TY  - JOUR
A1  - Zhang, Houbin
A1  - Hanke-Gogokhia, Christin
A1  - Jiang, Li
A1  - Li, Xiaobo
A1  - Wang, Pu
A1  - Gerstner, Cecilia D.
A1  - Frederick, Jeanne M.
A1  - Yang, Zhenglin
A1  - Baehr, Wolfgang
T1  - Mistrafficking of prenylated proteins causes retinitis pigmentosa 2
JF  - The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology
N2  - The retinitis pigmentosa 2 polypeptide (RP2) functions as a GTPase-activating protein (GAP) for ARL3 (Arf-like protein 3), a small GTPase. ARL3 is an effector of phosphodiesterase 6 Delta (PDE6D), a prenyl-binding protein and chaperone of prenylated protein in photoreceptors. Mutations in the human RP2 gene cause X-linked retinitis pigmentosa (XLRP) and cone-rod dystrophy (XL-CORD). To study mechanisms causing XLRP, we generated an RP2 knockout mouse. The RP2h(-/-) mice exhibited a slowly progressing rod-cone dystrophy simulating the human disease. RP2h(-/-) scotopic a-wave and photopic b-wave amplitudes declined at 1 mo of age and continued to decline over the next 6 mo. Prenylated PDE6 subunits and G-protein coupled receptor kinase 1 (GRK1) were unable to traffic effectively to the RP2h(-/-) outer segments. Mechanistically, absence of RP2 GAP activity increases ARL3-GTP levels, forcing PDE6D to assume a predominantly "closed" conformation that impedes binding of lipids. Lack of interaction disrupts trafficking of PDE6 and GRK1 to their destination, the photoreceptor outer segments. We propose that hyperactivity of ARL3-GTP in RP2 knockout mice and human patients with RP2 null alleles leads to XLRP resembling recessive rod-cone dystrophy.
KW  - rod-cone dystrophy
KW  - ARL3
KW  - PDE6D
KW  - RP2
KW  - XLRP
Y1  - 2015
U6  - https://doi.org/10.1096/fj.14-257915
SN  - 0892-6638
SN  - 1530-6860
VL  - 29
IS  - 3
SP  - 932
EP  - 942
PB  - Federation of American Societies for Experimental Biology
CY  - Bethesda
ER  -