Mutant WDR36 directly affects axon growth of retinal ganglion cells leading to progressive retinal degeneration in mice.
Primary open-angle glaucoma (POAG) is one of the three principal subtypes of glaucoma and among the leading cause of blindness worldwide. POAG is defined by cell death of the retinal ganglion cells (RGCs) and surrounding neuronal cells at higher or normal intraocular pressure (IOP). Coded by one of the three genes responsible for POAG, WD repeat-containing protein 36 (WDR36) has two domains with a similar folding. To address whether WDR36 is functionally important in the retina, we developed four transgenic mice strains overexpressing a wild-type (Wt) and three mutant variants of D606G, deletion of amino acids at positions 605-607 (Del605-607) and at 601-640 (Del601-640) equivalent to the location of the D658G mutation observed in POAG patients. A triple amino acid deletion of mouse Wdr36 at positions 605-607 corresponding to the deletion at positions 657-659 in humans developed progressive retinal degeneration at the peripheral retina with normal IOP. RGCs and connecting amacrine cell synapses were affected at the peripheral retina. Axon outgrowth rate of cultured RGC directly isolated from transgenic animal was significantly reduced by the Wdr36 mutation compared with Wt. Molecular modeling of wild and mutant mouse Wdr36 revealed that deletion at positions 605-607 removed three residues and a hydrogen bond, required to stabilize anti-parallel β-sheet of the 6th β-propeller in the second domain. We concluded that WDR36 plays an important functional role in the retina homeostasis and mutation to this gene can cause devastating retinal damage. These data will improve understanding of the functional property of WDR36 in the retina and provide a new animal model for glaucoma therapeutics.
Chi
Zai-Long
ZL
Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan.
Yasumoto
Fumie
F
Sergeev
Yuri
Y
Minami
Masayoshi
M
Obazawa
Minoru
M
Kimura
Itaru
I
Takada
Yuichiro
Y
Iwata
Takeshi
T
D000818:Animals; D017209:Apoptosis; D001369:Axons / Q000378:metabolism*; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D018450:Disease Progression; D005136:Eye Proteins / Q000737:chemistry / Q000378:metabolism*; D007150:Immunohistochemistry; D007429:Intraocular Pressure / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D050505:Mutant Proteins / Q000378:metabolism*; D012160:Retina / Q000473:pathology / Q000503:physiopathology; D012162:Retinal Degeneration / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology*; D013569:Synapses / Q000378:metabolism / Q000473:pathology
D005136:Eye Proteins; D050505:Mutant Proteins; C554605:WDR36 protein, mouse; D004247:DNA