Citation: Cheng HH, Ling SQ, Zhao PZ, Li WL, Deng J. The
heterozygous EDNRB mutation in a Chinese family with Waardenburg
syndrome type I. Int J Ophthalmol 2019;12(9):1507-1509
DOI:10.18240/ijo.2019.09.22
·Brief Report·
The
heterozygous EDNRB mutation in a Chinese family with Waardenburg
syndrome type I
Huan-Huan Cheng1, Shi-Qi Ling1,
Pei-Zhen Zhao2, Wei-Li Li1, Juan Deng1
1Department
of Ophthalmology, the Third Affiliated Hospital, Sun Yat-sen University,
Guangzhou 510630, Guangdong Province, China
2STD Control
Department, Dermatology Hospital, Southern Medical University, Guangzhou
510095, Guangdong Province, China
Correspondence
to: Juan Deng.
Department of Ophthalmology, the Third Affiliated Hospital of Sun Yat-sen
University, 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China.
viviadeng@163.com
Received:
Abstract
The genovariation of endothelin
receptor type B (EDNRB) was identified
in a Chinese family with Waardenburg syndrome type I (WS1) in the present
study. WS1 was diagnosed in a 19-year-old young man, his older sister and aunt
according to WS consortium criteria. After extracting genomic DNA from the
peripheral blood samples, the coding exons and intronic regions of EDNRB were sequenced. A missense
heterozygous mutation was found in the coding region of exon
KEYWORDS: EDNRB; Chinese family; Waardenburg
syndrome type I; gene mutation
DOI:10.18240/ijo.2019.09.22
Citation: Cheng
HH, Ling SQ, Zhao PZ, Li WL, Deng J. The heterozygous EDNRB mutation in
a Chinese family with Waardenburg syndrome type I. Int J Ophthalmol
2019;12(9):1507-1509
INTRODUCTION
Waardenburg
syndrome (WS) is a neurocristopathy characterized by pigmentation abnormality
and sensorineural deafness[1]. WS cases are
further divided into 4 subtypes based on additional signs. Dystopia canthorum
is a typical feature of WS1, but it is absent in WS2. The two types can be
distinguished according to the W index: W>1.95 is WS1 while W<1.95 is
WS2. WS3 is similar to WS1 except for additional upper-limb abnormalities and
WS4 resembles WS2 except for additional Hirschsprung disease (HD) or
gastrointestinal atresia[2]. WS not only has
heterogeneous clinical manifestations, but also presents genetic heterogeneity
depending on the gene involved[3].
The
endothelin pathway plays a key role in neural crest development[4]. Endothelin receptor type B (EDNRB) is integral
to the survival, proliferation and differentiation of melanoblasts[5]. EDNRB mutations (mainly homozygous and very
rare heterozygous) have been described in WS4 and its heterozygous mutations
have been reported in isolated HD[6]. However,
whether EDNRB mutations are associated with other subtypes of WS is
still enigmatic. Here we report the EDNRB mutation in a Chinese family
afflicted with WS1.
SUBJECTS AND METHODS
Ethical
Approval The study conformed to the
requirements of the Declaration of Helsinki. Informed consent was obtained from
all the subjects. This study was approved by the Ethics Committee of the Third
Affiliated Hospital of Sun Yat-sen University.
Patient and
Clinical Data A 19 year-old young patient
presented to our clinic with gradual exotropia for 2y. He had iris pigmentation
abnormality in the left eye and deafness in the left ear while no signs of
frontal white forelock or other hypo-pigmented areas were found. The paternal
aunt and the first older sister of the proband presented with bilateral blue
irises, unilateral deafness in the right ear and dystopia canthorum.
Routine
clinical, audiological examination and ophthalmologic evaluation including
anterior segment and fundus photography were performed on this patient. The W
index was calculated using the following equation: W=X+Y+(A/B) {X=[
Mutation
Analysis Peripheral blood samples of the
proband, his mother, paternal aunt, two older sisters, aunt and cousins were
collected at the Third Affiliated Hospital, Sun Yat-sen University. Genetic
analyses were performed at Jinyu Laboratory Groups, Genetics Division,
Guangzhou, China.
Protein
Structure Prediction Both the wild type and mutated
EDNRB sequences were used to conduct protein structure prediction with an
online tool I-TASSER (http://zhanglab.ccmb.med.umich.edu/I-TASSER/) as previously
described[7]. The pathogenicity of the mutation
was evaluated using the PolyPhen (http://genetics.bwh.harvard.edu/pph)
analytical tool.
RESULTS
Dystopia
canthorum and unilateral deafness were present in all affected patients, namely
the proband (II3), his paternal aunt (I2) and first older sister (II1) (Figure
Figure 1
Clinical features of the proband and pedigree chart of this family.
Figure 2
Sequence chromatography.
As detected
by PolyPhen, the substitution of isoleucine with valine results in a “possibly
damaging” effect. The mutation involves a highly conserved residue. As shown in
the red square, the isoleucine at position 157 is highly conserved for EDNRB,
which is demonstrated by analysis of 6 orthologs from different vertebrate
species (Figure 3). The wild type EDNRB protein consists of ten helices
(Figure
Figure 3
Analysis of the conservation of the EDNRB mutation [c
Figure 4
Protein structure prediction of wild-type EDNRB protein (A) and mutated
EDNRB (B).
DISCUSSION
At least 15%
of WS cases cannot be explained at the molecular level, which suggests the
potential involvement of other uncovered gene mutations[8].
The EDNRB gene spanning 24 kb and comprising 7 exons is located in
13q22.3[9]. To date, 32 EDNRB mutations
have been shown to be related to WS (http://grenada.lumc.nl/LOVD2/WS), whereas
the mutation in exon 2, c
EDN3/EDNRB interaction is indispensable to the
development of melanocytes and enteric neurons that originate from neural crest[10]. Mutation in the EDNRB gene was previously
thought to be causative for WS4. WS4 featured the common manifestations of WS
and the additional presence of HD[11]. However,
apart from heterochromia iridis, sensorineural deafness and dystopia canthorum,
the affected patients suffered no congenital aganglionic megacolon or
gastrointestinal atresia.
In most WS
cases, one or both of the proband’s parents are affected[12].
In a smaller proportion of WS1 cases, there isn’t any affected parent and the
proband is presumed to develop WS1 as a result of a sporadic de novo pathogenic
variant. In this family, the classical symptoms of WS
Taken
together, a missense heterozygous mutation [c
ACKNOWLEDGEMENTS
The authors
thank the patients and their family members for their collaboration in this
study. The authors also thank Dr. Yi-Zhao Luan for his technical assistance.
Foundations: Supported by Medical Scientific
Research Foundation of Guangdong Province (No.A2016271); Guangdong Natural
Science Foundation (No
Conflicts of
Interest: Cheng HH, None; Ling SQ, None; Zhao PZ, None; Li WL, None;
Deng J, None.
REFERENCES