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

MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY

MOLECULAR ASPECTS OF GIANTISM, ACROMEGALY AND PITUITARY DWARFISM

ACROMEGALY

Dwarf mice

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 activity

Arg201 is ribosylated by cholera toxin; Glu227 is in GTP/GDP binding site)

Defines the gsp oncogene

GH secretion

Gs AND ADENYLATE CYCLASE ACTIVATION

Gs

From Stryer

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)

TREATMENT OF ACROMEGALY

1. Surgery and/or irradiation

2. Octreotide (somatostatin analogue)

3. Dopamine agonists (e.g.bromocryptine)

4. GH antagonist - pegvisomant

From Drake et al (2001)

A GH-RECEPTOR ANTAGONIST

The GH-IGF-Somatic axis

PATTERNS OF HUMAN GH SECRETION

IGHD Type 1B

GH Neurosecretorydysfunction

Normal

GH

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ion

(n

g/m

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Time

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

A FAMILY OF PATIENTS SHOWING IGHD Type IA

From Phillips et al (1981)

DELETIONS OF THE hGH GENE CLUSTER

IGHD TYPE 1B

Low levels of GH retained, so GH treatment usually effectiveVarious causes, including:

•Inactivating GHRH mutations (including lit) mouse

•Defective GH, grossly altered so not detectable in RIA

From Frohman & Kineman (2002)

INACTIVATING MUTATIONS OF THE GHRH RECEPTOR UNDERLY SOME CASES OF IGHD IB

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

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.

BIOINACTIVE GH

GH 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)

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.

GH RECEPTOR MUTATIONS

From Johnston et al (1998)

GROWTH AND IGF-1 LEVELS IN PYGMIES

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

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?