Transcript G protein Mutations Causing Disease

G protein Mutations Causing
Disease
LiYang
GPCRs are known for their physiological
functions. Induction of these diverse
biological functions results from the
activation of a collection of heterotrimeric Gproteins, which consist of αsubunits and
closely associated β-γ subunits.
G-proteins, which consist of αsubunits and closely
associated β-γ subunits. The α subunit is responsible for
GTP and GDP binding and for GTP hydrolysis, whereas the
βand γ subunits are associated in a tightly linked βγcomplex.
Following a brief overview of G protein–
coupled signal transduction, we review the
growing body of evidence that mutations in
genes encoding GPCRs and G proteins are
an important cause of human disease.
Sorting of the diseases according the
mechanism
Inactive or absent Gs (αsubunit)
Constitutively active Gs (αsubunit)
Temperature-sensitive Gαs
Constitutively active Gi α2
gsp mutations of Gαs
G protein α subunit in its GTPbound form, highlighting amino
acids changed by point
mutations that cause human
endocrine diseases. Mutational
replacements of red residues
impair GTP hydrolysis; these
sites are mutated in growth
hormone secreting tumors of
the pituitary.
Replacement of either cyan
residue produces an inactive G
protein αsubunit, causing
pseudohypoparathyroidism.
Bound nucleotide is light green.
1.Inactive or absent Gs (a subunit)
Pseudohypoparathyroidism-- type I (PHP-I), is an inherited
human disease caused by mutational inactivation of the α
subunit of Gs
Multiple endocrine abnormalities in cAMP regulated organs
Occurs when bad gene inherited from mother
Pseudopseudohypoparathyroidism--clinically less severe
syndrome, same as mutation
in one Gs
Occurs when bad gene inherited from father
Both conditions--as protein levels about half of normal
Pseudohypoparathyroidism
Patients with this disease,
which manifests in a
short stature, round
face, one or more
foreshortened
metacarpal or
metatarsal bones
(particularly the fourth
metacarpal), obesity,
and subcutaneous
calcifications.
Albright's hereditary
osteodystrophy
Pseudohypoparathyroidism
One inactive copy of Gs α
Resistant to PTH（甲状旁腺
激素）, TSH（促甲状腺激
素）, ACTH（促肾上腺皮质
激素）(and others)
Complex tissue-specific
genetic imprinting:
syndrome worse if
inherit bad copy from mom
than from dad。
2. Constitutively active Gs (a subunit)
Tumors
Mutations in αs --block GTPase activity, cause constitutive
activity
as candidate oncogene (termed gsp)
Activating mutations found in 40% of growth hormone
secreting pituitary adenomas; found in other endocrine tumors
including pituitary, thyroid
McCune Albright Syndrome
Somatic mutation in αs in early embryonic development
Patients mosaic for constitutively active Gs (as)
McCune-Albright Syndrome.
Somatic mutation of Gs alpha early in development
Effects of activating MSH and gonadotrophin receptors
evident
3.Temperature-sensitive αs
--"Testotoxicosis"
Testotoxicosis ——the gain-of-function
disorder
Symptoms: Males have general features of
precocious puberty and hypoparathyroidism
with a mutant as that is inactive at 37°C and
constitutively active at testicular temperature
Both patients were found to contain a single amino acid
substitution in one of the Gαisoforms. The alternation in amino
acid sequence caused two effects on the mutant G protein.
 precocious puberty--indicating premature testicular activation
(normally testosterone production is stimulated by LH, a
GPCR coupled to cAMP formation)

hypoparathyroidism--impaired responses to PTH（甲状旁腺激
素）, TSH （促甲状腺激素）causing PTH and thyroid
abnormalities
At temperatures below normal body
temperature, the mutant G protein remained
in the active state, even in the absence of a
bound ligand. In contrast, at normal body
temperatures, the mutant G protein was
inactive, both in the presence and absence
of bound ligand, the testes, which are
housed outside of the body’s core, have a
lower temperature than the body’s visceral
organs (33℃ versus 37 ℃).
precocious puberty（青春期早熟）
Normally, the endocrine cells of the testes initiate
testosterone （睾丸激素）production at the time of
puberty in response to the pituitary hormone LH, which
begins to be produced at that time. The circulating LH
binds to LH receptors on the surface of the testicular cells,
inducing the synthesis of cAMP and subsequent
production of the male sex hormone, the testicular cells of
the patients bearing the G protein mutation were
stimulated to synthesize cAMP in the absence of the LH
ligand, leading to premature synthesis of testosterone and
precocious puberty.
Hypoparathyroidism
（甲状旁腺功能减退）
In contrast, the mutation in this same Gα subunit in
the cells of the parathyroid glands,which function at
a temperature of 37℃, caused the G protein to
remain inactive. As a result, the cells of the
parathyroid gland could not respond to stimuli that
would normally cause them to secrete parathyroid
hormone, leading to the condition of
hypoparathyroidism. The fact that most of the bodily
organs functioned in a normal manner in these
patients suggests that this particular Gα isoform is
not essential in the activities of most other cells.
Testotoxicosis
cAMP Produced
in cyc- cells
normal
mutation
37° 33° 37° 33°
37° 33° 37° 33°
Western Blot for Gs alpha
normal
α-s-A366S mutation
Gs α
Conclusion: Syndrome due to a temperature-sensitive Gs alpha
Protein inactive at 37° but constitutively active at the lower
temperature of the testes at32°C
4 Constitutively active Gi α2
Tumors
Mutations in ai2 --block GTPase activity,
cause constitutive activity
αi2 candidate oncogene (termed gip)
Activating mutations found in >30% of
adrenal, ovarian tumors
compare
ovarian
tumor
THE END