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):Arg201Ser, Cys or His; Glu227Arg or Leu.Somatic mutations - DNA from non-pituitary tissue not affected.Mutant G proteins have low GTPase activityArg201 is ribosylated by cholera toxin; Glu227 is in GTP/GDP binding site)Defines the gsp oncogene
7 Gs AND ADENYLATE CYCLASE ACTIVATION GasbgFrom 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 irradiationOctreotide (somatostatin analogue)Dopamine agonists (e.g.bromocryptine)GH antagonist - pegvisomant
10 A GH-RECEPTOR ANTAGONIST From Drake et al (2001)
12 PATTERNS OF HUMAN GH SECRETION IGHD Type 1BGH NeurosecretorydysfunctionNormalGH concentration (ng/ml)Time
13 HEREDITARY GH DEFICIENCY Type IA Autosomal recessive. Severe GH deficiency; may develop antibodies to GH used for treatmentType 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)
16 IGHD TYPE 1BLow levels of GH retained, so GH treatment usually effectiveVarious causes, including:Inactivating GHRH mutations (including lit) mouseDefective 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 MPHDOften 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 GHGH levels usually apparently normal, but patients respond to exogenous GH. Dwarfism due to production of inactive GH. Mutations identified include:Asp112 GlyArg77 Cys (dominant negative)
21 LARON DWARFISMVery 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 MUTATIONSFrom Johnston et al (1998)
24 IDIOPATHIC SHORT STATURE Cases of short stature with no obvious cause. May reflect:1. Impared secretion (GH neurosecretory dysfunction)2. Bioinactive3. GH insensity (but not Laron)- GH receptor defects with minor effects4. 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 AGEINGGH secretion in humans decreases with age. Suggestions that reversing this may overcome some effects of ageingPros include:increased muscle mass (but not necessarily strength)decreased body fatincreased “well-being”Cons include:increased risk of diabetes?joint problemsincreased cancer risk?