Identiﬁcation of a novel RPGRIP1 mutation in an Iranian family
with leber congenital amaurosis by exome sequencing
a, b, c, #
, Jingliang Cheng
, Abdolkarim Mobasher-Jannat
c, d, #
, Chunli Wei
, Lisha Yang
, Khosrow Jadidi
, Mohammad Hossein Khosravi
, Saman Mohazzab-
, Marzieh Dehghan Shasaltaneh
, Yumei Li
, Rui Chen
, Junjiang Fu
Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University,
Luzhou, Sichuan, China
Hunan Normal University Medical College, Changsha, Hunan, China
Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
The Honors College, University of Houston, Houston, TX, USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Department of Ophthalmology, Baqiyatallah University of Medical Sciences, Tehran, Iran
Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
Laboratory of Neuro-organic Chemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran,
Received: March 23, 2017; Accepted: October 13, 2017
Leber congenital amaurosis (LCA) is a heterogeneous, early-onset inherited retinal dystrophy, which is associated with severe visual impairment.
We aimed to determine the disease-causing variants in Iranian LCA and evaluate the clinical implications. Clinically, a possible LCA disease was
found through diagnostic imaging, such as fundus photography, autoﬂuorescence and optical coherence tomography. All affected patients showed
typical eye symptoms associated with LCA including narrow arterioles, blindness, pigmentary changes and nystagmus. Target exome sequencing
was performed to analyse the proband DNA. A homozygous novel c.2889delT (p.P963 fs) mutation in the RPGRIP1 gene was identiﬁed, which
was likely the deleterious and pathogenic mutation in the proband. Structurally, this mutation lost a retinitis pigmentosa GTPase regulator (RPGR)-
interacting domain at the C-terminus which most likely impaired stability in the RPGRIP1 with the distribution of polarised proteins in the cilium
connecting process. Sanger sequencing showed complete co-segregation in this pedigree. This study provides compelling evidence that the
c.2889delT (p.P963 fs) mutation in the RPGRIP1 gene works as a pathogenic mutation that contributes to the progression of LCA.
leber congenital amaurosis
target exome sequencing
Leber congenital amaurosis (LCA; MIM #204000) is an autosomal
recessive inherited heterogeneous retinopathy, affecting 1 in every
80,000 people worldwide [1, 2]. LCA consists of rare early-onset reti-
nal dystrophies that constitute <6% of all retinal dystrophies and
impact approximately 20% of children attending schools for the blind
. Severe and early visual loss (typically before the ﬁrst year of
age), an oculo-digital sign of Franceschetti, sluggish pupillary light
reﬂex, nystagmus, blindness, visual impairment presented in infancy
and near-absent pupillary reﬂexes are the main clinical symptoms of
LCA [4, 5]. LCA is characterised by severe pigmentary degeneration
of the fundus, which typically starts in the mid-periphery and
advances towards the fovea and macula [6, 7].
The molecular genetic basis underlying LCA is clinically and
genetically heterogeneous; to date, around 22 genes with mutations
have been associated with pathogenesis of LCA [6, 8]. These
These authors contributed equally to this work.
*Correspondence to: Junjiang FU, Ph.D.
ª 2017 The Authors.
Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the original work is properly cited.
J. Cell. Mol. Med. Vol 22, No 3, 2018 pp. 1733-1742