCR typically mutated?
Most commonly a loss of function (autosomal recessive) of the membrane spanning region
In the endocrine system how does mutations to the GPCR affect hormone secretion?
Mutations to the receptors of ACTH, TSH, FSH and GnRH will mimic hormone deficiency
What is the result of a loss of function mutations in LH, endothelin B and PTH/PTHrP receptors?
Developmental abnormalities
Describe the GPCR gain of function mutations
Autosomal dominant
- Missense mutations that disrupt inhibitory constrains
- Will cause it to mimic hormone excess
- e.g. LH - Familial male precocious puberty, TSH- non-autoimmune hyperthyroidism
Describe the mutation causing congenital hyponadotropic hypogonadism
GnRHR loss of function mutation
- Mutation cause inability to respond to GnRH
- Causes gonadotrophic deficiency
- Can be complete or partial gonadotropic deficiency
- Suspected in birth in males by micropenis and association with cryptorchidism.
Describe what happens in the LHR loss of function mutation
- GPCR which binds LH and hCG on the ovaries and testis affected.
- mutation cause infertility (females) and pseudohermaphroditism (males).
- Pseudohermaphroditism; cause foetal leyding cells not to produce testosterone and induce masculinisation. Leads to micropenis
Describe what happens in the LHR gain of function mutation
Autosomal dominant disorder causing testotoxicosis (or familial male precocious puberty)
- Progressive pubertal changes
- rapid physical growth
- skeletal maturation
- sexually aggressivity in first 2-3 years of life
Describe calcium sensing receptors loss of function mutation.
CaSR loss of function
- regulates systemic Ca2+ homeostasis
- Causes dysregulation of extracellular Ca2+ homeostasis due to altered set point for extracellular Ca2+ required for PTH regulation
- mutation results in familial hypocalciuric hypercalcaemia (FHH) or neonatal severe hyperparathyroidism (NHSPT).
PTH1R gain of function
- Constitutive activation of the receptor - jansens metaphyseal chondrodysplasia
- Rare autosomal disorder associated with hypercalcaemia and hypophosphataemia
- Mimicks effects of PTH over secretion
- Abnormal growth plate organisation causing short stature
PTH1R loss of function
- causing blomstrands lethal chondrodyplasia
- Rare autosomal recessive disorder resulting in ossification of the endocrine system and advanced skeletal maturation
vitamin D receptor loss of function
- Development of type II vitamin D resistant rickets (or hereditary vitamin D resistant rickets - HVDRR)
- Mutation occurs in the DNA binding domain preventing VDR binding to DNA
- Mutation to ligand binding domain disrupts ligand binding
- High 1,25OH Vit D, alopecia, impeded growth and deformity of long bones
Mutations include nonsense mutations, insertion/substitution, insertions/duplications, deletions, and splice site mutations
THR loss of function
- mutation causes thyroid hormone resistance - reduced sensitivity to T3/T4
- Clinical signs: goitre, short, decreased weight, tacchycardia, hearing loss
