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.
Khanna
Hemant
H
Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, USA.
Davis
Erica E
EE
Murga-Zamalloa
Carlos A
CA
Estrada-Cuzcano
Alejandro
A
Lopez
Irma
I
den Hollander
Anneke I
AI
Zonneveld
Marijke N
MN
Othman
Mohammad I
MI
Waseem
Naushin
N
Chakarova
Christina F
CF
Maubaret
Cecilia
C
Diaz-Font
Anna
A
MacDonald
Ian
I
Muzny
Donna M
DM
Wheeler
David A
DA
Morgan
Margaret
M
Lewis
Lora R
LR
Logan
Clare V
CV
Tan
Perciliz L
PL
Beer
Michael A
MA
Inglehearn
Chris F
CF
Lewis
Richard A
RA
Jacobson
Samuel G
SG
Bergmann
Carsten
C
Beales
Philip L
PL
Attié-Bitach
Tania
T
Johnson
Colin A
CA
Otto
Edgar A
EA
Bhattacharya
Shomi S
SS
Hildebrandt
Friedhelm
F
Gibbs
Richard A
RA
Koenekoop
Robert K
RK
Swaroop
Anand
A
Katsanis
Nicholas
N
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