1. MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY
MOLECULAR ASPECTS OF GIANTISM, ACROMEGALY AND PITUITARY DWARFISM

2. 1

3. ACROMEGALY

4. Dwarf mice

5. GH-SECRETING PITUITARY TUMOURS
~ 40% of human GH-producing tumours contain high level of cyclic AMP. Adenylate cyclase is constitutively active.
Gs was cloned from such tumours and showed single aa substitutions (Landis):
Arg201Ser, Cys or His; Glu227Arg or Leu.
Somatic mutations - DNA from non-pituitary tissue not affected.
Mutant G proteins have low GTPase activity
Arg201 is ribosylated by cholera toxin; Glu227 is in GTP/GDP binding site)
Defines the gsp oncogene

6. GH secretion

7. Gs AND ADENYLATE CYCLASE ACTIVATION
Gas bg
From Stryer

8. OTHER CAUSES OF ACROMEGALY
1. Inappropriate secretion of GHRH by somatotrophs (giving autocrine stimulation) [rare?].
2. Activating GHRH mutations [rare]
3. Loss of function mutations in regulatory subunit of PKA [rare]
4. Defects in alternative pathway for GH regulation (Ghrelin) [?]
5. Ectopic GHRH secretion by tumours of other tissues (esp. pancreas and lung) - less rare (but acromegaly may not be main problem)

9. TREATMENT OF ACROMEGALY
Surgery and/or irradiation
Octreotide (somatostatin analogue)
Dopamine agonists (e.g.bromocryptine)
GH antagonist - pegvisomant

10. A GH-RECEPTOR ANTAGONIST
From Drake et al (2001)

11. The GH-IGF-Somatic axis

12. PATTERNS OF HUMAN GH SECRETION
IGHD Type 1B
GH Neurosecretory
dysfunction
Normal
GH concentration (ng/ml)
Time

13. HEREDITARY GH DEFICIENCY
Type IA Autosomal recessive. Severe GH deficiency; may develop antibodies to GH used for treatment
Type IB Autosomal recessive. Some residual GH present.
Type II Autosomal dominant. GH mutation?
Type III X-linked

14. A FAMILY OF PATIENTS SHOWING IGHD Type IA
From Phillips et al (1981)

15. DELETIONS OF THE hGH GENE CLUSTER

16. IGHD TYPE 1B
Low levels of GH retained, so GH treatment usually effective
Various causes, including:
Inactivating GHRH mutations (including lit) mouse
Defective GH, grossly altered so not detectable in RIA

17. INACTIVATING MUTATIONS OF THE GHRH RECEPTOR UNDERLY SOME CASES OF IGHD IB
From Frohman & Kineman (2002)

18. IGHD Type II.
Often due to production of a mutant GH lacking Exon 3. Why is this dominant?
Shortened GH is not active, but seems to interfere with processing of normal GH in somatotroph

19. MPHD
Often due to transcription factor mutations that affect development of several different pituitary cell types and expression of several different hormones.
E.g dwarf (dw)mouse - mutant Pit 1 transcription factor - Trp  Cys mutation. Production of GH, PRL and TSH all affected.

20. BIOINACTIVE GH
GH levels usually apparently normal, but patients respond to exogenous GH. Dwarfism due to production of inactive GH. Mutations identified include:
Asp112  Gly
Arg77  Cys (dominant negative)

21. LARON DWARFISM
Very stunted growth, but GH levels normal or above normal.
No response to GH treatment.
Fibroblasts respond to IGF-I but not GH; no GH binding.
Due to deletions of GH receptor gene, point mutations (e.g. Phe96  Ser), frame shift mutations, chain termination mutations.
Mutations can have varying effects on binding, production of GH binding protein etc.

22. GH RECEPTOR MUTATIONS
From Johnston et al (1998)

23. GROWTH AND IGF-1 LEVELS IN PYGMIES

24. IDIOPATHIC SHORT STATURE
Cases of short stature with no obvious cause. May reflect:
1. Impared secretion (GH neurosecretory dysfunction)
2. Bioinactive
3. GH insensity (but not Laron)- GH receptor defects with minor effects
4. None of the above. Note that short stature may be unrelated to GH defects - e.g. Achondroplasia - point mutation of FGF receptor 3 (expressed in cartilage). Heterozygotes dwarfed; homozygote lethal. But aetiology different from dwarfism due to GH deficiency

25. GH AND AGEING
GH secretion in humans decreases with age. Suggestions that reversing this may overcome some effects of ageing
Pros include:
increased muscle mass (but not necessarily strength)
decreased body fat
increased “well-being”
Cons include:
increased risk of diabetes?
joint problems
increased cancer risk?