name: Autosomal Recessive Nonsyndromic Hearing Loss 104
creation_date: "2026-08-26T14:00:00Z"
category: Mendelian
disease_term:
  preferred_term: autosomal recessive nonsyndromic hearing loss 104
  term:
    id: MONDO:0014675
    label: autosomal recessive nonsyndromic hearing loss 104
synonyms:
- DFNB104
- deafness, autosomal recessive 104
- RIPOR2-related autosomal recessive nonsyndromic hearing loss
- FAM65B-related deafness
description: >-
  Congenital, profound, non-progressive sensorineural hearing loss caused by biallelic
  loss-of-function variants in RIPOR2 (formerly FAM65B). It is a disease of one small
  place: RIPOR2 forms a ring of oligomers around the basal taper of hair cell stereocilia,
  the narrow hinge where each stereocilium pivots when sound deflects the bundle. Remove
  it and stereocilia still start to grow, but the taper compartment loses its
  organisation, mechanotransduction fails, and the bundle deteriorates.

  The entry has two features that shaped how it is curated.

  The first is that RIPOR2 causes two different hearing-loss diseases, and they are easy
  to conflate. This one is recessive, congenital, profound and stable. A heterozygous
  in-frame deletion in the same gene causes an adult-onset, progressive, dominant hearing
  loss that is a common founder allele in the Netherlands. The deletion is not a milder
  version of this disease and evidence about it is not curated here; it appears under
  differential diagnoses instead.

  The second is a model mismatch that the field has stated explicitly. The Tunisian
  siblings with a homozygous nonsense allele have vestibular areflexia alongside their
  deafness, while the Ripor2 knockout mouse and a zebrafish model are deaf with normal
  vestibular function. The mouse is the source of nearly everything known about the
  mechanism, so the discrepancy matters, and it is recorded as a HUMAN_MODEL_MISMATCH
  rather than left as a footnote.

parents:
- Autosomal Recessive Nonsyndromic Hearing Loss
- Hereditary Hearing Loss

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Two consanguineous families are reported: a large Turkish kindred with six affected
    individuals homozygous for a splice-acceptor allele, and a Tunisian sibship of three
    homozygous for a nonsense allele. Each allele is private to its family. No prevalence
    estimate exists, and none is meaningful at this evidence base.
  evidence:
  - reference: PMID:24958875
    reference_title: "FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      The first family and the cosegregation on which the gene-disease claim rests.

pathophysiology:

- name: Biallelic RIPOR2 Loss-of-Function Variant
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Two reported alleles, in two consanguineous families, both loss of function and both
    homozygous.

    The Turkish allele c.102-1G>A destroys a splice acceptor site, causing exon skipping
    and an in-frame deletion of 52 residues from the PX membrane-localization domain. It
    is not a null: protein is made, but it is the wrong protein, and where it goes is the
    point of the next node.

    The Tunisian allele c.1561C>T (p.Arg521*) is a nonsense variant. It is the allele that
    comes with a vestibular phenotype, which the splice allele does not.
  genetic_context:
    gene:
      preferred_term: RIPOR2
      term:
        id: hgnc:13872
        label: RIPOR2
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Homozygous in both reported families, each of which is consanguineous. Typed
      LOSS_OF_FUNCTION for both alleles: the splice allele's product fails to reach its
      compartment and the nonsense allele truncates the protein.
  downstream:
  - target: Loss of RIPOR2 from the Stereociliary Taper
    causal_link_type: DIRECT
    description: >-
      Either allele removes functional RIPOR2 from the place it works.
  evidence:
  - reference: PMID:24958875
    reference_title: "FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation leads to exon skipping and deletion of 52-amino acid residues of a PX
      membrane localization domain.
    explanation: >-
      The molecular consequence of the Turkish allele, and the domain it removes.
  - reference: PMID:37864412
    reference_title: "RIPOR2: A new gene of non-syndromic cochleovestibular dysfunction, discrepancy between human pathology and animal models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in RIPOR2 (RHO family interacting cell polarization regulator 2) has been identified
      by WES in Tunisian siblings suffering from congenital bilateral profound hearing and
      vestibular dysfunctions.
    explanation: >-
      The second family and its allele, together with the phenotype that distinguishes it.

- name: Loss of RIPOR2 from the Stereociliary Taper
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    RIPOR2 works at the plasma membrane of stereocilia, and specifically at their base. In
    the mouse cochlea the wild-type protein localises to the stereociliary plasma membrane
    of inner and outer hair cells, and super-resolution imaging places it as a
    circumferential ring of oligomers around the basal taper - the narrow hinge where a
    stereocilium pivots when the bundle is deflected.

    The splice allele's product does not get there. Wild-type protein targets the plasma
    membrane while the mutant accumulates in cytoplasmic inclusion bodies, so this is a
    mislocalisation disease at the protein level rather than simple absence, even though
    the functional outcome is the same.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  cellular_components:
  - preferred_term: stereocilium
    term:
      id: GO:0032420
      label: stereocilium
  locations:
  - preferred_term: cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  downstream:
  - target: Disorganisation of the Taper Compartment
    causal_link_type: DIRECT
    description: >-
      RIPOR2 oligomerisation organises the taper; without it the compartment's other
      components are displaced.
  evidence:
  - reference: PMID:24958875
    reference_title: "FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      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.
    explanation: >-
      Establishes where the protein is, in the cell types this disease affects.
  - reference: PMID:24958875
    reference_title: "FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The wild-type protein targets the plasma membrane, whereas the mutant protein
      accumulates in cytoplasmic inclusion bodies and does not reach the membrane.
    explanation: >-
      The mislocalisation of the patient allele's product, which is the functional case
      for calling the splice variant loss of function.
  - reference: PMID:27269051
    reference_title: "Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using biochemistry and stochastic optical reconstruction microscopy (STORM), we show
      here that Fam65b oligomers form a circumferential ring near the basal taper of the
      mechanically sensitive stereocilia of murine hair cells.
    explanation: >-
      Refines the localisation from "stereocilia" to the taper ring, which is what makes
      the mechanism specific.

- name: Disorganisation of the Taper Compartment
  role: central_effector
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The taper is a distinct subcellular compartment with its own protein complement, and
    RIPOR2 organises it. Two dependencies are documented in mouse.

    Taperin, a second taper protein, forms a dense-core-like structure that is disrupted
    when Fam65b is absent - so the compartment loses its architecture, not just one of its
    components. And RIPOR2 is not self-organising: RhoC binds it, co-localises with it in
    stereocilia and regulates its oligomerisation, and both the RhoC interaction and the
    oligomerisation are required for function. That places the lesion in a small GTPase
    module rather than in a structural protein acting alone.

    All of this is mouse work. The claim curated here is about the mechanism, and the
    human evidence for it is the phenotype plus the mislocalisation of the patient allele.
  cell_types:
  - preferred_term: sensory hair cell
    term:
      id: CL:0000855
      label: sensory hair cell
  cellular_components:
  - preferred_term: stereocilium
    term:
      id: GO:0032420
      label: stereocilium
  biological_processes:
  - preferred_term: Rho protein signal transduction
    term:
      id: GO:0007266
      label: Rho protein signal transduction
  - preferred_term: auditory receptor cell stereocilium organization
    term:
      id: GO:0060088
      label: auditory receptor cell stereocilium organization
    modifier: ABNORMAL
  downstream:
  - target: Hair Bundle Malformation and Misorientation
    causal_link_type: DIRECT
    description: >-
      A disorganised taper gives a malformed bundle: stereocilia begin to develop and then
      deteriorate, and bundle orientation is set wrongly during morphogenesis.
  - target: Mechanotransduction Failure
    causal_link_type: DIRECT
    description: >-
      The taper is where the stereocilium pivots, so its disorganisation affects
      transduction directly and not only through the bundle's shape.
  evidence:
  - reference: PMID:27269051
    reference_title: "Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Taperin, a second protein near the taper, forms a dense-core-like structure that is
      disrupted in the absence of Fam65b.
    explanation: >-
      The dependency that makes this a compartment-organisation defect rather than the
      loss of one protein.
  - reference: PMID:27269051
    reference_title: "Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      RhoC co-localizes with Fam65b in stereocilia and regulates Fam65b oligomerization.
    explanation: >-
      The upstream regulator of the ring, placing the mechanism in Rho GTPase signalling.
  - reference: PMID:27269051
    reference_title: "Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Binding to RhoC and oligomerization are critical for Fam65b function.
    explanation: >-
      Establishes both dependencies as functionally required, not merely correlated.

- name: Hair Bundle Malformation and Misorientation
  role: effector
  biological_scale: CELLULAR
  description: >-
    Two distinct bundle defects follow, and they occur at different stages.

    During morphogenesis, the absence of Ripor2 affects the orientation of the hair bundle.
    The route runs through Myh9, the non-muscle myosin heavy chain encoded by a known
    deafness gene: Ripor2 interacts with Myh9, and in its absence Myh9 protein is low in
    the cochlea despite increased Myh9 transcript, while the kinocilium - which sets the
    bundle's axis - is aberrantly placed and its phosphorylated Myh9 content reduced. The
    transcript-protein discordance is the informative detail, because it makes this a
    protein-stability effect rather than a transcriptional one.

    After development, the bundle does not hold. Stereocilia of Fam65b-deficient hair
    cells start to develop but then deteriorate - so this is a maintenance failure on top
    of a morphogenetic one, and neither alone accounts for the phenotype.
  cell_types:
  - preferred_term: sensory hair cell
    term:
      id: CL:0000855
      label: sensory hair cell
  cellular_components:
  - preferred_term: stereocilium bundle
    term:
      id: GO:0032421
      label: stereocilium bundle
  - preferred_term: kinocilium
    term:
      id: GO:0060091
      label: kinocilium
  downstream:
  - target: Mechanotransduction Failure
    causal_link_type: DIRECT
    description: >-
      A misoriented, deteriorating bundle cannot transduce deflection reliably.
  evidence:
  - reference: PMID:30280293
    reference_title: "Ripor2 is involved in auditory hair cell stereociliary bundle structure and orientation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we demonstrate that during the morphogenesis of the hair cell bundle, absence
      of Ripor2 affects the orientation of this key subcellular structure.
    explanation: >-
      The morphogenetic half of this node.
  - reference: PMID:30280293
    reference_title: "Ripor2 is involved in auditory hair cell stereociliary bundle structure and orientation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Absence of Ripor2 is associated with low Myh9 abundance in the mouse cochlea despite
      increased amount of Myh9 transcripts.
    explanation: >-
      The Myh9 route, with the transcript-protein discordance that identifies it as
      post-transcriptional.
  - reference: PMID:30280293
    reference_title: "Ripor2 is involved in auditory hair cell stereociliary bundle structure and orientation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In Ripor2-deficient mice, kinocilium shows an aberrant localization which associates
      with a reduced content of phosphorylated Myh9.
    explanation: >-
      Links the misplaced kinocilium, which sets bundle orientation, to the Myh9 defect.
  - reference: PMID:27269051
    reference_title: "Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Stereocilia of Fam65b-deficient murine hair cells start to develop, but
      mechanotransduction is affected and stereocilia deteriorate.
    explanation: >-
      The maintenance half: development starts normally and the structure is then lost.

- name: Mechanotransduction Failure
  role: effector
  biological_scale: CELLULAR
  description: >-
    Hair cells lacking RIPOR2 fail to convert bundle deflection into a receptor current.
    The failure is reported alongside, not after, the structural deterioration, which is
    why it is drawn from both the taper node and the bundle node rather than only from the
    structural one.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  biological_processes:
  - preferred_term: sensory perception of mechanical stimulus
    term:
      id: GO:0050954
      label: sensory perception of mechanical stimulus
    modifier: DECREASED
  downstream:
  - target: Congenital Profound Sensorineural Hearing Loss
    causal_link_type: DIRECT
    description: >-
      No transduction current means no auditory signal, from birth.
  - target: Vestibular End-Organ Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Vestibular hair cells carry stereociliary bundles built on the same plan as cochlear
      ones, so they are presumed to share the taper defect. That presumption is all this
      edge is: the taper mechanism has been shown in cochlear hair cells only, no human
      vestibular tissue has been examined, and the mouse and zebrafish models are
      vestibularly normal despite being deaf. Typed with unknown intermediates for those
      reasons, and see the model-mismatch discussion attached to the target node.
  evidence:
  - reference: PMID:27269051
    reference_title: "Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our findings thus reveal a highly organized compartment near the base of stereocilia
      that is critical for hair cell function and affected in disease.
    explanation: >-
      The paper's summary claim, connecting the taper compartment to hair cell function
      and to this disease.

- name: Congenital Profound Sensorineural Hearing Loss
  role: outcome
  biological_scale: ORGANISM
  description: >-
    Bilateral, symmetric, profound, prelingual, and non-progressive. It is the constant
    feature of the disease: present in all six affected members of the Turkish kindred and
    all three Tunisian siblings.
  locations:
  - preferred_term: cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  biological_processes:
  - preferred_term: sensory perception of sound
    term:
      id: GO:0007605
      label: sensory perception of sound
    modifier: ABSENT
  evidence:
  - reference: PMID:24958875
    reference_title: "FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      The phenotype in the first family: recessive, nonsyndromic, prelingual, profound.
  - reference: PMID:24958875
    reference_title: "FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We conclude that FAM65B is a plasma membrane-associated protein of hair cell
      stereocilia that is essential for hearing.
    explanation: >-
      The gene-function conclusion that the hearing phenotype rests on.

- name: Vestibular End-Organ Dysfunction
  role: outcome
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    Reported in one of the two families. The Tunisian siblings homozygous for p.Arg521*
    have vestibular dysfunction alongside their deafness, while the Turkish kindred with
    the splice allele had no balance problems.

    Marked PROVISIONAL because with two families and two alleles it is not possible to
    tell whether the difference is allele-specific, background-dependent, or an artefact
    of how carefully vestibular function was assessed in the earlier family. The mouse
    cannot arbitrate: it is deaf with normal vestibular function, which is curated as a
    model mismatch rather than as evidence against the human finding.
  locations:
  - preferred_term: semicircular canal
    term:
      id: UBERON:0001840
      label: semicircular canal
  - preferred_term: internal ear
    term:
      id: UBERON:0001846
      label: internal ear
  evidence:
  - reference: PMID:37864412
    reference_title: "RIPOR2: A new gene of non-syndromic cochleovestibular dysfunction, discrepancy between human pathology and animal models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in RIPOR2 (RHO family interacting cell polarization regulator 2) has been identified
      by WES in Tunisian siblings suffering from congenital bilateral profound hearing and
      vestibular dysfunctions.
    explanation: >-
      The combined cochleovestibular phenotype in the family that has it.

phenotypes:

- category: Otologic
  name: Congenital Profound Sensorineural Hearing Loss
  frequency: OBLIGATE
  severity: SEVERE
  description: >-
    Bilateral, symmetric and profound from birth, and non-progressive - a point of
    contrast with most dominant hereditary hearing losses and with the dominant RIPOR2
    disorder in particular.
  phenotype_term:
    preferred_term: Profound sensorineural hearing impairment
    term:
      id: HP:0011476
      label: Profound sensorineural hearing impairment
    clinical_course: STABLE
  evidence:
  - reference: PMID:24958875
    reference_title: "FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Establishes the severity and the prelingual onset in the founding family.

- category: Otologic
  name: Prelingual Onset
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Prelingual sensorineural hearing impairment
    term:
      id: HP:0000399
      label: Prelingual sensorineural hearing impairment
  description: >-
    Onset before speech acquisition, which is what makes early habilitation the whole of
    the clinical management question in this disease.
  evidence:
  - reference: PMID:24958875
    reference_title: "FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      States the onset directly.

- category: Otologic
  name: Bilateral Involvement
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Bilateral sensorineural hearing impairment
    term:
      id: HP:0008619
      label: Bilateral sensorineural hearing impairment
  evidence:
  - reference: PMID:37864412
    reference_title: "RIPOR2: A new gene of non-syndromic cochleovestibular dysfunction, discrepancy between human pathology and animal models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in RIPOR2 (RHO family interacting cell polarization regulator 2) has been identified
      by WES in Tunisian siblings suffering from congenital bilateral profound hearing and
      vestibular dysfunctions.
    explanation: >-
      States the hearing loss is bilateral and congenital.

- category: Otologic
  name: Vestibular Areflexia
  frequency: OCCASIONAL
  description: >-
    Present in the Tunisian siblings, absent in the Turkish kindred. Curated as OCCASIONAL
    on the strength of one family out of two rather than on a measured frequency, and read
    alongside the knowledge gap on allele specificity below.
  phenotype_term:
    preferred_term: Vestibular areflexia
    term:
      id: HP:0008568
      label: Vestibular areflexia
  evidence:
  - reference: PMID:37864412
    reference_title: "RIPOR2: A new gene of non-syndromic cochleovestibular dysfunction, discrepancy between human pathology and animal models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to the vestibular areflexia observed in our patients, deaf Ripor2 KO
      mouse model and our zebrafish model have normal vestibular function.
    explanation: >-
      Names the areflexia in the patients, and in the same sentence the model discrepancy
      that the discussion below is about.

genetic:

- name: RIPOR2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: RIPOR2
    term:
      id: hgnc:13872
      label: RIPOR2
  association: >-
    Biallelic loss-of-function variants in RIPOR2 cause DFNB104. The gene-disease claim
    rests on perfect cosegregation in a large consanguineous Turkish kindred, functional
    demonstration that the mutant protein fails to reach the plasma membrane, expression
    of the wild-type protein in the right cells at the right developmental stages, and
    loss of hair cells on knockdown in zebrafish - all in the founding report - with an
    unrelated Tunisian family and a second allele added later.

    RIPOR2 is also a dominant deafness gene, and that is a separate disease. A heterozygous
    12-nucleotide in-frame deletion causes adult-onset progressive hearing loss and is a
    frequent, highly penetrant founder allele in the Netherlands. Variant class and
    zygosity, not the gene, decide which disease a patient has.
  evidence:
  - reference: PMID:24958875
    reference_title: "FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that FAM65B is a plasma membrane-associated protein of hair cell
      stereocilia that is essential for hearing.
    explanation: >-
      The gene-function conclusion of the founding report.
  - reference: PMID:24958875
    reference_title: "FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In zebrafish, knockdown of fam65b leads to significant reduction of numbers of
      saccular hair cells and neuromasts and to hearing loss.
    explanation: >-
      The independent functional support for the gene, from a model organism rather than
      from the family.
  - reference: PMID:32631815
    reference_title: "A RIPOR2 in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study expands the phenotypic spectrum associated with RIPOR2 defects which had
      so far only been described to underlie early-onset recessively inherited HL.
    explanation: >-
      Curated on the gene rather than on any phenotype node: it establishes that RIPOR2
      carries two distinct diseases, and confirms from the outside that the recessive,
      early-onset one is the disease this entry describes.

inheritance:

- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Both reported families are consanguineous and both affected sibships are homozygous;
    heterozygous relatives are unaffected for this phenotype. Consanguinity is not
    incidental here - it is how two private alleles came to be homozygous at all, and it
    is why the reported families come from populations where consanguineous marriage is
    common rather than from anywhere the gene is enriched.
  evidence:
  - reference: PMID:24958875
    reference_title: "FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Recessive inheritance with cosegregation, in a consanguineous kindred.

animal_models:

- name: Fam65b/Ripor2 knockout mouse
  species: Mouse
  genotype: Fam65b (Ripor2) constitutive knockout, homozygous
  publication: PMID:27269051
  description: >-
    The homozygous null mouse, which matches the biallelic human genotype in kind. It is
    the source of essentially everything known about how RIPOR2 works: the taper ring,
    the taperin dependency, the RhoC interaction, and the observation that stereocilia
    develop before they deteriorate.
  modeled_mechanisms:
  - target: Disorganisation of the Taper Compartment
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Loss of the RIPOR2 ring, with disruption of taperin's dense-core structure at the
      same site.
    limitations: >-
      A constitutive null, whereas the Turkish human allele produces a mislocalised
      protein. Whether a mislocalised product is inert or mildly interfering is not
      addressed by a knockout.
    readouts:
    - name: Taperin dense-core structure at the stereociliary taper
      target: Disorganisation of the Taper Compartment
      direction: ALTERED
      interpretation: >-
        Taperin's organisation at the taper is disrupted in the absence of Fam65b,
        establishing the compartment-level defect.
      evidence:
      - reference: PMID:27269051
        reference_title: "Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Taperin, a second protein near the taper, forms a dense-core-like structure that
          is disrupted in the absence of Fam65b.
        explanation: >-
          The imaging result behind this readout.
    evidence:
    - reference: PMID:27269051
      reference_title: "Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Using biochemistry and stochastic optical reconstruction microscopy (STORM), we
        show here that Fam65b oligomers form a circumferential ring near the basal taper
        of the mechanically sensitive stereocilia of murine hair cells.
      explanation: >-
        Supports the model as the system in which the taper mechanism was defined.
  - target: Mechanotransduction Failure
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Mechanotransduction is affected in the knockout, and stereocilia deteriorate after
      beginning to develop.
    limitations: >-
      Mouse hair cell transduction is measured directly; the human equivalent is inferred
      from profound congenital deafness with no cochlear malformation, so the two are
      linked by argument rather than by a shared measurement.
    readouts:
    - name: Hair cell mechanotransduction and stereocilia integrity
      target: Mechanotransduction Failure
      direction: DECREASED
      interpretation: >-
        Transduction is impaired and stereocilia deteriorate despite normal initiation of
        development.
      evidence:
      - reference: PMID:27269051
        reference_title: "Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Stereocilia of Fam65b-deficient murine hair cells start to develop, but
          mechanotransduction is affected and stereocilia deteriorate.
        explanation: >-
          Both halves of the readout in one sentence: function and structure.
    evidence:
    - reference: PMID:27269051
      reference_title: "Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our findings thus reveal a highly organized compartment near the base of
        stereocilia that is critical for hair cell function and affected in disease.
      explanation: >-
        The authors' own statement linking the model's compartment to human disease.
  - target: Loss of RIPOR2 from the Stereociliary Taper
    relationship: RESCUES
    fidelity: HIGH
    description: >-
      Putting Fam65b back into deficient hair cells after birth restores the bundle, which
      is the closest thing this disease has to a proof that the protein's absence is what
      causes the structural defect rather than something downstream of a developmental
      programme that has already gone wrong.

      The rescue is also RhoC-dependent: a Fam65b construct that cannot bind RhoC fails to
      rescue, which is what ties the taper mechanism to the GTPase rather than leaving
      the interaction as a correlation.
    limitations: >-
      Re-expression by injectoporation into cochlear explants prepared at postnatal day 2
      and cultured for two days, scored on bundle morphology. That is an ex vivo
      preparation, which is why this link's evidence is typed IN_VITRO rather than
      MODEL_ORGANISM even though it sits under `animal_models`. It says nothing about whether an equivalent intervention is
      deliverable in a human cochlea, or about a timepoint after which the bundle can no
      longer be restored.
    readouts:
    - name: Stereocilia morphology after Fam65b re-expression
      target: Loss of RIPOR2 from the Stereociliary Taper
      direction: RESTORED
      interpretation: >-
        Bundle defects are rescued by wild-type Fam65b but not by the RhoC-binding-deficient
        construct, separating the structural requirement from the protein's mere presence.
      evidence:
      - reference: PMID:27269051
        reference_title: "Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Note morphological defects of stereocilia were rescued by Fam65b-GFP but not by
          Fam65bRL/AA-GFP.
        explanation: >-
          The rescue and its RhoC-binding-dependent control in one result.
    evidence:
    - reference: PMID:27269051
      reference_title: "Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The acute rescue of hair cell morphology by re-expression of Fam65b at postnatal
        ages also suggests that defects in hair bundle morphology are likely not a
        secondary consequence of perturbations in an overall developmental program but are
        more specifically linked to a role of Fam65b in stereocilia.
      explanation: >-
        The authors' own reading of what the rescue establishes: a direct structural role
        rather than a developmental knock-on. That is what makes the model a rescue system
        for this node.
  - target: Vestibular End-Organ Dysfunction
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The knockout mouse is deaf but vestibularly normal, while the Tunisian patients have
      vestibular areflexia. The negative result is recorded because it is the substance of
      this entry's model-mismatch discussion, not an incidental difference.
    limitations: >-
      The mouse is a constitutive null and the patients carry a nonsense allele, so the
      comparison is close but not exact; and the discrepancy is reported by a paper whose
      own zebrafish model behaves like the mouse, which strengthens the observation rather
      than explaining it. Paralogue compensation has been proposed and not tested.
    evidence:
    - reference: PMID:37864412
      reference_title: "RIPOR2: A new gene of non-syndromic cochleovestibular dysfunction, discrepancy between human pathology and animal models."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In contrast to the vestibular areflexia observed in our patients, deaf Ripor2 KO
        mouse model and our zebrafish model have normal vestibular function.
      explanation: >-
        REFUTE against the proposition that the mouse reproduces the human vestibular
        phenotype - which is exactly what FAILS_TO_RECAPITULATE asserts.

- name: Ripor2 knockout mouse (hair bundle morphogenesis)
  species: Mouse
  genotype: Ripor2 knockout, homozygous
  publication: PMID:30280293
  description: >-
    The same null genotype studied for bundle orientation rather than taper
    ultrastructure, and the source of the Myh9 route.
  modeled_mechanisms:
  - target: Hair Bundle Malformation and Misorientation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Misoriented hair bundles during morphogenesis, aberrant kinocilium placement, and
      reduced Myh9 protein despite increased transcript.
    limitations: >-
      MODERATE because bundle orientation has not been examined in human RIPOR2 tissue and
      cannot be - the inner ear is not biopsied - so the human counterpart of this
      structural readout is unobserved rather than confirmed.
    readouts:
    - name: Cochlear Myh9 protein abundance
      target: Hair Bundle Malformation and Misorientation
      direction: DECREASED
      interpretation: >-
        Myh9 protein falls in the Ripor2-null cochlea while its transcript rises,
        identifying a post-transcriptional dependency.
      evidence:
      - reference: PMID:30280293
        reference_title: "Ripor2 is involved in auditory hair cell stereociliary bundle structure and orientation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Absence of Ripor2 is associated with low Myh9 abundance in the mouse cochlea
          despite increased amount of Myh9 transcripts.
        explanation: >-
          The measurement, with the transcript comparison that makes it interpretable.
    evidence:
    - reference: PMID:30280293
      reference_title: "Ripor2 is involved in auditory hair cell stereociliary bundle structure and orientation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we demonstrate that during the morphogenesis of the hair cell bundle,
        absence of Ripor2 affects the orientation of this key subcellular structure.
      explanation: >-
        Supports the model as informative for the bundle-morphogenesis node.

- name: fam65b zebrafish morphant
  species: Zebrafish
  genotype: fam65b morpholino knockdown
  publication: PMID:24958875
  description: >-
    Knockdown in zebrafish, used in the founding report as independent functional support
    for the gene. It reduces saccular hair cell and neuromast numbers and impairs hearing.
  modeled_mechanisms:
  - target: Congenital Profound Sensorineural Hearing Loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Reproduces hearing loss on knockdown, alongside a loss of hair cells.
    limitations: >-
      A morpholino knockdown rather than a genetic null, in a species whose hair cells
      regenerate and whose lateral line has no human counterpart. The hair cell loss also
      goes further than the mouse phenotype, where cells are present but their bundles
      deteriorate - so the two models disagree on whether cells die, and neither
      observation has a human correlate.
    evidence:
    - reference: PMID:24958875
      reference_title: "FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In zebrafish, knockdown of fam65b leads to significant reduction of numbers of
        saccular hair cells and neuromasts and to hearing loss.
      explanation: >-
        PARTIAL because knockdown supports gene function in hearing without modelling the
        human allele or its cellular consequence.

diagnosis:

- name: Comprehensive Hearing Loss Gene Panel or Exome Sequencing
  description: >-
    DFNB104 is clinically indistinguishable from the many other causes of congenital
    profound nonsyndromic deafness, so it is found by sequencing rather than by
    phenotyping. Both reported families were solved by exome sequencing in a consanguineous
    pedigree, where homozygosity mapping narrows the search substantially.
  evidence:
  - reference: PMID:37864412
    reference_title: "RIPOR2: A new gene of non-syndromic cochleovestibular dysfunction, discrepancy between human pathology and animal models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in RIPOR2 (RHO family interacting cell polarization regulator 2) has been identified
      by WES in Tunisian siblings suffering from congenital bilateral profound hearing and
      vestibular dysfunctions.
    explanation: >-
      Names the diagnostic method used in the second family.

- name: Vestibular Function Testing
  description: >-
    Worth doing in a RIPOR2 patient rather than assuming the deafness is isolated. The
    Tunisian siblings' vestibular involvement was characterised by cervical VEMP and video
    head-impulse testing; the Turkish kindred, assessed clinically, had no balance
    problems. Whether the difference is real or a difference in how hard anyone looked is
    the open question below.
  evidence:
  - reference: PMID:37864412
    reference_title: "RIPOR2: A new gene of non-syndromic cochleovestibular dysfunction, discrepancy between human pathology and animal models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to the vestibular areflexia observed in our patients, deaf Ripor2 KO
      mouse model and our zebrafish model have normal vestibular function.
    explanation: >-
      Documents that vestibular function was formally assessed in these patients and what
      it showed, which is the argument for testing rather than assuming - and, in the same
      sentence, why the animal data cannot substitute for the test.

treatments:

- name: Cochlear Implantation
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  description: >-
    The standard intervention for congenital profound sensorineural hearing loss, and the
    only one that addresses the phenotype. The mechanism supports it in principle: the
    lesion is in the hair cell bundle, upstream of the spiral ganglion that an implant
    stimulates, and no cochlear structural malformation has been described in this
    disease.

    No outcome data exist for RIPOR2 patients specifically. Recorded without an evidence
    item rather than with a quote from the general cochlear-implant literature, which
    would not be about this disease.
  target_mechanisms:
  - target: Mechanotransduction Failure
    treatment_effect: BYPASSES
    description: >-
      Bypasses the failed transduction step by stimulating the auditory nerve directly.
  notes: >-
    Carries no evidence item deliberately. The published RIPOR2 literature reports no
    implant outcomes; the mechanistic rationale above is this entry's inference and is
    labelled as such.

    The treatment term is the generic surgical action, which is what implantation is.
    NCIT:C157820 `Cochlear Implant` names the device rather than a clinical action and
    is not reachable from NCIT:C25218, so it cannot be the `term:` of a TreatmentTerm.
    The specificity is carried by `preferred_term`, and the device itself is attached
    as a qualifier so it stays queryable rather than surviving only as free text. An
    earlier version bound NCIT:C15315 Rehabilitation and cited
    Jervell_and_Lange-Nielsen_Syndrome_1.yaml as the convention; that entry has been
    corrected to the surgical term too.

- name: Early Identification and Habilitation
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: auditory habilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  description: >-
    Because the loss is prelingual and profound, the outcome that is actually modifiable
    is spoken-language development, and the modifier is how early the loss is identified
    and habilitated. Newborn hearing screening detects it. As with implantation, there are
    no disease-specific data.
  notes: >-
    No evidence item, for the same reason as above. This is general practice for congenital
    profound deafness, not a RIPOR2 finding.

- name: Vestibular Rehabilitation
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: vestibular rehabilitation
    term:
      id: NCIT:C15302
      label: Physical Therapy
  description: >-
    Relevant only to the subgroup with vestibular involvement. Congenital bilateral
    vestibular areflexia is compensated for by vision and proprioception rather than
    recovered from, and balance training targets that compensation. As with the auditory
    interventions there are no RIPOR2-specific data; this is standard practice for
    bilateral vestibular loss.
  target_mechanisms:
  - target: Vestibular End-Organ Dysfunction
    treatment_effect: BYPASSES
    description: >-
      Does not act on the mechanism. It trains substitute sensory strategies around a
      deficit that remains.
  notes: >-
    No evidence item. Nothing in the RIPOR2 literature reports vestibular rehabilitation
    outcomes, and the delayed independent walking documented in the affected siblings is
    in the paper's full text rather than its cached abstract, so it is not quotable here.

- name: Genetic Counselling
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  description: >-
    Autosomal recessive inheritance with a 25% recurrence risk per pregnancy for carrier
    couples. Both reported families are consanguineous, which raises the prior for a
    recessive cause in a similar family and makes carrier testing of at-risk relatives
    worth offering.

differential_diagnoses:

- name: RIPOR2-related autosomal dominant hearing loss (DFNA21)
  description: >-
    The allelic dominant disorder, and the entity most likely to be confused with this one
    because it is the same gene. A heterozygous 12-nucleotide in-frame deletion causes
    adult-onset progressive hearing loss, segregating dominantly in twelve Dutch families
    and highly penetrant. It is common enough in the southeast Netherlands to be found in
    people not selected for hearing loss at all, which is the opposite epidemiological
    situation from the private recessive alleles of DFNB104.
  distinguishing_features:
  - Heterozygous in-frame deletion rather than biallelic loss of function
  - Adult onset, with a mean around the fourth decade, rather than congenital
  - Progressive rather than stable
  - A frequent founder allele in one population rather than a family-private variant
  evidence:
  - reference: PMID:32631815
    reference_title: "A RIPOR2 in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An in-frame deletion of 12 nucleotides in RIPOR2 was identified as a highly
      penetrant cause of adult-onset progressive hearing loss that segregated as an
      autosomal dominant trait in 12 families from the Netherlands.
    explanation: >-
      The dominant disorder in full - allele, onset, course and inheritance - every one of
      which differs from this entry's disease.
  - reference: PMID:32631815
    reference_title: "A RIPOR2 in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study expands the phenotypic spectrum associated with RIPOR2 defects which had
      so far only been described to underlie early-onset recessively inherited HL.
    explanation: >-
      States that the two RIPOR2 phenotypes are distinct, and that the recessive
      early-onset one came first.

- name: Usher syndrome
  description: >-
    Relevant only for the family with vestibular involvement. Congenital profound deafness
    with vestibular areflexia is the classic type 1 Usher presentation, so a RIPOR2 patient
    with that combination can be mistaken for one until the retina is examined and found
    normal. There is no retinitis pigmentosa in DFNB104.
  distinguishing_features:
  - No retinitis pigmentosa or other retinal degeneration
  - Biallelic RIPOR2 variants rather than variants in an Usher gene

discussions:

- discussion_id: mismatch_vestibular_phenotype
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Vestibular End-Organ Dysfunction
  - animal_models#Fam65b/Ripor2 knockout mouse
  prompt: >-
    Why do RIPOR2-null mice and zebrafish have normal vestibular function when human
    patients with a homozygous RIPOR2 nonsense allele have vestibular areflexia?
  rationale: >-
    This is a mismatch rather than a gap: the model evidence exists and is clear, and it
    disagrees with the patients. The mouse knockout is deaf with normal vestibular
    function, and a zebrafish model behaves the same way, while the Tunisian siblings have
    documented vestibular areflexia with abnormal cervical VEMPs and video head-impulse
    testing. The paper reporting the patients names the discrepancy in its own title.

    It matters because the mouse is the whole mechanistic account of this disease. Every
    claim in the pathophysiology section above about the taper ring, taperin, RhoC and
    Myh9 comes from an animal in which one of the two affected end organs behaves
    normally. If the vestibular epithelium can tolerate RIPOR2 loss in mouse but not in
    human, the mouse cochlear mechanism cannot be assumed to transfer without checking.

    A specific hypothesis is available: RIPOR1 and RIPOR3 are close paralogues, and
    compensation by them in the mouse vestibular epithelium could mask the phenotype.
    Nobody has tested it, and an alternative - that human vestibular hair cells depend
    more heavily on the taper compartment than mouse ones do - would have quite different
    implications for reading the rest of the mouse data.
  proposed_experiments:
  - experiment_id: ripor_paralogue_expression_vestibular
    name: Paralogue expression and compensation in mouse versus human vestibular epithelium
    description: >-
      Compare RIPOR1, RIPOR2 and RIPOR3 expression across cochlear and vestibular hair
      cells in mouse and in human inner ear tissue, then test whether removing the
      paralogues alongside Ripor2 in mouse vestibular hair cells unmasks a vestibular
      phenotype.
    would_support:
    - pathophysiology#Vestibular End-Organ Dysfunction
    supporting_outcome:
    - >-
      Paralogue expression is higher in mouse vestibular hair cells than in the human
      equivalent, and combined removal produces vestibular dysfunction in mouse - which
      would make the mismatch a compensation artefact and leave the cochlear mechanism
      transferable.
    refuting_outcome:
    - >-
      Paralogue expression is comparable across species and combined removal leaves
      vestibular function intact, which would point to a genuine species difference in how
      the taper compartment is used and would weaken the case for reading any of the mouse
      mechanism straight across.

- discussion_id: gap_allele_specific_vestibular
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Vestibular Areflexia
  - genetic#RIPOR2
  prompt: >-
    Is the vestibular phenotype specific to the nonsense allele, or was it simply not
    looked for in the first family?
  rationale: >-
    The two reported families differ on vestibular involvement and also differ on allele
    class and on how vestibular function was assessed. The Turkish kindred was reported as
    having no balance problems on clinical assessment; the Tunisian siblings were
    characterised with cervical VEMPs and video head-impulse testing, which detect
    dysfunction that a clinical balance history does not.

    So there are at least three live readings - an allele-specific effect, a
    genetic-background effect, and an ascertainment difference - and two families cannot
    distinguish them. The practical stake is whether to counsel a newly diagnosed RIPOR2
    patient about vestibular involvement, and whether to test for it.
  proposed_experiments:
  - experiment_id: vestibular_testing_all_ripor2_families
    name: Uniform vestibular testing across all reported and newly ascertained RIPOR2 families
    description: >-
      Apply the same vestibular battery - cervical and ocular VEMPs, video head-impulse
      testing, and developmental motor milestones - to affected individuals from both
      published recessive families and any newly ascertained ones, and record the result
      against allele class.
    would_support:
    - phenotypes#Vestibular Areflexia
    supporting_outcome:
    - >-
      Formal testing finds vestibular dysfunction in splice-allele patients too, making
      vestibular involvement part of the disease rather than an allele-specific feature.
    refuting_outcome:
    - >-
      Splice-allele patients test normal on the same battery, which would support a real
      allele-specific difference and make variant class relevant to counselling.

notes: >-
  Named entity check. RIPOR2 carries two hearing-loss diseases and the literature does not
  always separate them in its titles. This entry is the recessive one - DFNB104, biallelic
  loss of function, congenital, profound, stable. The dominant in-frame-deletion disorder
  (adult-onset, progressive, a Dutch founder allele) is a different disease and is curated
  only under differential diagnoses, where PMID:32631815 is cited for what it actually
  reports. The one place that paper is cited outside that section is on the gene entry,
  for its statement that the two phenotypes are distinct.

  Gene symbol. RIPOR2 was formerly FAM65B, and the founding paper and the 2016 mouse work
  both use the old symbol throughout. Snippets quote whichever symbol the source used;
  the ontology binding is to the current one.

  Model provenance. Every mechanistic claim in the pathophysiology section other than the
  protein-mislocalisation result comes from mouse, and the evidence items are typed
  MODEL_ORGANISM to keep that visible. Human inner ear tissue is not obtainable, so this
  is not a curation shortcut that better sources would fix.

references:
- reference: PMID:24958875
  title: "FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing."
- reference: PMID:27269051
  title: "Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function."
- reference: PMID:30280293
  title: "Ripor2 is involved in auditory hair cell stereociliary bundle structure and orientation."
- reference: PMID:37864412
  title: "RIPOR2: A new gene of non-syndromic cochleovestibular dysfunction, discrepancy between human pathology and animal models."
- reference: PMID:32631815
  title: "A RIPOR2 in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss."