Biomedical Engineering Reference
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Ulloa-Aguirre
2010,
2011
;
Conn et al. 2007
; Mendes et al.
2005
; Noorwez et al.
2003,
2004
; Robben and Deen
2007
; Robben et al.
2007
; Tao
2010
) .
14.3
Rescue of Misfolded Mutant GPCRs
with Pharmacoperones
As mentioned above, mutations or deletions in the sequence of GPCRs may cause
misrouting of otherwise functional proteins and lead to disease due to loss-of-
function of the compromised receptor (Table
14.1
) (Ulloa-Aguirre and Conn
2009
;
Ulloa-Aguirre et al.
2004a
). Mutations in the vasopressin V2 receptor (V2R) gene
cause X-linked nephrogenic diabetes insipidus, a disease characterized by an
inadequate ability to concentrate urine despite normal or elevated plasma concentra-
tions of the antidiuretic hormone arginine vasopressin (Bichet
2006
; Fujiwara and
Bichet
2005
). The majority of human V2R mutants causing X-linked diabetes insip-
idus are unable to reach the cell surface membrane and to respond to agonist stimu-
lation (Hermosilla et al.
2004
). In retinitis pigmentosa, trapping in the ER of
misfolded class III mutant rhodopsins eventually leads to rod photoreceptor degen-
eration followed by cone degeneration (Mendes et al.
2005
; Noorwez et al.
2003
;
Saliba et al.
2002
). Mutations leading to receptor misfolding of the hGnRHR cause
congenital hypogonadotropic hypogonadism (HH), a disease characterized by
absence or incomplete pubertal development and reproductive failure due to partial
or complete inability of the gonadotropes to respond to the gonadotropin-releasing
hormone (GnRH) peptide (Beranova et al.
2001
; Ulloa-Aguirre et al.
2004b
) . As
with the V2R, the majority (~90%) of the GnRHR mutants, whose function has
been examined
in vitro,
are misfolded trafficking-defective protein receptors as
revealed by their response to genetic approaches or pharmacoperones (Conn and
Ulloa-Aguirre
2010
; Leanos-Miranda et al.
2002
; Ulloa-Aguirre et al.
2003
) .
Mutations in the melanocortin-1 receptor gene have been described in patients
with skin and hair abnormalities, and increased susceptibility to certain skin cancers
(Beaumont et al.
2005,
2007
); among the ~60 mutants described to date, at least
four exhibit reduced PM expression (Beaumont et al.
2005
) . Misfolding and intracel-
lular retention of mutants from two other melanocortin receptors, the melanocortin-3
and melanocortin-4 receptors associated with regulation of fat deposition and energy
homeostasis, have also been found in patients with morbid obesity (Tao
2010
; Tao
and Segaloff
2003
). Trafficking-defective mutants of the glycoprotein hormone
receptors, luteinizing hormone receptor (LHR), follicle-stimulating hormone recep-
tor (FSHR), and thyrotropin receptor (TSHR), have been described as a cause of
male pseudohermaphroditism due to Leydig cell hypoplasia (Gromoll et al.
2002
;
Martens et al.
2002
), premature ovarian failure (Aittomaki et al.
1995
; Rannikko
et al.
2002
; Tranchant et al.
2011
), and congenital hypothyroidism (Biebermann
et al.
1997
; Calebiro et al.
2005
), respectively. Mutations in the calcium-sensing
receptor may cause intracellular retention of the mutant receptor and provoke famil-
ial hypocalciuric hypercalcemia (D'Souza-Li et al.
2002
) , while mutations that
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