The R172W mutation in peripherin/rds causes a cone-rod dystrophy in transgenic mice

被引:82
作者
Ding, XQ
Nour, M
Ritter, LM
Goldberg, AFX
Fliesler, SJ
Naash, MI
机构
[1] Univ Oklahoma, Hlth Sci Ctr, Dept Cell Biol, Oklahoma City, OK 73104 USA
[2] Oakland Univ, Eye Res Inst, Rochester, MI 48309 USA
[3] St Louis Univ, Sch Med, Dept Ophthalmol, St Louis, MO 63104 USA
[4] St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63104 USA
关键词
D O I
10.1093/hmg/ddh211
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Peripherin/rds (P/rds) is a membrane glycoprotein essential for the photoreceptor outer segment disc morphogenesis and maintenance. More than half of the disease-causing mutations in P/rds have been linked to different forms of macular dystrophy; the most common one is substitution of tryptophan for arginine at position 172 (R172W). Here we confirm the patient phenotype associated with the expression of R172W mutation in transgenic mice. Functional, structural and biochemical analyses showed that, while R172W P/rds is appropriately localized, a direct correlation exists between transgene expression levels and the onset/severity of the phenotype. In the wild-type background, both cone and rod photoreceptors' structure and function were significantly diminished, which indicates a dominant-negative, cone-rod defect. Whereas rds(+/-) mice maintained the normal cone function at early ages, cone responses in R172W/rds(+/-) mice were diminished to 41% of the wild-type level signifying a preferential damaging effect of the mutation on cones. Conversely, R172W/rds(+/-) mice showed a significant rescue of rod function and improvement of rod outer segment structure. Although rds(-/-) mice have no detectable rod or cone responses, R172W/rds(-/-) animals retained 30% of wild-type structure and rod function, but no significant rescue of cone function was detected at 1 month of age. No biochemical abnormalities were observed in complex formation and association with Rom-1; however, R172W protein was more sensitive to tryptic digestion, indicative of a change in protein conformation, possibly contributing to the cone-dominated phenotype. As the first animal model for P/rds-associated cone-rod dystrophy, R172W mice provide a valuable tool for studying the pathophysiology of P/rds-associated human retinal dystrophies and the development of therapeutic strategies to intervene in these diseases.
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页码:2075 / 2087
页数:13
相关论文
共 58 条
[1]   BILATERAL RETINAL AND BRAIN-TUMORS IN TRANSGENIC MICE EXPRESSING SIMIAN VIRUS-40 LARGE T-ANTIGEN UNDER CONTROL OF THE HUMAN INTERPHOTORECEPTOR RETINOID-BINDING PROTEIN PROMOTER [J].
ALUBAIDI, MR ;
FONT, RL ;
QUIAMBAO, AB ;
KEENER, MJ ;
LIOU, GI ;
OVERBEEK, PA ;
BAEHR, W .
JOURNAL OF CELL BIOLOGY, 1992, 119 (06) :1681-1687
[2]   LOCALIZATION OF PERIPHERIN/RDS IN THE DISK MEMBRANES OF CONE AND ROD PHOTORECEPTORS - RELATIONSHIP TO DISK MEMBRANE MORPHOGENESIS AND RETINAL DEGENERATION [J].
ARIKAWA, K ;
MOLDAY, LL ;
MOLDAY, RS ;
WILLIAMS, DS .
JOURNAL OF CELL BIOLOGY, 1992, 116 (03) :659-667
[3]   Peripherin/rds fusogenic function correlates with subunit assembly [J].
Boesze-Battaglia, K ;
Stefano, FP .
EXPERIMENTAL EYE RESEARCH, 2002, 75 (02) :227-231
[4]  
Boesze-Battaglia K, 2002, INT REV CYTOL, V217, P183
[5]   FOLDING AND INTRACELLULAR-TRANSPORT OF THE YEAST PLASMA-MEMBRANE H+-ATPASE - EFFECTS OF MUTATIONS IN KAR2 AND SEC65 [J].
CHANG, A ;
ROSE, MD ;
SLAYMAN, CW .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (12) :5808-5812
[6]   The effect of peripherin/rds haploinsufficiency on rod and cone photoreceptors [J].
Cheng, T ;
Peachey, NS ;
Li, SH ;
Goto, Y ;
Cao, Y ;
Naash, MI .
JOURNAL OF NEUROSCIENCE, 1997, 17 (21) :8118-8128
[7]   A SEQUENCE UPSTREAM OF THE MOUSE BLUE VISUAL PIGMENT GENE DIRECTS BLUE CONE-SPECIFIC TRANSGENE EXPRESSION IN MOUSE RETINAS [J].
CHIU, MI ;
NATHANS, J .
VISUAL NEUROSCIENCE, 1994, 11 (04) :773-780
[8]   Rom-1 is required for rod photoreceptor viability and the regulation of disk morphogenesis [J].
Clarke, G ;
Goldberg, AFX ;
Vidgen, D ;
Collins, L ;
Ploder, L ;
Schwarz, L ;
Molday, LL ;
Rossant, J ;
Szél, A ;
Molday, RS ;
Birch, DG ;
McInnes, RR .
NATURE GENETICS, 2000, 25 (01) :67-73
[9]   PHOTORECEPTOR PERIPHERIN IS THE NORMAL PRODUCT OF THE GENE RESPONSIBLE FOR RETINAL DEGENERATION IN THE RDS MOUSE [J].
CONNELL, G ;
BASCOM, R ;
MOLDAY, L ;
REID, D ;
MCINNES, RR ;
MOLDAY, RS .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (03) :723-726
[10]  
Dejneka NS, 2003, DEV OPHTHALMOL, V37, P188