SLC33A1

Chr 3ARAD

solute carrier family 33 member 1

Also known as: ACATN, AT-1, AT1, CCHLND, HPBDS, SPG42

NCBI Gene: 9197 ENSG00000169359 UniProt: O00400 OMIM: 603690

This protein is an acetyl-CoA transporter that imports acetyl-CoA into the endoplasmic reticulum for protein acetylation and is necessary for O-acetylation of gangliosides. Mutations cause Huppke-Brendel syndrome (autosomal recessive) and spastic paraplegia 42 (autosomal dominant), affecting the nervous system with spasticity as a key feature. The gene shows low constraint to loss-of-function variation (pLI 0.0001, LOEUF 0.807).

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is required for the formation of O-acetylated (Ac) gangliosides. The encoded protein is predicted to contain 6 to 10 transmembrane domains, and a leucine zipper motif in transmembrane domain III. Defects in this gene have been reported to cause spastic paraplegia autosomal dominant type 42 (SPG42) in one Chinese family, but not in similar patients of European descent. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.812 OMIM phenotypes

Clinical Summary— SLC33A1

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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?

0.81LOEUF

pLI 0.000

Z-score 2.23

OE 0.48 (0.29–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.98Z-score

OE missense 0.67 (0.60–0.76)

193 obs / 287.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.48 (0.29–0.81)

0≤0.351.4

Missense OE?0.67 (0.60–0.76)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 10 / 21.0Missense obs/exp: 193 / 287.3Syn Z: -0.35

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSLC33A1-related congenital cataracts and hearing loss with low serum copper and ceruloplasminLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.73top 25%

GOF

0.6638th %ile

LOF

0.2776th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNCoinjection of S113R mutant human SLC33A1 reduced the rescue effect of wildtype human SLC33A1, suggesting that the S113R mutation has a dominant-negative effect.1

LOFCross-species alignment of the amino acid sequences for SLC33A1 also shows that the serine at position 113 is highly conserved among vertebrates (Figure 3E). Thus, the S113R mutation probably renders SLC33A1 nonfunctional and leads to a functional haploinsufficiency in the heterozogtes.2

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

References