PUBLICATION

Mutation of IFNLR1, an interferon lambda receptor 1, is associated with autosomal-dominant non-syndromic hearing loss.

Authors

Gao, X., Yuan, Y.Y., Lin, Q.F., Xu, J.C., Wang, W.Q., Qiao, Y.H., Kang, D.Y., Bai, D., Xin, F., Huang, S.S., Qiu, S.W., Guan, L.P., Su, Y., Wang, G.J., Han, M.Y., Jiang, Y., Liu, H.K., Dai, P.

ID

ZDB-PUB-180223-33

Date

2018

Source

Journal of Medical Genetics 55(5): 298-306 (Journal)

Registered Authors

Keywords

ADNSHL, IFNLR1, JAK/STAT pathway, deafness gene

MeSH Terms

Humans
Animals
STAT3 Transcription Factor/genetics
Janus Kinase 1/genetics
Receptors, Interferon/genetics*
Receptors, Cytokine/genetics*
Mutation, Missense/genetics
Genetic Predisposition to Disease*
Signal Transduction
Exome Sequencing
Gene Knockdown Techniques
Genetic Linkage
Hearing Loss, Sensorineural/genetics*
Hearing Loss, Sensorineural/physiopathology
Zebrafish/genetics
Mice
Heterozygote
Morpholines

(all 18)

PubMed

29453195 Full text @ J. Med. Genet.

Abstract

Background Hereditary sensorineural hearing loss is a genetically heterogeneous disorder. Objectives This study was designed to explore the genetic etiology of deafness in a large Chinese family with autosomal dominant, nonsyndromic, progressive sensorineural hearing loss (ADNSHL). Methods Whole exome sequencing and linkage analysis were performed to identify pathogenic mutation. Inner ear expression of Ifnlr1 was investigated by immunostaining in mice. ifnlr1 Morpholino knockdown Zebrafish were constructed to explore the deafness mechanism. Results We identified a cosegregating heterozygous missense mutation, c.296G>A (p.Arg99His) in the gene encoding interferon lambda receptor 1 (IFNLR1) - a protein that functions in the Jak/ STAT pathway- are associated with ADNSHL Morpholino knockdown of ifnlr1 leads to a significant decrease in hair cells and non-inflation of the swim bladder in late-stage zebrafish, which can be reversed by injection with normal Zebrafish ifnlr1 mRNA. Knockdown of ifnlr1 in zebrafish causes significant upregulation of cytokine receptor family member b4 (interleukin-10r2), jak1, tyrosine kinase 2, stat3, and stat5b in the Jak1/STAT3 pathway at the mRNA level. ConclusionIFNLR1 function is required in the auditory system and that IFNLR1 mutations are associated with ADNSHL. To the best of our knowledge, this is the first study implicating an interferon lambda receptor in auditory function.

Genes / Markers

Figures

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Expression

Fish	Conditions	Stage	Anatomy	Assay	Figure
AB	control	Day 4	whole organism	RTPCR	Fig. 5
AB + MO3-ifnlr1	standard conditions	Day 4	whole organism	RTPCR	Fig. 5
s356tTg	control	Day 6	neuromast hair cell	IHC	Fig. 3
s356tTg + MO3-ifnlr1	standard conditions	Day 6	neuromast hair cell	IHC	Fig. 3
AB	control	Day 4	whole organism	RTPCR	Fig. 5
AB + MO3-ifnlr1	standard conditions	Day 4	whole organism	RTPCR	Fig. 5
AB	control	Day 4	whole organism	RTPCR	Fig. 5
AB + MO3-ifnlr1	standard conditions	Day 4	whole organism	RTPCR	Fig. 5
AB	control	Day 4	whole organism	RTPCR	Fig. 5
AB + MO3-ifnlr1	standard conditions	Day 4	whole organism	RTPCR	Fig. 5

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB + MO3-ifnlr1	standard conditions	Protruding-mouth	whole organism apoptotic process occurrence, normal	Fig. S3
AB + MO3-ifnlr1	standard conditions	Day 4	cell surface receptor signaling pathway via JAK-STAT increased occurrence, abnormal	Fig. 5
AB + MO3-ifnlr1	standard conditions	Day 4	whole organism crfb4 expression increased amount, abnormal	Fig. 5
AB + MO3-ifnlr1	standard conditions	Day 4	whole organism jak1 expression increased amount, abnormal	Fig. 5
AB + MO3-ifnlr1	standard conditions	Day 4	whole organism stat3 expression increased amount, abnormal	Fig. 5
AB + MO3-ifnlr1	standard conditions	Day 4	whole organism stat5b expression increased amount, abnormal	Fig. 5
AB + MO3-ifnlr1	standard conditions	Day 4	whole organism tyk2 expression increased amount, abnormal	Fig. 5
AB + MO3-ifnlr1	standard conditions	Day 6	neuromast decreased amount, abnormal	Fig. 4
AB + MO3-ifnlr1	standard conditions	Day 6	neuromast hair cell decreased amount, abnormal	Fig. 4
AB + MO3-ifnlr1	standard conditions	Day 6	swim bladder uninflated, abnormal	Fig. 4

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
s356tTg	Tg(pou4f3:GAP-GFP)	Transgenic Insertion
zf2163Tg	Tg2(lyz:EGFP)	Transgenic Insertion

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
sensorineural hearing loss			TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
ifnlr1	MO3-ifnlr1	MRPHLNO

Fish

Fish
AB
AB + MO3-ifnlr1
s356tTg
s356tTg + MO3-ifnlr1
zf2163Tg + MO3-ifnlr1

Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab10-sox2	polyclonal		IgG	Rabbit

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
GFP	EFG	GFP

Mapping

Gao et al., 2018 ZDB-PUB-180223-33 PMID:29453195

Mutation of IFNLR1, an interferon lambda receptor 1, is associated with autosomal-dominant non-syndromic hearing loss.

Gao et al., 2018

ZDB-PUB-180223-33
PMID:29453195