Hypokalemic Tubulopathy and Deafness

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic KCNJ16 variants, identified by a candidate gene approach and whole-exome sequencing in eight patients.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:33811157 SUPPORT Human Clinical

"Biallelic variants in KCNJ16 were identified in patients with a novel disease phenotype comprising a variable proximal and distal tubulopathy associated with deafness."

Establishes biallelic KCNJ16 variants, and therefore recessive inheritance, as the cause.

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Discussions and Knowledge Gaps

1

Why does loss of Kir5.1 cause sensorineural hearing loss in humans but leave hearing unaffected in the Kcnj16 knockout mouse?

HUMAN MODEL MISMATCH kcnj16_murine_hearing_mismatch

Attached to

pathophysiology#Cochlear Potassium Homeostasis Failure phenotypes#Sensorineural Hearing Loss

Evidence exists on both sides and they disagree, which is the defining shape of a model-fidelity gap rather than an absence of evidence. Human patients with biallelic KCNJ16 variants have sensorineural hearing loss consistently enough for it to be part of the disease definition, yet a Kcnj16 knockout mouse hears normally. The review proposes murine compensation, but that is a hypothesis rather than a demonstrated mechanism, and it is unresolved which compensating conductance is responsible. This matters beyond bookkeeping: it means the cochlear arm of this disease currently has no validated animal model, so the Kir5.1 role in the spiral ligament rests on human genetics plus expression data rather than on reproduction in a model system.

Show evidence (1 reference)

PMID:35370765 SUPPORT Other

"This may indicate efficient compensatory mechanisms in this strain of Kir5.1 knockout mice that are not present to the same extent in humans with biallelic Kir5.1 mutations."

States the proposed explanation for the mismatch and marks it as provisional.

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Pathophysiology

5

Kir5.1 Loss of Function

KCNJ16 encodes Kir5.1. Unlike most channel subunits, Kir5.1 is an obligate partner rather than a channel in its own right, so its variants act by crippling the heteromers it forms. Coexpressing mutant KCNJ16 with either KCNJ15 or KCNJ10 in Xenopus oocytes significantly reduces currents, and disease-associated variants scattered across different functional domains all strongly affect heteromers with Kir4.1 or Kir4.2. This is why one gene produces a tubulopathy spanning two nephron segments that use different partner subunits.

KCNJ16 hgnc:6262

inward rectifier potassium channel activity GO:0005242 ↓ DECREASED

Downstream

Failure of Basolateral Potassium Recycling

Show evidence (2 references)

PMID:33811157 SUPPORT In Vitro

"Coexpression of mutant KCNJ16 together with KCNJ15 or KCNJ10 in Xenopus oocytes significantly reduced currents."

Electrophysiological demonstration that the patient variants reduce current through both heteromeric partnerships, establishing loss of function.

PMID:35370765 SUPPORT In Vitro

"Unlike Kir4.1, Kir5.1 does not appear to form homomeric channels, but forms heteromeric channels primarily with Kir4.1 and Kir4.2."

Establishes that Kir5.1 acts only as a heteromeric partner, which is why its loss is expressed through the channels it would otherwise complete.

Failure of Basolateral Potassium Recycling

Kir4.1/Kir5.1 and Kir4.2/Kir5.1 heteromers make the major basolateral potassium conductance of the distal and proximal tubule respectively. That conductance recycles potassium across the basolateral membrane so the Na+/K+-ATPase can keep running, and it is highly pH-sensitive, which is how the channel couples acid-base status to sodium handling. Losing it therefore disables the driving force for transepithelial transport in both segments at once.

kidney distal convoluted tubule epithelial cell CL:1000849 epithelial cell of proximal tubule CL:0002306

potassium ion transmembrane transport GO:0071805 ↓ DECREASED

distal convoluted tubule UBERON:0001292 proximal tubule UBERON:0004134

Downstream

Disturbed Proximal Bicarbonate Handling

Impaired Distal Salt Reabsorption

Cochlear Potassium Homeostasis Failure

Show evidence (2 references)

PMID:33811157 SUPPORT Human Clinical

"We identified mutations in the KCNJ16 gene encoding KCNJ16, which along with KCNJ15 and KCNJ10, constitutes the major basolateral potassium channel of the proximal and distal tubules, respectively."

Places the affected channel at the basolateral membrane of both nephron segments, which is the anatomical basis of the mixed tubulopathy.

PMID:33811157 SUPPORT Human Clinical

"Basolateral potassium channels in tubular cells not only mediate potassium recycling for proper Na+,K+-ATPase function but are also involved in potassium and pH sensing."

States the dual role of these channels in potassium recycling and pH sensing, both of which are lost here.

Disturbed Proximal Bicarbonate Handling

In the proximal tubule, where Kir5.1 partners Kir4.2, loss of the basolateral conductance disturbs bicarbonate handling. This is the arm that produces the acid-base abnormality, and it is the axis on which this disease separates most sharply from EAST/SeSAME: KCNJ16 patients show acidosis of variable severity rather than the hypokalemic metabolic alkalosis of Kir4.1 disease.

bicarbonate transport GO:0015701 ↓ DECREASED

proximal tubule UBERON:0004134

Animal models

Kir5.1-null mouse (Kcnj16 knockout) Mouse partially recapitulates The knockout reproduces the hypokalemia and the acidotic direction of the acid-base disturbance that distinguishes this disease from Kir4.1 disease.

Downstream

Metabolic Acidosis

Show evidence (3 references)

PMID:33811157 SUPPORT Human Clinical

"Variants affect the function of heteromeric potassium channels, disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption."

Directly attributes disturbed proximal bicarbonate handling to the heteromeric channel defect.

PMID:35370765 SUPPORT Human Clinical

"In an acid load test, patients with mutations in Kir5.1 show preserved ability to acidify urine, but increased urinary ammonium excretion is absent."

Locates the acid-base defect specifically: proton secretion is intact and the failure is in ammoniagenesis, a proximal tubular function, which is consistent with this node rather than a distal one.

PMID:35370765 SUPPORT Human Clinical

"although sensorineural hearing loss and hypokalemia are replicated, there is no alkalosis, but rather acidosis of variable severity; in contrast to EAST/SeSAME syndrome, the CNS is unaffected"

States the acid-base direction in Kir5.1 disease and its contrast with EAST/SeSAME, supporting acidosis rather than alkalosis as the consequence.

Impaired Distal Salt Reabsorption

In the distal convoluted tubule, where Kir5.1 partners Kir4.1, loss of the basolateral potassium conductance impairs sodium reabsorption, producing renal salt wasting and urinary potassium loss with consequent hypokalemia.

sodium ion transport GO:0006814 ↓ DECREASED

distal convoluted tubule UBERON:0001292

Downstream

Renal Salt Wasting

Hypokalemia

Show evidence (1 reference)

PMID:33811157 SUPPORT Human Clinical

"disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption"

Attributes impaired distal salt reabsorption to the same channel defect.

Cochlear Potassium Homeostasis Failure

Kir4.1 and Kir5.1 are both expressed in the inner ear, but not in the same compartment, and the distinction matters here. Kir4.1 sits in the intermediate cells of the stria vascularis and is what generates the endocochlear potential; Kir5.1 is expressed mainly in the root and spindle cells of the spiral ligament, where it is proposed to participate in potassium cycling and may contribute to establishing that potential. The Kir5.1 role is therefore proposed rather than established, and this node is worded to reflect that: loss of the Kir5.1-containing conductance in the spiral ligament is the best-supported route to the sensorineural deafness, which is the one major extrarenal feature of this disease and the feature it shares with EAST/SeSAME. An earlier revision of this entry bound the stria vascularis here. That was wrong in exactly the way this entry's notes warn about -- it assigned Kir5.1 the compartment the cited review assigns to Kir4.1.

potassium ion transmembrane transport GO:0071805 ↓ DECREASED

root and spindle cells of the spiral ligament UBERON:0006725

Downstream

Sensorineural Hearing Loss

Show evidence (5 references)

PMID:35370765 SUPPORT Model Organism

"In addition to the tissues shown in Figure 2, Kir4.1 and Kir5.1 are also expressed in the inner ear."

Establishes inner-ear expression of both subunits. Graded MODEL_ORGANISM because the underlying inner-ear expression data the review cites are rodent immunohistochemistry, not human tissue.

PMID:35370765 SUPPORT Model Organism

"Kir5.1 is expressed mainly in the root cells and spindle cells of the spiral ligament"

Localises Kir5.1 to the spiral ligament rather than the stria vascularis, which is the compartment this node binds.

PMID:35370765 SUPPORT Model Organism

"Kir4.1 is expressed primarily in intermediate cells of the stria vascularis and is responsible for endolymph composition and endocochlear potential"

Assigns the stria vascularis and the endocochlear potential to Kir4.1, the partner subunit, which is why this node does not claim them for Kir5.1.

+ 2 more references

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

4

Ear 1

Sensorineural Hearing Loss VERY_FREQUENT Sensorineural hearing impairment HP:0000407

Onset: CHILDHOOD

Show evidence (3 references)

PMID:33811157 SUPPORT Human Clinical

"variable proximal and distal tubulopathy associated with deafness"

Records deafness as a constant association of the tubulopathy.

PMID:35370765 SUPPORT Human Clinical

"although sensorineural hearing loss and hypokalemia are replicated"

Confirms sensorineural hearing loss as a feature shared with EAST/SeSAME.

PMID:35370765 SUPPORT Human Clinical

"The hearing loss affected mainly the higher frequencies, similar to the hearing loss in EAST/SeSAME syndrome."

Gives the audiometric pattern and records that it does not discriminate this disease from EAST/SeSAME.

Genitourinary 1

Renal Salt Wasting VERY_FREQUENT HP:0000127

Show evidence (1 reference)

PMID:33811157 SUPPORT Human Clinical

"a hypokalemic tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness"

Records renal salt wasting among the defining features.

Metabolism 2

Hypokalemia OBLIGATE HP:0002900

Show evidence (1 reference)

PMID:33811157 SUPPORT Human Clinical

"eight patients with a novel disease phenotype comprising a hypokalemic tubulopathy with renal salt wasting"

Records hypokalemia as a defining feature of the eight-patient founding cohort.

Metabolic Acidosis FREQUENT HP:0001942

Severity: VARIABLE

Show evidence (2 references)

PMID:35370765 SUPPORT Human Clinical

"there is no alkalosis, but rather acidosis of variable severity"

States acidosis, not alkalosis, as the acid-base phenotype of Kir5.1 disease, and notes its variable severity.

PMID:35370765 SUPPORT INDIRECT Human Clinical

"one patient presented with alkalosis"

A reported exception in the opposite direction, which is why this phenotype is FREQUENT rather than obligate.

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Genetic Associations

1

KCNJ16 loss of function

Gene: KCNJ16 hgnc:6262 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:33811157 SUPPORT Human Clinical

"A candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients"

Describes how the causative gene was identified in the founding cohort.

PMID:35370765 SUPPORT Human Clinical

"as all Kir5.1 mutations investigated, scattered over different functional domains of Kir5.1, strongly affected heteromers with either Kir4.1 or Kir4.2"

Establishes that the causative variants act uniformly through impaired heteromer function regardless of which domain they affect.

PMID:35370765 SUPPORT In Vitro

"functional consequences were generally more severe when Kir5.1 mutants were coexpressed with Kir4.2"

Shows the defect is more severe with the proximal partner Kir4.2, helping explain the prominence of the proximal tubular arm.

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Medical Actions

1

Potassium and Alkali Replacement

Action: potassium and alkali supplementation Ontology label: Nutritional Support NCIT:C15433

Agent: potassium chloride CHEBI:32588 sodium bicarbonate CHEBI:32139

Platform: Small molecule

Supportive electrolyte management: potassium supplementation for the urinary losses, with alkali as required for the acidosis. Symptomatic rather than mechanism-directed — there is no therapy that restores the channel — so this entry deliberately claims no target_mechanisms link. The mouse data hinting at thiazide responsiveness are a model finding, not human evidence, and are recorded under animal_models rather than proposed as treatment here.

Target Phenotypes: Hypokalemia HP:0002900 Metabolic acidosis HP:0001942

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Diagnosis

1

Molecular confirmation by KCNJ16 sequencing

The clinical picture -- hypokalemia with salt wasting, a disturbed acid-base state and sensorineural deafness -- overlaps EAST/SeSAME syndrome closely enough that genotype is what separates them, so diagnosis rests on identifying biallelic KCNJ16 variants. The acid-base direction is the useful clinical discriminator to prompt that test: acidosis points to KCNJ16 where alkalosis points to KCNJ10.

Show evidence (3 references)

PMID:33811157 SUPPORT Human Clinical

"A candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients"

Documents sequencing as the route by which the diagnosis was established.

PMID:35370765 SUPPORT Human Clinical

"there is no alkalosis, but rather acidosis of variable severity; in contrast to EAST/SeSAME syndrome, the CNS is unaffected"

Gives the acid-base and CNS features that clinically discriminate this disease from EAST/SeSAME before genotyping.

PMID:35370765 SUPPORT Human Clinical

"In an acid load test, patients with mutations in Kir5.1 show preserved ability to acidify urine, but increased urinary ammonium excretion is absent."

The acid load test separates this disease from a distal renal tubular acidosis: urinary acidification is preserved, so the defect lies in ammoniagenesis rather than in distal proton secretion.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Eight patients in the 2021 report that delineated the entity. The disease was only separated from EAST/SeSAME at that point, so the count reflects how recently it was defined as much as its true rarity, and cases may previously have been recorded under other salt-losing tubulopathies.

Show evidence (1 reference)

PMID:33811157 SUPPORT Human Clinical

"whole-exome sequencing determined the underlying genetic defect in eight patients with a novel disease phenotype"

Gives the size of the founding cohort, the only case count reported for this recently delineated entity.

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Animal Models

2

Kir5.1-null mouse (Kcnj16 knockout)

Targeted disruption of Kcnj16 produces hypokalemic, hyperchloremic metabolic acidosis with hypercalciuria, and exaggerated short-term responses to hydrochlorothiazide indicating excessive distal convoluted tubule sodium absorption. Chronic hydrochlorothiazide normalised urinary sodium and calcium and abolished the acidosis. Electrophysiology of the DCT basolateral membrane showed increased potassium conductance despite the absence of Kir5.1, because the remaining homomeric Kir4.1 channels lose their pH sensitivity — a compensation, not a preserved normal state. Important context: this study was published in 2011, a decade before the human KCNJ16 disease was delineated in 2021. Its authors could only compare their mice against EAST/SeSAME, and on that comparison described the renal phenotype as the opposite of it. Read against the human entity now known, the acidotic mouse anticipates rather than contradicts the human phenotype.

Species

Mouse

Genotype

Kcnj16 -/-

Publication

PMID:21633011

Pathograph links

Disturbed Proximal Bicarbonate Handling partially recapitulates fidelity: moderate observes: organism The knockout reproduces the hypokalemia and the acidotic direction of the acid-base disturbance that distinguishes this disease from Kir4.1 disease.

Limitations: The paper predates the human disease and frames its findings against EAST/SeSAME rather than against KCNJ16 patients, so the correspondence is one drawn here rather than claimed by the authors. The murine acidosis is specifically hyperchloremic with hypercalciuria, which is a more precisely specified picture than the "variable severity" acidosis reported in patients, so the match should not be over-read. Deafness is not addressed by this study.

Divergences from the human mechanism

species mismatch qualifying

In the knockout mouse, remaining homomeric Kir4.1 channels lose pH sensitivity and basolateral potassium conductance actually rises. Whether the same compensation occurs in human patients is not established, so the residual-conductance state of the murine tubule may not represent the human one.

temporal scope qualifying

The characterisation is of an adult constitutive knockout under acute and chronic thiazide challenge, not of the developmental course or natural history of the human disease.

Show evidence (2 references)

PMID:21633011 SUPPORT Model Organism

"The Kir5.1(-/-) mice displayed hypokalemic, hyperchloremic metabolic acidosis with hypercalciuria."

Reports the knockout's hypokalemia and metabolic acidosis, the two features corresponding to the human KCNJ16 phenotype.

+ 1 more reference

Kir5.1-null mouse, auditory phenotype (Lv et al.)

A separate Kcnj16 knockout line in which hearing function was unaffected. Recorded as its own model entry rather than folded into the renal knockout above, because it makes the opposite kind of claim: a negative result on the deafness arm. The review that reports it proposes compensatory mechanisms present in the mouse strain but not to the same extent in humans with biallelic Kir5.1 mutations. The primary source is Lv et al. 2021; it is cited here through the review, which is the version available in this entry's reference cache.

Species

Mouse

Genotype

Kcnj16 -/-

Publication

PMID:35370765

{ }

Source YAML

click to show

name: Hypokalemic Tubulopathy and Deafness
creation_date: "2026-09-04T03:55:00Z"
category: Genetic
description: >-
  Hypokalemic tubulopathy and deafness is an autosomal recessive channelopathy
  caused by biallelic variants in KCNJ16, which encodes the inwardly rectifying
  potassium channel subunit Kir5.1. Kir5.1 does not form functional channels on
  its own; it works as an obligate partner, heteromerising with Kir4.1 (KCNJ10)
  in the distal nephron and with Kir4.2 (KCNJ15) in the proximal tubule to make
  the major basolateral potassium conductance of each segment. That conductance
  recycles potassium to sustain the basolateral Na+/K+-ATPase, and it is
  strongly pH-sensitive, so Kir5.1 also acts as a pH sensor coupling acid-base
  status to salt transport. Loss of Kir5.1 therefore produces a tubulopathy with
  both proximal and distal components — disturbed bicarbonate handling and
  impaired distal salt reabsorption — presenting with hypokalemia, renal salt
  wasting and a disturbed acid-base picture, together with sensorineural
  deafness from the equivalent channel in the inner ear. Unlike its Kir4.1
  counterpart, the central nervous system is spared.
disease_term:
  preferred_term: hypokalemic tubulopathy and deafness
  term:
    id: MONDO:0859167
    label: hypokalemic tubulopathy and deafness
synonyms:
- KCNJ16-related tubulopathy
- Kir5.1 channelopathy
parents:
- Renal Tubulopathy
notes: >-
  Named Entity Confusion guardrail, and the main risk on this entry. EAST/SeSAME
  syndrome (already curated as EAST_Syndrome) is caused by KCNJ10/Kir4.1, the
  obligate *partner* subunit of the very channel disrupted here. The two entries
  will therefore look alike, and the literature frequently discusses them
  together. They are different diseases, and the review cited here states the
  differences directly:

  - Shared: sensorineural hearing loss and hypokalemia.
  - Different: EAST/SeSAME produces hypokalemic metabolic *alkalosis*, whereas
    KCNJ16 loss produces *acidosis* of variable severity.
  - Different: the CNS is unaffected in KCNJ16 disease — no epilepsy, ataxia or
    intellectual disability, which are cardinal in EAST/SeSAME.

  Evidence must come from KCNJ16-specific reports and must not be borrowed from
  the KCNJ10 literature. The existing EAST_Syndrome entry mentions KCNJ16
  contextually; that mention is correct and is not an entry for this disease.

  A second, subtler trap concerns the mouse model. The Kcnj16-null mouse was
  published in 2011, a decade before this human entity was delineated in 2021,
  so its authors compared their acidotic mice against EAST/SeSAME and described
  the phenotype as the opposite of it. Read today, that mouse anticipates the
  human KCNJ16 phenotype rather than contradicting it. The animal_models block
  is worded to report what the paper measured without attributing to it a
  comparison it could not have made.
references:
- reference: PMID:33811157
  title: "Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness."
- reference: PMID:35370765
  title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
- reference: PMID:21633011
  title: "Renal phenotype in mice lacking the Kir5.1 (Kcnj16) K+ channel subunit contrasts with that observed in SeSAME/EAST syndrome."
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic KCNJ16 variants, identified by a candidate gene approach and
    whole-exome sequencing in eight patients.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33811157
    reference_title: "Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic variants in KCNJ16 were identified in patients with a novel disease phenotype comprising a variable proximal and distal tubulopathy associated with deafness."
    explanation: >-
      Establishes biallelic KCNJ16 variants, and therefore recessive
      inheritance, as the cause.
pathophysiology:
- name: Kir5.1 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    KCNJ16 encodes Kir5.1. Unlike most channel subunits, Kir5.1 is an obligate
    partner rather than a channel in its own right, so its variants act by
    crippling the heteromers it forms. Coexpressing mutant KCNJ16 with either
    KCNJ15 or KCNJ10 in Xenopus oocytes significantly reduces currents, and
    disease-associated variants scattered across different functional domains all
    strongly affect heteromers with Kir4.1 or Kir4.2. This is why one gene
    produces a tubulopathy spanning two nephron segments that use different
    partner subunits.
  gene:
    preferred_term: KCNJ16
    term:
      id: hgnc:6262
      label: KCNJ16
  molecular_functions:
  - preferred_term: inward rectifier potassium channel activity
    term:
      id: GO:0005242
      label: inward rectifier potassium channel activity
    modifier: DECREASED
  evidence:
  - reference: PMID:33811157
    reference_title: "Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Coexpression of mutant KCNJ16 together with KCNJ15 or KCNJ10 in Xenopus oocytes significantly reduced currents."
    explanation: >-
      Electrophysiological demonstration that the patient variants reduce current
      through both heteromeric partnerships, establishing loss of function.
  - reference: PMID:35370765
    reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Unlike Kir4.1, Kir5.1 does not appear to form homomeric channels, but forms heteromeric channels primarily with Kir4.1 and Kir4.2."
    explanation: >-
      Establishes that Kir5.1 acts only as a heteromeric partner, which is why
      its loss is expressed through the channels it would otherwise complete.
  downstream:
  - target: Failure of Basolateral Potassium Recycling
    causal_link_type: DIRECT
- name: Failure of Basolateral Potassium Recycling
  biological_scale: CELLULAR
  description: >-
    Kir4.1/Kir5.1 and Kir4.2/Kir5.1 heteromers make the major basolateral
    potassium conductance of the distal and proximal tubule respectively. That
    conductance recycles potassium across the basolateral membrane so the
    Na+/K+-ATPase can keep running, and it is highly pH-sensitive, which is how
    the channel couples acid-base status to sodium handling. Losing it therefore
    disables the driving force for transepithelial transport in both segments at
    once.
  cell_types:
  - preferred_term: kidney distal convoluted tubule epithelial cell
    term:
      id: CL:1000849
      label: kidney distal convoluted tubule epithelial cell
  - preferred_term: epithelial cell of proximal tubule
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  locations:
  - preferred_term: distal convoluted tubule
    term:
      id: UBERON:0001292
      label: distal convoluted tubule
  - preferred_term: proximal tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  biological_processes:
  - preferred_term: potassium ion transmembrane transport
    term:
      id: GO:0071805
      label: potassium ion transmembrane transport
    modifier: DECREASED
  evidence:
  - reference: PMID:33811157
    reference_title: "Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified mutations in the KCNJ16 gene encoding KCNJ16, which along with KCNJ15 and KCNJ10, constitutes the major basolateral potassium channel of the proximal and distal tubules, respectively."
    explanation: >-
      Places the affected channel at the basolateral membrane of both nephron
      segments, which is the anatomical basis of the mixed tubulopathy.
  - reference: PMID:33811157
    reference_title: "Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Basolateral potassium channels in tubular cells not only mediate potassium recycling for proper Na+,K+-ATPase function but are also involved in potassium and pH sensing."
    explanation: >-
      States the dual role of these channels in potassium recycling and pH
      sensing, both of which are lost here.
  downstream:
  - target: Disturbed Proximal Bicarbonate Handling
    causal_link_type: DIRECT
  - target: Impaired Distal Salt Reabsorption
    causal_link_type: DIRECT
  - target: Cochlear Potassium Homeostasis Failure
    causal_link_type: DIRECT
- name: Disturbed Proximal Bicarbonate Handling
  biological_scale: TISSUE
  description: >-
    In the proximal tubule, where Kir5.1 partners Kir4.2, loss of the basolateral
    conductance disturbs bicarbonate handling. This is the arm that produces the
    acid-base abnormality, and it is the axis on which this disease separates most
    sharply from EAST/SeSAME: KCNJ16 patients show acidosis of variable severity
    rather than the hypokalemic metabolic alkalosis of Kir4.1 disease.
  locations:
  - preferred_term: proximal tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  biological_processes:
  - preferred_term: bicarbonate transport
    term:
      id: GO:0015701
      label: bicarbonate transport
    modifier: DECREASED
  evidence:
  - reference: PMID:33811157
    reference_title: "Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants affect the function of heteromeric potassium channels, disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption."
    explanation: >-
      Directly attributes disturbed proximal bicarbonate handling to the
      heteromeric channel defect.
  - reference: PMID:35370765
    reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In an acid load test, patients with mutations in Kir5.1 show preserved ability to acidify urine, but increased urinary ammonium excretion is absent."
    explanation: >-
      Locates the acid-base defect specifically: proton secretion is intact and
      the failure is in ammoniagenesis, a proximal tubular function, which is
      consistent with this node rather than a distal one.
  - reference: PMID:35370765
    reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "although sensorineural hearing loss and hypokalemia are replicated, there is no alkalosis, but rather acidosis of variable severity; in contrast to EAST/SeSAME syndrome, the CNS is unaffected"
    explanation: >-
      States the acid-base direction in Kir5.1 disease and its contrast with
      EAST/SeSAME, supporting acidosis rather than alkalosis as the consequence.
  downstream:
  - target: Metabolic Acidosis
    causal_link_type: DIRECT
- name: Impaired Distal Salt Reabsorption
  biological_scale: TISSUE
  description: >-
    In the distal convoluted tubule, where Kir5.1 partners Kir4.1, loss of the
    basolateral potassium conductance impairs sodium reabsorption, producing
    renal salt wasting and urinary potassium loss with consequent hypokalemia.
  locations:
  - preferred_term: distal convoluted tubule
    term:
      id: UBERON:0001292
      label: distal convoluted tubule
  biological_processes:
  - preferred_term: sodium ion transport
    term:
      id: GO:0006814
      label: sodium ion transport
    modifier: DECREASED
  evidence:
  - reference: PMID:33811157
    reference_title: "Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption"
    explanation: >-
      Attributes impaired distal salt reabsorption to the same channel defect.
  downstream:
  - target: Renal Salt Wasting
    causal_link_type: DIRECT
  - target: Hypokalemia
    causal_link_type: DIRECT
- name: Cochlear Potassium Homeostasis Failure
  biological_scale: TISSUE
  description: >-
    Kir4.1 and Kir5.1 are both expressed in the inner ear, but not in the same
    compartment, and the distinction matters here. Kir4.1 sits in the
    intermediate cells of the stria vascularis and is what generates the
    endocochlear potential; Kir5.1 is expressed mainly in the root and spindle
    cells of the spiral ligament, where it is proposed to participate in
    potassium cycling and may contribute to establishing that potential. The
    Kir5.1 role is therefore proposed rather than established, and this node is
    worded to reflect that: loss of the Kir5.1-containing conductance in the
    spiral ligament is the best-supported route to the sensorineural deafness,
    which is the one major extrarenal feature of this disease and the feature it
    shares with EAST/SeSAME.

    An earlier revision of this entry bound the stria vascularis here. That was
    wrong in exactly the way this entry's notes warn about -- it assigned Kir5.1
    the compartment the cited review assigns to Kir4.1.
  locations:
  - preferred_term: root and spindle cells of the spiral ligament
    term:
      id: UBERON:0006725
      label: spiral ligament
  biological_processes:
  - preferred_term: potassium ion transmembrane transport
    term:
      id: GO:0071805
      label: potassium ion transmembrane transport
    modifier: DECREASED
  evidence:
  - reference: PMID:35370765
    reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In addition to the tissues shown in Figure 2, Kir4.1 and Kir5.1 are also expressed in the inner ear."
    explanation: >-
      Establishes inner-ear expression of both subunits. Graded MODEL_ORGANISM
      because the underlying inner-ear expression data the review cites are
      rodent immunohistochemistry, not human tissue.
  - reference: PMID:35370765
    reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Kir5.1 is expressed mainly in the root cells and spindle cells of the spiral ligament"
    explanation: >-
      Localises Kir5.1 to the spiral ligament rather than the stria vascularis,
      which is the compartment this node binds.
  - reference: PMID:35370765
    reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Kir4.1 is expressed primarily in intermediate cells of the stria vascularis and is responsible for endolymph composition and endocochlear potential"
    explanation: >-
      Assigns the stria vascularis and the endocochlear potential to Kir4.1, the
      partner subunit, which is why this node does not claim them for Kir5.1.
  - reference: PMID:35370765
    reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "proposed that Kir5.1 is involved in K+ cycling and may play a role in the establishment of the endocochlear potential"
    explanation: >-
      States the Kir5.1 cochlear role as proposed rather than established, which
      is the hedging this node's description adopts.
    directness: INDIRECT
  - reference: PMID:33811157
    reference_title: "Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a novel disease phenotype comprising a hypokalemic tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness"
    explanation: >-
      Records sensorineural deafness as part of the defining phenotype produced
      by KCNJ16 loss.
  downstream:
  - target: Sensorineural Hearing Loss
    causal_link_type: DIRECT
phenotypes:
- category: Phenotypic
  name: Hypokalemia
  description: >-
    Low serum potassium from urinary potassium loss, one of the two features
    shared with EAST/SeSAME syndrome.
  phenotype_term:
    preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  frequency: OBLIGATE
  evidence:
  - reference: PMID:33811157
    reference_title: "Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "eight patients with a novel disease phenotype comprising a hypokalemic tubulopathy with renal salt wasting"
    explanation: >-
      Records hypokalemia as a defining feature of the eight-patient founding
      cohort.
- category: Phenotypic
  name: Renal Salt Wasting
  description: >-
    Urinary sodium loss from impaired distal tubular reabsorption.
  phenotype_term:
    preferred_term: Renal salt wasting
    term:
      id: HP:0000127
      label: Renal salt wasting
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33811157
    reference_title: "Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a hypokalemic tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness"
    explanation: >-
      Records renal salt wasting among the defining features.
- category: Phenotypic
  name: Metabolic Acidosis
  description: >-
    Acidosis of variable severity, the discriminating feature against
    EAST/SeSAME syndrome, which instead produces metabolic alkalosis. Severity
    varies between patients.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
    severity: VARIABLE
  frequency: FREQUENT
  evidence:
  - reference: PMID:35370765
    reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there is no alkalosis, but rather acidosis of variable severity"
    explanation: >-
      States acidosis, not alkalosis, as the acid-base phenotype of Kir5.1
      disease, and notes its variable severity.
  - reference: PMID:35370765
    reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one patient presented with alkalosis"
    explanation: >-
      A reported exception in the opposite direction, which is why this
      phenotype is FREQUENT rather than obligate.
    directness: INDIRECT
- category: Phenotypic
  name: Sensorineural Hearing Loss
  description: >-
    Sensorineural deafness from failure of cochlear potassium homeostasis; the
    principal extrarenal manifestation. It appears in childhood or adolescence
    rather than at birth, and affects mainly the higher frequencies -- the same
    audiometric pattern as EAST/SeSAME syndrome, so the audiogram does not
    discriminate the two diseases even though the acid-base picture does.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
    onset:
      onset_category: CHILDHOOD
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33811157
    reference_title: "Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "variable proximal and distal tubulopathy associated with deafness"
    explanation: >-
      Records deafness as a constant association of the tubulopathy.
  - reference: PMID:35370765
    reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "although sensorineural hearing loss and hypokalemia are replicated"
    explanation: >-
      Confirms sensorineural hearing loss as a feature shared with EAST/SeSAME.
  - reference: PMID:35370765
    reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The hearing loss affected mainly the higher frequencies, similar to the hearing loss in EAST/SeSAME syndrome."
    explanation: >-
      Gives the audiometric pattern and records that it does not discriminate
      this disease from EAST/SeSAME.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Eight patients in the 2021 report that delineated the entity. The disease was
    only separated from EAST/SeSAME at that point, so the count reflects how
    recently it was defined as much as its true rarity, and cases may previously
    have been recorded under other salt-losing tubulopathies.
  evidence:
  - reference: PMID:33811157
    reference_title: "Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "whole-exome sequencing determined the underlying genetic defect in eight patients with a novel disease phenotype"
    explanation: >-
      Gives the size of the founding cohort, the only case count reported for
      this recently delineated entity.
diagnosis:
- name: Molecular confirmation by KCNJ16 sequencing
  description: >-
    The clinical picture -- hypokalemia with salt wasting, a disturbed acid-base
    state and sensorineural deafness -- overlaps EAST/SeSAME syndrome closely
    enough that genotype is what separates them, so diagnosis rests on
    identifying biallelic KCNJ16 variants. The acid-base direction is the useful
    clinical discriminator to prompt that test: acidosis points to KCNJ16 where
    alkalosis points to KCNJ10.
  evidence:
  - reference: PMID:33811157
    reference_title: "Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients"
    explanation: >-
      Documents sequencing as the route by which the diagnosis was established.
  - reference: PMID:35370765
    reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there is no alkalosis, but rather acidosis of variable severity; in contrast to EAST/SeSAME syndrome, the CNS is unaffected"
    explanation: >-
      Gives the acid-base and CNS features that clinically discriminate this
      disease from EAST/SeSAME before genotyping.
  - reference: PMID:35370765
    reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In an acid load test, patients with mutations in Kir5.1 show preserved ability to acidify urine, but increased urinary ammonium excretion is absent."
    explanation: >-
      The acid load test separates this disease from a distal renal tubular
      acidosis: urinary acidification is preserved, so the defect lies in
      ammoniagenesis rather than in distal proton secretion.

genetic:
- name: KCNJ16 loss of function
  gene_term:
    preferred_term: KCNJ16
    term:
      id: hgnc:6262
      label: KCNJ16
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic KCNJ16 variants, first delineated in 2021 in eight patients by a
    candidate gene approach plus whole-exome sequencing. Disease-associated
    variants are scattered across different functional domains of Kir5.1 and all
    strongly impair heteromers with Kir4.1 or Kir4.2, which is consistent with
    Kir5.1 acting only as an obligate partner subunit. The absence of CNS
    involvement in patients is itself informative: it argues against Kir5.1
    forming functionally important channels with other partners in the brain.
    Functional consequences were generally more severe when Kir5.1 mutants were
    coexpressed with Kir4.2 than with Kir4.1, consistent with the prominence of
    the proximal tubular arm, since Kir4.2 is the proximal partner.
  evidence:
  - reference: PMID:33811157
    reference_title: "Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients"
    explanation: >-
      Describes how the causative gene was identified in the founding cohort.
  - reference: PMID:35370765
    reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as all Kir5.1 mutations investigated, scattered over different functional domains of Kir5.1, strongly affected heteromers with either Kir4.1 or Kir4.2"
    explanation: >-
      Establishes that the causative variants act uniformly through impaired
      heteromer function regardless of which domain they affect.
  - reference: PMID:35370765
    reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "functional consequences were generally more severe when Kir5.1 mutants were coexpressed with Kir4.2"
    explanation: >-
      Shows the defect is more severe with the proximal partner Kir4.2, helping
      explain the prominence of the proximal tubular arm.
animal_models:
- name: Kir5.1-null mouse (Kcnj16 knockout)
  species: Mouse
  genotype: Kcnj16 -/-
  publication: PMID:21633011
  description: >-
    Targeted disruption of Kcnj16 produces hypokalemic, hyperchloremic metabolic
    acidosis with hypercalciuria, and exaggerated short-term responses to
    hydrochlorothiazide indicating excessive distal convoluted tubule sodium
    absorption. Chronic hydrochlorothiazide normalised urinary sodium and calcium
    and abolished the acidosis. Electrophysiology of the DCT basolateral membrane
    showed increased potassium conductance despite the absence of Kir5.1, because
    the remaining homomeric Kir4.1 channels lose their pH sensitivity — a
    compensation, not a preserved normal state.

    Important context: this study was published in 2011, a decade before the
    human KCNJ16 disease was delineated in 2021. Its authors could only compare
    their mice against EAST/SeSAME, and on that comparison described the renal
    phenotype as the opposite of it. Read against the human entity now known,
    the acidotic mouse anticipates rather than contradicts the human phenotype.
  modeled_mechanisms:
  - target: Disturbed Proximal Bicarbonate Handling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The knockout reproduces the hypokalemia and the acidotic direction of the
      acid-base disturbance that distinguishes this disease from Kir4.1 disease.
    limitations: >-
      The paper predates the human disease and frames its findings against
      EAST/SeSAME rather than against KCNJ16 patients, so the correspondence is
      one drawn here rather than claimed by the authors. The murine acidosis is
      specifically hyperchloremic with hypercalciuria, which is a more precisely
      specified picture than the "variable severity" acidosis reported in
      patients, so the match should not be over-read. Deafness is not addressed
      by this study.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        In the knockout mouse, remaining homomeric Kir4.1 channels lose pH
        sensitivity and basolateral potassium conductance actually rises. Whether
        the same compensation occurs in human patients is not established, so the
        residual-conductance state of the murine tubule may not represent the
        human one.
    - divergence_type: TEMPORAL_SCOPE
      materiality: QUALIFYING
      description: >-
        The characterisation is of an adult constitutive knockout under acute and
        chronic thiazide challenge, not of the developmental course or natural
        history of the human disease.
    evidence:
    - reference: PMID:21633011
      reference_title: "Renal phenotype in mice lacking the Kir5.1 (Kcnj16) K+ channel subunit contrasts with that observed in SeSAME/EAST syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The Kir5.1(-/-) mice displayed hypokalemic, hyperchloremic metabolic acidosis with hypercalciuria."
      explanation: >-
        Reports the knockout's hypokalemia and metabolic acidosis, the two
        features corresponding to the human KCNJ16 phenotype.
    - reference: PMID:21633011
      reference_title: "Renal phenotype in mice lacking the Kir5.1 (Kcnj16) K+ channel subunit contrasts with that observed in SeSAME/EAST syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "there is an increased K(+) conductance caused by the decreased pH sensitivity of the remaining homomeric Kir4.1 channels"
      explanation: >-
        Documents the compensatory change in residual Kir4.1 channels recorded as
        a species divergence, since it is unestablished in human patients.
- name: Kir5.1-null mouse, auditory phenotype (Lv et al.)
  species: Mouse
  genotype: Kcnj16 -/-
  publication: PMID:35370765
  description: >-
    A separate Kcnj16 knockout line in which hearing function was unaffected.
    Recorded as its own model entry rather than folded into the renal knockout
    above, because it makes the opposite kind of claim: a negative result on the
    deafness arm. The review that reports it proposes compensatory mechanisms
    present in the mouse strain but not to the same extent in humans with
    biallelic Kir5.1 mutations.

    The primary source is Lv et al. 2021; it is cited here through the review,
    which is the version available in this entry's reference cache.
  modeled_mechanisms:
  - target: Sensorineural Hearing Loss
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Loss of Kir5.1 in the mouse does not reproduce the sensorineural hearing
      loss that is a defining feature of the human disease.
    limitations: >-
      This is a negative result whose interpretation is unsettled. It does not
      show that Kir5.1 is dispensable for human hearing; the review's reading is
      that murine compensation masks the deficit. Because the model fails on
      precisely the phenotype it would be used to study, it cannot be used to
      investigate the cochlear arm of this disease, and a reader should not infer
      from the renal knockout above that the auditory question is merely
      unstudied.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: INVALIDATING
      description: >-
        The review attributes the discrepancy to compensatory mechanisms present
        in this mouse strain that are not present to the same extent in humans
        carrying biallelic Kir5.1 mutations, so the murine auditory system does
        not stand in for the human one here.
    evidence:
    - reference: PMID:35370765
      reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Surprisingly, hearing function has been shown to be unaffected in a Kir5.1 knockout mouse model (Lv et al., 2021)."
      explanation: >-
        Reports the negative auditory result that this link records.
    - reference: PMID:35370765
      reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "This may indicate efficient compensatory mechanisms in this strain of Kir5.1 knockout mice that are not present to the same extent in humans with biallelic Kir5.1 mutations."
      explanation: >-
        Gives the review's interpretation of the negative result, which is the
        basis for the species divergence recorded here.
discussions:
- discussion_id: kcnj16_murine_hearing_mismatch
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Why does loss of Kir5.1 cause sensorineural hearing loss in humans but leave
    hearing unaffected in the Kcnj16 knockout mouse?
  attaches_to:
  - pathophysiology#Cochlear Potassium Homeostasis Failure
  - phenotypes#Sensorineural Hearing Loss
  rationale: >-
    Evidence exists on both sides and they disagree, which is the defining shape
    of a model-fidelity gap rather than an absence of evidence. Human patients
    with biallelic KCNJ16 variants have sensorineural hearing loss consistently
    enough for it to be part of the disease definition, yet a Kcnj16 knockout
    mouse hears normally. The review proposes murine compensation, but that is a
    hypothesis rather than a demonstrated mechanism, and it is unresolved which
    compensating conductance is responsible.

    This matters beyond bookkeeping: it means the cochlear arm of this disease
    currently has no validated animal model, so the Kir5.1 role in the spiral
    ligament rests on human genetics plus expression data rather than on
    reproduction in a model system.
  evidence:
  - reference: PMID:35370765
    reference_title: "EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This may indicate efficient compensatory mechanisms in this strain of Kir5.1 knockout mice that are not present to the same extent in humans with biallelic Kir5.1 mutations."
    explanation: >-
      States the proposed explanation for the mismatch and marks it as
      provisional.
treatments:
- name: Potassium and Alkali Replacement
  description: >-
    Supportive electrolyte management: potassium supplementation for the urinary
    losses, with alkali as required for the acidosis. Symptomatic rather than
    mechanism-directed — there is no therapy that restores the channel — so this
    entry deliberately claims no target_mechanisms link. The mouse data hinting
    at thiazide responsiveness are a model finding, not human evidence, and are
    recorded under animal_models rather than proposed as treatment here.
  therapeutic_modality: SMALL_MOLECULE
  notes: >-
    Deliberately carries no evidence item. None of the three sources cached for
    this entry states a management recommendation -- the review only gestures at
    future channel-targeting compounds -- so there is no quotable clinical
    statement to attach, and manufacturing one would be worse than leaving the
    treatment uncited. The murine finding that chronic hydrochlorothiazide
    normalised urinary sodium and calcium and abolished the acidosis is recorded
    under animal_models, not here: it is model data and has not been shown in
    patients.
  treatment_term:
    preferred_term: potassium and alkali supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: potassium chloride
      term:
        id: CHEBI:32588
        label: potassium chloride
    - preferred_term: sodium bicarbonate
      term:
        id: CHEBI:32139
        label: sodium hydrogencarbonate
  target_phenotypes:
  - preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  - preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis

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References & Deep Research

References

3

PMID:33811157

Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness.

No top-level findings curated for this source.

PMID:35370765

EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies.

No top-level findings curated for this source.

PMID:21633011

Renal phenotype in mice lacking the Kir5.1 (Kcnj16) K+ channel subunit contrasts with that observed in SeSAME/EAST syndrome.

No top-level findings curated for this source.

Hypokalemic Tubulopathy and Deafness

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