SLC26A6-related hyperoxaluria and nephrolithiasis is a rare inherited oxalate transport disorder reported in a family with a heterozygous dominant-negative SLC26A6 variant. SLC26A6 encodes an apical epithelial secretory oxalate transporter. The reported p.R507W variant reduced chloride-dependent oxalate transport and membrane surface expression, cosegregated with hyperoxaluria, and was associated with calcium oxalate nephrolithiasis. Earlier cohort data did not support common SLC26A6 variants as a frequent monogenic cause, so this entry is intentionally scoped to the rare deleterious dominant-negative mechanism.
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name: SLC26A6-Related Hyperoxaluria and Nephrolithiasis
creation_date: "2026-07-06T06:09:44Z"
description: >-
SLC26A6-related hyperoxaluria and nephrolithiasis is a rare inherited oxalate
transport disorder reported in a family with a heterozygous dominant-negative
SLC26A6 variant. SLC26A6 encodes an apical epithelial secretory oxalate
transporter. The reported p.R507W variant reduced chloride-dependent oxalate
transport and membrane surface expression, cosegregated with hyperoxaluria,
and was associated with calcium oxalate nephrolithiasis. Earlier cohort data
did not support common SLC26A6 variants as a frequent monogenic cause, so this
entry is intentionally scoped to the rare deleterious dominant-negative
mechanism.
category: Metabolic Disorder
parents:
- Genetic Kidney Disease
- Disorder of Glyoxylate and Oxalate Metabolism
synonyms:
- SLC26A6 deficiency
- SLC26A6-related enteric hyperoxaluria
- SLC26A6-related calcium oxalate nephrolithiasis
classifications:
icimd_category:
- classification_value: glyoxylate_and_oxalate
notes: >-
ICIMD category 13.1, disorders of glyoxylate and oxalate metabolism.
SLC26A6 is grouped here through oxalate transport and calcium oxalate
stone pathophysiology.
inheritance:
- name: Autosomal dominant inheritance reported
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:35115415
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This mutation cosegregated with hyperoxaluria in the family."
explanation: Family cosegregation supports dominant inheritance for the reported heterozygous SLC26A6 variant.
pathophysiology:
- name: Dominant-Negative SLC26A6 Oxalate Transporter Dysfunction
description: >-
A rare heterozygous SLC26A6 p.R507W variant impairs the secretory oxalate
transporter by reducing chloride-dependent oxalate transport and cell-surface
expression, with dominant-negative effects on wild-type protein.
role: trigger
genes:
- preferred_term: SLC26A6
term:
id: hgnc:14472
label: SLC26A6
molecular_functions:
- preferred_term: carboxylic acid transmembrane transporter activity
term:
id: GO:0046943
label: carboxylic acid transmembrane transporter activity
modifier: DECREASED
biological_processes:
- preferred_term: oxalate transport
term:
id: GO:0019532
label: oxalate transport
modifier: DECREASED
cell_types:
- preferred_term: intestinal epithelial cell
term:
id: CL:0002563
label: intestinal epithelial cell
locations:
- preferred_term: intestine
term:
id: UBERON:0000160
label: intestine
evidence:
- reference: PMID:35115415
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a rare heterozygous missense mutation (c.1519C>T/p.R507W) in the SLC26A6 gene that encodes a secretory oxalate transporter."
explanation: Supports the heterozygous SLC26A6 variant and transporter identity.
- reference: PMID:35115415
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "mutant SLC26A6 demonstrated that Cl--dependent oxalate transport was dramatically reduced"
explanation: Functional data support reduced oxalate transport.
- reference: PMID:35115415
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Cotransfection studies demonstrated strong dominant-negative effects of the mutant on the wild-type protein"
explanation: Supports the dominant-negative mechanism.
downstream:
- target: Reduced Intestinal Oxalate Secretion
causal_link_type: DIRECT
description: Impaired apical SLC26A6 transport reduces intestinal oxalate secretion.
- name: Reduced Intestinal Oxalate Secretion
description: >-
SLC26A6 normally limits net intestinal oxalate absorption by mediating
epithelial oxalate secretion. Loss of function increases net absorption,
producing enteric hyperoxaluria.
role: amplifier
biological_processes:
- preferred_term: oxalate transport
term:
id: GO:0019532
label: oxalate transport
modifier: DECREASED
chemical_entities:
- preferred_term: oxalate
term:
id: CHEBI:132952
label: oxalate
modifier: INCREASED
evidence:
- reference: PMID:16532010
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "mice lacking Slc26a6 have a defect in intestinal oxalate secretion resulting in enhanced net absorption of oxalate."
explanation: Model-organism data support the intestinal secretion mechanism.
- reference: PMID:35115415
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This mutation cosegregated with hyperoxaluria in the family."
explanation: Human family data support hyperoxaluria downstream of the SLC26A6 variant.
downstream:
- target: Enteric Hyperoxaluria
causal_link_type: DIRECT
description: Reduced intestinal oxalate secretion raises urinary oxalate.
- name: Enteric Hyperoxaluria
description: >-
Increased net intestinal oxalate absorption raises urinary oxalate excretion,
creating a calcium oxalate lithogenic state.
role: central_effector
chemical_entities:
- preferred_term: oxalate
term:
id: CHEBI:132952
label: oxalate
modifier: INCREASED
evidence:
- reference: PMID:35115415
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SLC26A6 inactivation can cause inherited enteric hyperoxaluria with calcium oxalate NL."
explanation: Supports inherited enteric hyperoxaluria with calcium oxalate nephrolithiasis.
downstream:
- target: Urinary Calcium Oxalate Supersaturation
causal_link_type: DIRECT
description: Hyperoxaluria raises urinary calcium oxalate supersaturation.
- name: Urinary Calcium Oxalate Supersaturation
conforms_to: "nephrolithiasis_crystal_nucleation#Urinary Supersaturation"
description: >-
Hyperoxaluria raises calcium oxalate supersaturation, specializing the
nephrolithiasis module to SLC26A6-related enteric oxalate transport failure.
role: central_effector
biological_processes:
- preferred_term: Renal Excretion of Oxalate
term:
id: GO:0007588
label: excretion
modifier: INCREASED
chemical_entities:
- preferred_term: calcium oxalate
term:
id: CHEBI:60579
label: calcium oxalate
modifier: INCREASED
evidence:
- reference: PMID:35115415
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Hyperoxaluria is a major risk factor for NL."
explanation: Supports hyperoxaluria as the lithogenic state leading to nephrolithiasis.
downstream:
- target: Calcium Oxalate Nephrolithiasis
causal_link_type: DIRECT
description: Calcium oxalate supersaturation leads to nephrolithiasis.
- name: Calcium Oxalate Nephrolithiasis
conforms_to: "nephrolithiasis_crystal_nucleation#Symptomatic Kidney Stones"
description: >-
The reported family presented with calcium oxalate nephrolithiasis, and the
stone burden improved when dietary calcium was increased to reduce intestinal
oxalate absorption.
role: consequence
locations:
- preferred_term: kidney
term:
id: UBERON:0002113
label: kidney
evidence:
- reference: PMID:35115415
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We used a whole exome-based approach in a patient with calcium oxalate NL."
explanation: Supports calcium oxalate nephrolithiasis in the index patient.
phenotypes:
- category: Biochemical
name: Hyperoxaluria
description: Hyperoxaluria cosegregated with the reported SLC26A6 variant.
phenotype_term:
preferred_term: Hyperoxaluria
term:
id: HP:0003159
label: Hyperoxaluria
evidence:
- reference: PMID:35115415
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This mutation cosegregated with hyperoxaluria in the family."
explanation: Supports hyperoxaluria in SLC26A6-related disease.
- category: Clinical
name: Calcium oxalate nephrolithiasis
description: Calcium oxalate nephrolithiasis was the index clinical presentation.
phenotype_term:
preferred_term: Calcium oxalate nephrolithiasis
term:
id: HP:0008672
label: Calcium oxalate nephrolithiasis
evidence:
- reference: PMID:35115415
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We used a whole exome-based approach in a patient with calcium oxalate NL."
explanation: Supports calcium oxalate nephrolithiasis in the SLC26A6 index case.
discussions:
- discussion_id: gap_slc26a6_disease_boundary
prompt: >-
Beyond the reported dominant-negative p.R507W family, what is the penetrance
and mutational spectrum of SLC26A6-related hyperoxaluria and nephrolithiasis?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Dominant-Negative SLC26A6 Oxalate Transporter Dysfunction
rationale: >-
A newer family supports a rare dominant-negative disease mechanism, but an
earlier cohort found that SLC26A6 was not the monogenic cause of their
non-PH1/PH2 hyperoxaluria cohort and that identified common variants had no
significant effect on oxalate excretion. Additional families are needed to
define the disease boundary and penetrance.
evidence:
- reference: PMID:18951670
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SLC26A6 was effectively ruled out as the disease gene in this non-PH1/PH2 cohort."
explanation: Earlier cohort screening limits overgeneralization of SLC26A6 as a common monogenic cause.
notes: >-
Package seed 13.1.05.01; OMIM:610068. No exact MONDO disease term was found
in the local MONDO adapter, so the entry is named by causal gene and phenotype.