Defective subunit assembly underlies a digenic form of retinitis pigmentosa linked to mutations in peripherin rds and rom-1

被引:98
作者
Goldberg, AFX [1 ]
Molday, RS [1 ]
机构
[1] UNIV BRITISH COLUMBIA,DEPT BIOCHEM & MOL BIOL,VANCOUVER,BC V6T 1Z3,CANADA
关键词
D O I
10.1073/pnas.93.24.13726
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Retinitis pigmentosa (RP) is a group of progressive retinal dystrophies that include the most common hereditary degenerative diseases affecting the retina. Although most disease phenotypes appear to result from defects at single genetic loci (monogenic), at least one instance of RP appears to require a coinheritance of defects in the unlinked peripherin/rds and rom-l alleles (digenic), which encode the polypeptide subunits of an oligomeric transmembrane protein complex present at photoreceptor outer segment disc rims. Sedimentation velocity analysis was performed upon the affected gene products expressed heterologously in COS-I cells to examine the assembly of the subunit polypeptides. The results indicate that the missense peripherin/rds mutant, L185P, which segregates with instances of digenically inherited RP, is conditionally defective with respect to its subunit assembly. Unlike wild-type peripherin/rds, the L185P mutant does not form native-like homotetramers on its own: however the L185P mutant can assemble with wild-type rom-l to form a structurally normal heterotetrameric complex. These findings provide a novel molecular-based rationale for the unusual digenic disease inheritance pattern and offer insight into regions of peripherin/rds and rom-l, which contribute to subunit-subunit Interactions.
引用
收藏
页码:13726 / 13730
页数:5
相关论文
共 36 条
  • [1] LOCALIZATION OF PERIPHERIN/RDS IN THE DISK MEMBRANES OF CONE AND ROD PHOTORECEPTORS - RELATIONSHIP TO DISK MEMBRANE MORPHOGENESIS AND RETINAL DEGENERATION
    ARIKAWA, K
    MOLDAY, LL
    MOLDAY, RS
    WILLIAMS, DS
    [J]. JOURNAL OF CELL BIOLOGY, 1992, 116 (03) : 659 - 667
  • [2] CLONING OF THE CDNA FOR A NOVEL PHOTORECEPTOR MEMBRANE-PROTEIN (ROM-1) IDENTIFIES A DISK RIM PROTEIN FAMILY IMPLICATED IN HUMAN RETINOPATHIES
    BASCOM, RA
    MANARA, S
    COLLINS, L
    MOLDAY, RS
    KALNINS, VI
    MCINNES, RR
    [J]. NEURON, 1992, 8 (06) : 1171 - 1184
  • [3] MUTATION ANALYSIS OF THE ROM1 GENE IN RETINITIS-PIGMENTOSA
    BASCOM, RA
    LIU, L
    HECKENLIVELY, JR
    STONE, EM
    MCINNES, RR
    [J]. HUMAN MOLECULAR GENETICS, 1995, 4 (10) : 1895 - 1902
  • [4] BERSON EL, 1993, INVEST OPHTH VIS SCI, V34, P1659
  • [5] MOLECULAR-CLONING, PRIMARY STRUCTURE, AND ORIENTATION OF THE VERTEBRATE PHOTORECEPTOR CELL PROTEIN PERIPHERIN IN THE ROD OUTER SEGMENT DISK MEMBRANE
    CONNELL, GJ
    MOLDAY, RS
    [J]. BIOCHEMISTRY, 1990, 29 (19) : 4691 - 4698
  • [6] CORRELATION OF PHENOTYPE WITH GENOTYPE IN INHERITED RETINAL DEGENERATION
    DAIGER, SP
    SULLIVAN, LS
    RODRIGUEZ, JA
    [J]. BEHAVIORAL AND BRAIN SCIENCES, 1995, 18 (03) : 452 - 467
  • [7] DOI T, 1990, P NATL ACAD SCI USA, V87, P4991, DOI 10.1073/pnas.87.13.4991
  • [8] MOLECULAR-GENETICS OF RETINITIS-PIGMENTOSA
    DRYJA, TP
    LI, T
    [J]. HUMAN MOLECULAR GENETICS, 1995, 4 : 1739 - 1743
  • [9] A 3-BASE-PAIR DELETION IN THE PERIPHERIN-RDS GENE IN ONE FORM OF RETINITIS-PIGMENTOSA
    FARRAR, GJ
    KENNA, P
    JORDAN, SA
    KUMARSINGH, R
    HUMPHRIES, MM
    SHARP, EM
    SHEILS, DM
    HUMPHRIES, P
    [J]. NATURE, 1991, 354 (6353) : 478 - 480
  • [10] FARRAR GJ, 1992, GENOMICS, V14, P805