SLC29A4

Chr 7

solute carrier family 29 member 4

ENSG00000164638 UniProt: Q7RTT9 OMIM: 609149

The protein functions as an electrogenic voltage-dependent transporter that mediates uptake of monoamine neurotransmitters (serotonin, dopamine, norepinephrine) and clearance of cationic compounds from cerebrospinal fluid through the blood-brain barrier. Mutations cause autosomal recessive developmental and epileptic encephalopathy, characterized by early-onset seizures, severe developmental delay, and progressive neurodegeneration. The gene shows low constraint against loss-of-function variants (pLI near 0), consistent with the recessive inheritance pattern observed clinically.

OMIM ResearchSummary from RefSeq, UniProt

Electrogenic voltage-dependent transporter that mediates the transport of a variety of endogenous bioactive amines, cationic xenobiotics and drugs (PubMed:15448143, PubMed:16099839, PubMed:16873718, PubMed:17018840, PubMed:17121826, PubMed:20592246, PubMed:20858707, PubMed:22396231, PubMed:31537831). Utilizes the physiologic inside-negative membrane potential as a driving force to facilitate cellular uptake of organic cations (PubMed:15448143, PubMed:20592246, PubMed:22396231). Functions as a Na(+)- and Cl(-)-independent bidirectional transporter (PubMed:15448143, PubMed:16099839, PubMed:22396231, PubMed:31537831). Substrate transport is pH-dependent and enhanced under acidic condition, which is most likely the result of allosteric changes in the transporter structure (PubMed:16873718, PubMed:17018840, PubMed:20592246, PubMed:22396231, PubMed:31537831). Implicated in monoamine neurotransmitters uptake such as serotonin, dopamine, adrenaline/epinephrine, noradrenaline/norepinephrine, histamine and tyramine, thereby supporting a role in homeostatic regulation of aminergic neurotransmission in the central nervous system (PubMed:15448143, PubMed:16099839, PubMed:17018840, PubMed:17121826, PubMed:20858707, PubMed:22396231). Also responsible for the uptake of bioactive amines and drugs through the blood-cerebrospinal fluid (CSF) barrier, from the CSF into choroid plexus epithelial cells, thereby playing a significant role in the clearance of cationic neurotoxins, xenobiotics and metabolic waste in the brain (By similarity). Involved in bidirectional transport of the purine nucleoside adenosine and plays a role in the regulation of extracellular adenosine concentrations in cardiac tissues, in particular during ischemia (PubMed:16873718, PubMed:20592246, PubMed:31537831). May be involved in organic cation uptake from the tubular lumen into renal tubular cells, thereby contributing to organic cation reabsorption in the kidney (PubMed:17018840). Also transports guanidine (PubMed:16099839)

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.92

Clinical Summary— SLC29A4

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.92LOEUF

pLI 0.000

Z-score 1.82

OE 0.56 (0.35–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-1.00Z-score

OE missense 1.15 (1.06–1.24)

420 obs / 366.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.56 (0.35–0.92)

0≤0.351.4

Missense OE?1.15 (1.06–1.24)

0≤0.61.4

Synonymous OE?1.69

0≤1.21.6

LoF obs/exp: 11 / 19.7Missense obs/exp: 420 / 366.1Syn Z: -7.15

This gene — mechanism propensity

0.77top 25%

GOF

0.75top 25%

LOF

0.2385th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.