Dominant Leber congenital amaurosis, cone-rod degeneration, and retinitis pigmentosa caused by mutant versions of the transcription factor CRX

被引:99
作者
Rivolta, C
Berson, EL
Dryja, TP
机构
[1] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Mol Genet Inst, Boston, MA 02114 USA
[2] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02114 USA
关键词
congenital retinal blindness; Leber congenital amaurosis; LCA1; cone-rod degeneration; CORD; retinitis pigmentosa; RP; CRX; transcription factor; homeobox gene; inherited retinopathy;
D O I
10.1002/humu.1226
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
We summarize 18 mutations in the human CRX gene that have been associated with Leber congenital amaurosis (congenital retinal blindness), cone,rod degeneration, or retinitis pigmentosa. Except for one obviously null allele not definitely associated with a phenotype (a frameshift in codon 9), all CRX mutations appear to be completely penetrant and cause disease in heterozygotes. These dominant alleles fall into two categories. In one group are missense mutations and short, in-frame deletions; in the second group are frameshift mutations, all of which are in the last exon. All of these dominant mutations are likely to produce stable mRNA that is translated. Mutations in the missense group preferentially affect the conserved homeobox (codons 39-98), and all frameshift mutations leave the homeodomain intact but alter the OTX motif encoded by codons 284-295 at the carboxy terminus. We could not uncover any correlation between type of disease (congenital amaurosis vs. cone,rod degeneration or retinitis pigmentosa) and the type of mutation (missense vs. frameshift). Four of the 18 mutations (similar to 20%) were de novo mutations, and all of these were found in isolate cases of Leber congenital amaurosis. Dominant CRX mutations have not been associated with mental retardation or developmental delay that has sometimes been found in Leber congenital amaurosis caused by other genes. Implications regarding potential future therapies are discussed. Hum Mutat 18:488-498, 2001. (C) 2001 Wiley-Liss, Inc.
引用
收藏
页码:488 / 498
页数:11
相关论文
共 48 条
[1]  
Antonarakis SE, 1998, HUM MUTAT, V11, P1
[2]   Temporal and spatial expression patterns of the CRX transcription factor and its downstream targets.: Critical differences during human and mouse eye development. [J].
Bibb, LC ;
Holt, JKL ;
Tarttelin, EE ;
Hodges, MD ;
Gregory-Evans, K ;
Rutherford, A ;
Lucas, RJ ;
Sowden, JC ;
Gregory-Evans, CY .
HUMAN MOLECULAR GENETICS, 2001, 10 (15) :1571-1579
[3]   Functional domains of the cone-rod homeobox (CRX) transcription factor [J].
Chau, KY ;
Chen, SM ;
Zack, DJ ;
Ono, SJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (47) :37264-37270
[4]   Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes [J].
Chen, SM ;
Wang, QL ;
Nie, ZQ ;
Sun, H ;
Lennon, G ;
Copeland, NG ;
Gilbert, DJ ;
Jenkins, NA ;
Zack, DJ .
NEURON, 1997, 19 (05) :1017-1030
[5]  
Dharmaraj S R, 2000, Ophthalmic Genet, V21, P135
[6]   Null RPGRIP1 alleles in patients with Leber congenital amaurosis [J].
Dryja, TP ;
Adams, SM ;
Grimsby, JL ;
McGee, TL ;
Hong, DH ;
Li, TS ;
Andreasson, S ;
Berson, EL .
AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 68 (05) :1295-1298
[7]   GENETIC-LINKAGE OF CONE-ROD RETINAL DYSTROPHY TO CHROMOSOME 19Q AND EVIDENCE FOR SEGREGATION DISTORTION [J].
EVANS, K ;
FRYER, A ;
INGLEHEARN, C ;
DUVALLYOUNG, J ;
WHITTAKER, JL ;
GREGORY, CY ;
BUTLER, R ;
EBENEZER, N ;
HUNT, DM ;
BHATTACHARYA, S .
NATURE GENETICS, 1994, 6 (02) :210-213
[8]  
Francois J, 1968, Int Ophthalmol Clin, V8, P929
[9]   De novo mutations in the CRX homeobox gene associated with Leber congenital amaurosis [J].
Freund, CL ;
Wang, QL ;
Chen, SM ;
Muskat, BL ;
Wiles, CD ;
Sheffield, VC ;
Jacobson, SG ;
McInnes, RR ;
Zack, DJ ;
Stone, EM .
NATURE GENETICS, 1998, 18 (04) :311-312
[10]   Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor [J].
Freund, CL ;
GregoryEvans, CY ;
Furukawa, T ;
Papaioannou, M ;
Looser, J ;
Ploder, L ;
Bellingham, J ;
Ng, D ;
Herbrick, JAS ;
Duncan, A ;
Scherer, SW ;
Tsui, LC ;
LoutradisAnagnostou, A ;
Jacobson, SG ;
Cepko, CL ;
Bhattacharya, SS ;
McInnes, RR .
CELL, 1997, 91 (04) :543-553