A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies.
Despite rapid advances in the identification of genes involved in disease, the predictive power of the genotype remains limited, in part owing to poorly understood effects of second-site modifiers. Here we demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein-1 like), a ciliary gene mutated in Meckel-Gruber (MKS) and Joubert (JBTS) syndromes, is associated with the development of retinal degeneration in individuals with ciliopathies caused by mutations in other genes. As part of our resequencing efforts of the ciliary proteome, we identified several putative loss-of-function RPGRIP1L mutations, including one common variant, A229T. Multiple genetic lines of evidence showed this allele to be associated with photoreceptor loss in ciliopathies. Moreover, we show that RPGRIP1L interacts biochemically with RPGR, loss of which causes retinal degeneration, and that the Thr229-encoded protein significantly compromises this interaction. Our data represent an example of modification of a discrete phenotype of syndromic disease and highlight the importance of a multifaceted approach for the discovery of modifier alleles of intermediate frequency and effect.
Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, USA.
Hemant
H
Khanna
Erica E
EE
Davis
Carlos A
CA
Murga-Zamalloa
Alejandro
A
Estrada-Cuzcano
Irma
I
Lopez
Anneke I
AI
den Hollander
Marijke N
MN
Zonneveld
Mohammad I
MI
Othman
Naushin
N
Waseem
Christina F
CF
Chakarova
Cecilia
C
Maubaret
Anna
A
Diaz-Font
Ian
I
MacDonald
Donna M
DM
Muzny
David A
DA
Wheeler
Margaret
M
Morgan
Lora R
LR
Lewis
Clare V
CV
Logan
Perciliz L
PL
Tan
Michael A
MA
Beer
Chris F
CF
Inglehearn
Richard A
RA
Lewis
Samuel G
SG
Jacobson
Carsten
C
Bergmann
Philip L
PL
Beales
Tania
T
Attié-Bitach
Colin A
CA
Johnson
Edgar A
EA
Otto
Shomi S
SS
Bhattacharya
Friedhelm
F
Hildebrandt
Richard A
RA
Gibbs
Robert K
RK
Koenekoop
Anand
A
Swaroop
Nicholas
N
Katsanis
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000483:Alleles; D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000235:genetics; D002924:Ciliary Body / Q000503:physiopathology; D005060:Europe / Q000453:epidemiology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D012162:Retinal Degeneration / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control; D012174:Retinitis Pigmentosa / Q000201:enzymology / Q000235:genetics; D014605:Uveitis / Q000453:epidemiology / Q000235:genetics; D015027:Zebrafish / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D012333:RNA, Messenger; C532826:RPGRIP1L protein, human; D020558:GTP Phosphohydrolases