Abnormal receptors Flashcards

1
Q

Difference between somatic and germline mutations?

A

Somatic - sporadic

Germline - hereditary

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2
Q

State some different types of genetic mutations

A
  • Substitution
  • deletion
  • inversion
  • reciprocal translocation
  • chromosomal rearrangement
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3
Q

What effect can mutations have?

A

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)
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4
Q

How are the GPCR typically mutated?

A

Most commonly a loss of function (autosomal recessive) of the membrane spanning region

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5
Q

In the endocrine system how does mutations to the GPCR affect hormone secretion?

A

Mutations to the receptors of ACTH, TSH, FSH and GnRH will mimic hormone deficiency

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6
Q

What is the result of a loss of function mutations in LH, endothelin B and PTH/PTHrP receptors?

A

Developmental abnormalities

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7
Q

Describe the GPCR gain of function mutations

A

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
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8
Q

Describe the mutation causing congenital hyponadotropic hypogonadism

A

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.
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9
Q

Describe what happens in the LHR loss of function mutation

A
  • 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
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10
Q

Describe what happens in the LHR gain of function mutation

A

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
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11
Q

Describe calcium sensing receptors loss of function mutation.

A

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).
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12
Q

PTH1R gain of function

A
  • 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
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13
Q

PTH1R loss of function

A
  • causing blomstrands lethal chondrodyplasia

- Rare autosomal recessive disorder resulting in ossification of the endocrine system and advanced skeletal maturation

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14
Q

vitamin D receptor loss of function

A
  • 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

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15
Q

THR loss of function

A
  • mutation causes thyroid hormone resistance - reduced sensitivity to T3/T4
  • Clinical signs: goitre, short, decreased weight, tacchycardia, hearing loss
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16
Q

Her-2 Gain of function

A
  • Activating mutation of receptor tyrosine kinase
  • Amplification or overexpression of the ERBB2
  • Common in breast cancers
  • Her2 positive breast cancers allow treatment of herceptin
17
Q

How does a mutation cause insulin resistance?

A

Insulin resistance: a reduced response to the glucose-lowering effects of insulin
- Seen in T2DM, atherosclerosis, PCOS and hepatic steatosis

18
Q

What is the most severe form of insulin resistance?

A

Donohue syndrome (autosomal recessive)

  • Caused by homozygous or heterozygous mutations in the insulin receptor
  • insulin receptors are inactive
  • Treated using continuous oral naso-gastric glucose infusion, insulin/insulin sensitisers and a newer rhlGF-1 therapy
  • Fatal within 7 years