A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans.
Adult
Alleles
Amino Acid Substitution
Animals
Base Sequence
Chromosome Mapping
Chromosomes, Human, Pair 4
/ chemistry
Consanguinity
Female
Gene Expression
Genes, Recessive
Hair Cells, Auditory, Inner
/ metabolism
Hearing Loss, Sensorineural
/ genetics
Humans
Male
Membrane Proteins
/ deficiency
Mice
Pedigree
Point Mutation
Tetraspanins
/ deficiency
Exome Sequencing
Zebrafish
Journal
Human genetics
ISSN: 1432-1203
Titre abrégé: Hum Genet
Pays: Germany
ID NLM: 7613873
Informations de publication
Date de publication:
Jun 2021
Jun 2021
Historique:
received:
25
09
2020
accepted:
31
12
2020
pubmed:
27
1
2021
medline:
13
5
2021
entrez:
26
1
2021
Statut:
ppublish
Résumé
Deafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.
Identifiants
pubmed: 33496845
doi: 10.1007/s00439-020-02254-z
pii: 10.1007/s00439-020-02254-z
pmc: PMC8099798
mid: NIHMS1697649
doi:
Substances chimiques
CLRN2 protein, human
0
Membrane Proteins
0
Tetraspanins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
915-931Subventions
Organisme : HearInNoise
ID : ANR-17-CE16-0017
Organisme : Medizinischen Fakultät, Eberhard Karls Universität Tübingen
ID : 2545-1-0
Organisme : NIH HHS
ID : GM007748
Pays : United States
Organisme : ANR light4deaf
ID : ANR-15-RHUS-0001
Organisme : NIH HHS
ID : GM103636 (Project 3)
Pays : United States
Organisme : NIDCD NIH HHS
ID : DC002842
Pays : United States
Organisme : Medical Research Council
ID : MC_UP_1503/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : 1774724
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : T32 GM007748
Pays : United States
Organisme : NIDCD NIH HHS
ID : R01 DC012049
Pays : United States
Organisme : NIDCD NIH HHS
ID : R01 DC002842
Pays : United States
Organisme : NIDCD NIH HHS
ID : DC012049
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103636
Pays : United States
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