Modification of Human Hearing Loss by Plasma-Membrane Calcium Pump PMCA2

Schultz, Julie M.; Yang, Yandan; Caride, Ariel J.; Filoteo, Adelaida G.; Penheiter, Alan R.; Lagziel, Ayala; Morell, Robert J.; Mohiddin, Saidi A.; Fananapazir, Lameh; Madeo, Anne C.; Penniston, John T.; Griffith, Andrew J.

doi:10.1056/nejmoa043899

Cited by 167 publications

(141 citation statements)

References 22 publications

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“…This profile is very similar to that of calcium-ATPase2, previously shown to localize at the plasma membrane of stereocilia (5). Mutations in the gene encoding for this transporter cause deafness in mice (6), and have been reported to be a genetic modifier of hearing loss in humans (7). Confocal scans of the basolateral poles of transfected hair cells revealed FAM65B-GFP in cytosol but not in plasma membrane, suggesting that it is in intracellular membrane trafficking compartments (Fig.…”

Section: Fam65b Is Present In Apical Plasma Membrane Of Mammalian Hairsupporting

confidence: 79%

FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing

Diaz‐Horta

Subasioglu-Uzak

Grati³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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In a large consanguineous Turkish kindred with recessive nonsyndromic, prelingual, profound hearing loss, we identified in the gene FAM65B (MIM611410) a splice site mutation (c.102-1G>A) that perfectly cosegregates with the phenotype in the family. The mutation leads to exon skipping and deletion of 52-amino acid residues of a PX membrane localization domain. FAM65B is known to be involved in myotube formation and in regulation of cell adhesion, polarization, and migration. We show that wild-type Fam65b is expressed during embryonic and postnatal development stages in murine cochlea, and that the protein localizes to the plasma membranes of the stereocilia of inner and outer hair cells of the inner ear. The wild-type protein targets the plasma membrane, whereas the mutant protein accumulates in cytoplasmic inclusion bodies and does not reach the membrane. In zebrafish, knockdown of fam65b leads to significant reduction of numbers of saccular hair cells and neuromasts and to hearing loss. We conclude that FAM65B is a plasma membrane-associated protein of hair cell stereocilia that is essential for hearing.deafness | whole-exome sequencing | congenital | Mendelian disorder | sensorineural H earing loss is the most common sensory problem, affecting approximately 1 in 500 newborns. Most cases are the consequence of mutations in single genes with specific functions in the inner ear (1) (http://hereditaryhearingloss.org). Hearing depends on the ability of the inner ear to convert acoustic waves into electrical signals. This process originates in the stereocilia, actin-rich structures that project from the apical pole of cochlear hair cells and are interconnected in the shape of a staircase to form the hair bundle. Most of the ∼50 hair-bundle proteins identified so far are the products of genes that when mutated lead to hearing loss (2). Thus, the genetic approach has played a major role in elucidating the molecular components of normal hearing.Here we present Family With Sequence Similarity 65, Member B (FAM65B, MIM611410) as a previously unrecognized, plasma membrane-associated protein of hair cell stereocilia. The critical role of FAM65B in human hearing was revealed by genetic analysis of a large family with hereditary deafness. In the zebrafish, knocking down the ortholog of FAM65B led to sensorineural hearing loss. Results A Splice Site Mutation in FAM65B Causes Profound SensorineuralHearing Loss in a Turkish Family. In a large consanguineous kindred of Turkish origin (Fig. 1A), six affected individuals had symmetric profound sensorineural hearing loss (Fig. 1B). Anamnestic evaluation and audiograms indicated congenital/prelingual onset hearing loss in all affected individuals. Available audiograms do not suggest progression of hearing loss. Transient evoked otoacoustic emissions and acoustic reflexes were negative in all affected members of the family. Auditory brainstem responses were absent as well. Affected individuals had neither delay in gross motor development nor balance problems, vertigo, dizziness, or n...

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Section: Fam65b Is Present In Apical Plasma Membrane Of Mammalian Hairsupporting

confidence: 79%

FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing

Diaz‐Horta

Subasioglu-Uzak

Grati³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Reciprocally, in humans, a hypofunctional variant (V586M) in ATP2B2 has also been found associated with increased HL caused by a homozygous mutation in CDH23 in a manner analogous to the interaction between the dfw 2J allele of Atp2b2 and the ahl allele of Cdh23 in mice. Additionally, ATP2B2 V 586M has been found to modify the severity of HL due to a mutation in MYO6 and has been suggested to predispose to NIHL [48].…”

Section: Heritability Allelism and Genetic Modifiers Of Presbycusismentioning

confidence: 99%

Ageing and hearing loss

Yan

2007

The Journal of Pathology

270

178

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Although many adults retain good hearing as they age, hearing loss associated with ageing is common among elderly persons. There are a number of pathophysiolological processes underlying age-related changes to functional components in the inner ear. Genetic factors determine the ageing process but are under the influence of intrinsic and environmental factors. It is difficult to distinguish changes of normal ageing from those of other contributing factors. The effects of age-related deafness can have significant physical, functional and mental health consequences. Although a deficit in hearing can be corrected to some degree by a hearing aid or other appropriate amplification devices, hearing-related rehabilitative needs are much more than simply amplifying external sound. Only by better understanding the process of ageing and its effect on the auditory function can we better accommodate elderly people in our day-to-day interactions. We review here the structure and function of the inner ear, pathophysiology associated with age-related hearing loss (ARHL), heritability, allelism and modifier genes of ARHL, and evaluate the genetic analyses for identification of genetic factors that are involved.

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“…5] downstream of the phospholipids binding domain of the pump (deafwaddler mouse, dfw). A mutation next to the active center (V586M) was later found to depress pump activity and to increase hearing loss in heterozygous patients that also carried a homozygous mutation in cadherin 23 (CDH23) (34). A mutation has now been identified in the human PMCA2 gene that replaces a conserved glycine residue (G293S) 10 residues downstream of the dfw mutation.…”

mentioning

confidence: 99%

A functional study of plasma-membrane calcium-pump isoform 2 mutants causing digenic deafness

Ficarella

Leva²,

Bortolozzi

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

114

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Ca 2؉ enters the stereocilia of hair cells through mechanoelectrical transduction channels opened by the deflection of the hair bundle and is exported back to endolymph by an unusual splicing isoform (w/a) of plasma-membrane calcium-pump isoform 2 (PMCA2). Ablation or missense mutations of the pump cause deafness, as described for the G283S mutation in the deafwaddler (dfw) mouse. A deafness-inducing missense mutation of PMCA2 (G293S) has been identified in a human family. The family also was screened for mutations in cadherin 23, which accentuated hearing loss in a previously described human family with a PMCA2 mutation. A T1999S substitution was detected in the cadherin 23 gene of the healthy father and affected son but not in that of the unaffected mother, who presented instead the PMCA2 mutation. The w/a isoform was overexpressed in CHO cells. At variance with the other PMCA2 isoforms, it became activated only marginally when exposed to a Ca 2؉ pulse. The G293S and G283S mutations delayed the dissipation of Ca 2؉ transients induced in CHO cells by InsP3. In organotypic cultures, Ca 2؉ imaging of vestibular hair cells showed that the dissipation of stereociliary Ca 2؉ transients induced by Ca 2؉ uncaging was compromised in the dfw and PMCA2 knockout mice, as was the sensitivity of the mechanoelectrical transduction channels to hair bundle displacement in cochlear hair cells.hereditary hearing loss ͉ mutations ͉ calcium homeostasis ͉ calcium transport T he receptive organelle of sensory hair cells in the mammalian cochlea, the stereocilia bundle, protrudes from the cell's apical surface. Inner hair cells transduce mechanical vibrations into electrical signals that are eventually transmitted to the brain to be transformed into hearing signals (1), whereas outer hair cells (OHCs) (2) amplify the vibrations of the basilar membrane (3). Mechanical stimuli that are detected as excitatory deflect a hair bundle, thus increasing tension in the tip link, a filament stretched between the tops of stereocilia. This tension is conveyed to mechanosensitive transduction (MET) channels that open to allow ions into the cell (4). The apical surface of hair cells is bathed in endolymph, which is rich in K ϩ but low in Na ϩ and Ca 2ϩ (5). K ϩ carries most the transduction current, but MET channels are Ca 2ϩ selective, i.e., Ca 2ϩ influx is significant even at the low Ca 2ϩ levels of the endolymph, which are much lower than those of other extracellular fluids (6-10): 20-23 M in the rodent cochlea (11, 12), 200-250 M in the vestibular system, possibly because of the presence there of calcium carbonate crystals (13,14). Approximately 10% of the MET current may actually be carried by Ca 2ϩ ions (15). Ca 2ϩ entering through MET channels is rapidly sequestered by buffers in the stereocilia (16,17) and is shuttled back to endolymph by the plasma membrane Ca 2ϩ pump (PMCA) (18,19), which is very concentrated in the stereocilia membrane (Ϸ2,000 per squared micrometer) (15, 19-21). The PMCA is assumed to increase Ca 2ϩ in the immediate pro...

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Modification of Human Hearing Loss by Plasma-Membrane Calcium Pump PMCA2

Cited by 167 publications

References 22 publications

FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing

FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing

Ageing and hearing loss

A functional study of plasma-membrane calcium-pump isoform 2 mutants causing digenic deafness

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