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Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human.

Charizopoulou N, Lelli A, Schraders M, Ray K, Hildebrand MS, Ramesh A, Srisailapathy CR, Oostrik J, Admiraal RJ, Neely HR, Latoche JR, Smith RJ, Northup JK, Kremer H, Holt JR, Noben-Trauth K - Nat Commun (2011)

Bottom Line: A missense mutation in the PDZ domain has an attenuating effect on mechanotransduction and the acquisition of mature inner hair cell potassium currents.The Gipc3(343A) allele disrupts the structure of the stereocilia bundle and affects long-term function of auditory hair cells and spiral ganglion neurons.Our study suggests a pivotal role of Gipc3 in acoustic signal acquisition and propagation in cochlear hair cells.

View Article: PubMed Central - PubMed

Affiliation: Section on Neurogenetics, Laboratory of Molecular Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland 20850, USA.

ABSTRACT
Sensorineural hearing loss affects the quality of life and communication of millions of people, but the underlying molecular mechanisms remain elusive. Here, we identify mutations in Gipc3 underlying progressive sensorineural hearing loss (age-related hearing loss 5, ahl5) and audiogenic seizures (juvenile audiogenic monogenic seizure 1, jams1) in mice and autosomal recessive deafness DFNB15 and DFNB95 in humans. Gipc3 localizes to inner ear sensory hair cells and spiral ganglion. A missense mutation in the PDZ domain has an attenuating effect on mechanotransduction and the acquisition of mature inner hair cell potassium currents. Magnitude and temporal progression of wave I amplitude of afferent neurons correlate with susceptibility and resistance to audiogenic seizures. The Gipc3(343A) allele disrupts the structure of the stereocilia bundle and affects long-term function of auditory hair cells and spiral ganglion neurons. Our study suggests a pivotal role of Gipc3 in acoustic signal acquisition and propagation in cochlear hair cells.

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GIPC3 mutations and human deafness.(a) Sequencing chromatograms indicating the guanine (G) and adenine (A) in family W98-042 (top) and control (bottom) at nucleotide position c.903 changing the tryptophan (Trp) residue at position p.301 to a stop codon (p.Trp301X). (b) Shown is the two-generation pedigree of consanguinues family W98-042 with first-cousin parents. Hearing-impaired brothers homozygous for the mutation (II.I and II.3; A/A) are indicated by filled black boxes and normal hearing relatives are indicated by open symbols. (c) Mean pure-tone audiograms of the two affected individuals II.1 and II.3 of family W98-042 at different ages are given in years (y). Note the threshold shifts of 80–120 dB HL above normal hearing levels. (d) Sequence chromatogram showing c.785T>G (p.Leu262Arg) mutation in GIPC3 in individual II-5. (e) Pedigree of the Indian family with prelingual, profound autosomal recessive non-syndromic hearing impairment. The c.785 genotype is shown. Open symbols unaffected; filled black symbols affected; double line consanguineous event. (f) Multi-sequence alignment of GIPC family proteins showing the high conservation of the Leu262 residue.
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f4: GIPC3 mutations and human deafness.(a) Sequencing chromatograms indicating the guanine (G) and adenine (A) in family W98-042 (top) and control (bottom) at nucleotide position c.903 changing the tryptophan (Trp) residue at position p.301 to a stop codon (p.Trp301X). (b) Shown is the two-generation pedigree of consanguinues family W98-042 with first-cousin parents. Hearing-impaired brothers homozygous for the mutation (II.I and II.3; A/A) are indicated by filled black boxes and normal hearing relatives are indicated by open symbols. (c) Mean pure-tone audiograms of the two affected individuals II.1 and II.3 of family W98-042 at different ages are given in years (y). Note the threshold shifts of 80–120 dB HL above normal hearing levels. (d) Sequence chromatogram showing c.785T>G (p.Leu262Arg) mutation in GIPC3 in individual II-5. (e) Pedigree of the Indian family with prelingual, profound autosomal recessive non-syndromic hearing impairment. The c.785 genotype is shown. Open symbols unaffected; filled black symbols affected; double line consanguineous event. (f) Multi-sequence alignment of GIPC family proteins showing the high conservation of the Leu262 residue.

Mentions: To test whether mutations in GIPC3 also underlie human SNHL, we screened panels of families of Dutch and Indian origin presenting with autosomal recessive nonsyndromic hearing impairment. In one Dutch family, W98-042, a homozygous region at 19p13.11-p13.3 encompassing GIPC3 was shared by the two affected siblings (rs11880407–rs6512152; assigned locus symbol: DFNB95). GIPC3 mutation analysis revealed a homozygous nucleotide substitution in exon 6, c.903G>A that segregated with the disease in the family (Fig. 4a,b and Supplementary Table S2). The c.903G>A change is predicted to truncate the protein after residue 300 (p.Trp301X) causing the deletion of the C-terminal 12 amino acids of the protein. The mutation was not found in 156 (312 chromosomes) ethnically matched control individuals.


Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human.

Charizopoulou N, Lelli A, Schraders M, Ray K, Hildebrand MS, Ramesh A, Srisailapathy CR, Oostrik J, Admiraal RJ, Neely HR, Latoche JR, Smith RJ, Northup JK, Kremer H, Holt JR, Noben-Trauth K - Nat Commun (2011)

GIPC3 mutations and human deafness.(a) Sequencing chromatograms indicating the guanine (G) and adenine (A) in family W98-042 (top) and control (bottom) at nucleotide position c.903 changing the tryptophan (Trp) residue at position p.301 to a stop codon (p.Trp301X). (b) Shown is the two-generation pedigree of consanguinues family W98-042 with first-cousin parents. Hearing-impaired brothers homozygous for the mutation (II.I and II.3; A/A) are indicated by filled black boxes and normal hearing relatives are indicated by open symbols. (c) Mean pure-tone audiograms of the two affected individuals II.1 and II.3 of family W98-042 at different ages are given in years (y). Note the threshold shifts of 80–120 dB HL above normal hearing levels. (d) Sequence chromatogram showing c.785T>G (p.Leu262Arg) mutation in GIPC3 in individual II-5. (e) Pedigree of the Indian family with prelingual, profound autosomal recessive non-syndromic hearing impairment. The c.785 genotype is shown. Open symbols unaffected; filled black symbols affected; double line consanguineous event. (f) Multi-sequence alignment of GIPC family proteins showing the high conservation of the Leu262 residue.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105340&req=5

f4: GIPC3 mutations and human deafness.(a) Sequencing chromatograms indicating the guanine (G) and adenine (A) in family W98-042 (top) and control (bottom) at nucleotide position c.903 changing the tryptophan (Trp) residue at position p.301 to a stop codon (p.Trp301X). (b) Shown is the two-generation pedigree of consanguinues family W98-042 with first-cousin parents. Hearing-impaired brothers homozygous for the mutation (II.I and II.3; A/A) are indicated by filled black boxes and normal hearing relatives are indicated by open symbols. (c) Mean pure-tone audiograms of the two affected individuals II.1 and II.3 of family W98-042 at different ages are given in years (y). Note the threshold shifts of 80–120 dB HL above normal hearing levels. (d) Sequence chromatogram showing c.785T>G (p.Leu262Arg) mutation in GIPC3 in individual II-5. (e) Pedigree of the Indian family with prelingual, profound autosomal recessive non-syndromic hearing impairment. The c.785 genotype is shown. Open symbols unaffected; filled black symbols affected; double line consanguineous event. (f) Multi-sequence alignment of GIPC family proteins showing the high conservation of the Leu262 residue.
Mentions: To test whether mutations in GIPC3 also underlie human SNHL, we screened panels of families of Dutch and Indian origin presenting with autosomal recessive nonsyndromic hearing impairment. In one Dutch family, W98-042, a homozygous region at 19p13.11-p13.3 encompassing GIPC3 was shared by the two affected siblings (rs11880407–rs6512152; assigned locus symbol: DFNB95). GIPC3 mutation analysis revealed a homozygous nucleotide substitution in exon 6, c.903G>A that segregated with the disease in the family (Fig. 4a,b and Supplementary Table S2). The c.903G>A change is predicted to truncate the protein after residue 300 (p.Trp301X) causing the deletion of the C-terminal 12 amino acids of the protein. The mutation was not found in 156 (312 chromosomes) ethnically matched control individuals.

Bottom Line: A missense mutation in the PDZ domain has an attenuating effect on mechanotransduction and the acquisition of mature inner hair cell potassium currents.The Gipc3(343A) allele disrupts the structure of the stereocilia bundle and affects long-term function of auditory hair cells and spiral ganglion neurons.Our study suggests a pivotal role of Gipc3 in acoustic signal acquisition and propagation in cochlear hair cells.

View Article: PubMed Central - PubMed

Affiliation: Section on Neurogenetics, Laboratory of Molecular Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland 20850, USA.

ABSTRACT
Sensorineural hearing loss affects the quality of life and communication of millions of people, but the underlying molecular mechanisms remain elusive. Here, we identify mutations in Gipc3 underlying progressive sensorineural hearing loss (age-related hearing loss 5, ahl5) and audiogenic seizures (juvenile audiogenic monogenic seizure 1, jams1) in mice and autosomal recessive deafness DFNB15 and DFNB95 in humans. Gipc3 localizes to inner ear sensory hair cells and spiral ganglion. A missense mutation in the PDZ domain has an attenuating effect on mechanotransduction and the acquisition of mature inner hair cell potassium currents. Magnitude and temporal progression of wave I amplitude of afferent neurons correlate with susceptibility and resistance to audiogenic seizures. The Gipc3(343A) allele disrupts the structure of the stereocilia bundle and affects long-term function of auditory hair cells and spiral ganglion neurons. Our study suggests a pivotal role of Gipc3 in acoustic signal acquisition and propagation in cochlear hair cells.

Show MeSH
Related in: MedlinePlus