Alternative titles; symbols
HGNC Approved Gene Symbol: SLC33A1
SNOMEDCT: 763070001, 773648002;
Cytogenetic location: 3q25.31 Genomic coordinates (GRCh38): 3:155,821,024-155,854,427 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q25.31 | Huppke-Brendel syndrome | 614482 | Autosomal recessive | 3 |
| Spastic paraplegia 42, autosomal dominant | 612539 | Autosomal dominant | 3 |
The structural diversity and complexity of sugar chains in membrane gangliosides are caused in part by the occurrence of several different species of sialic acid molecules, including O-acetylated forms. Acetylation of sialic acid residues of glycoproteins and gangliosides occurs in the lumen of the Golgi apparatus, using acetyl-CoA as the acetate donor. By expression cloning, Kanamori et al. (1997) isolated a human melanoma cell line cDNA encoding AT1, a protein that directed the formation of 9-O-acetylated ganglioside GD3 in mammalian cells. The predicted 549-amino acid protein contained 6 to 10 transmembrane domains and a leucine zipper motif in transmembrane domain III. Immunofluorescence experiments indicated that the 58-kD protein is localized to the cytoplasm. Using in vitro assays with semi-intact cells, Kanamori et al. (1997) demonstrated that the AT1 protein functioned as an acetyl-CoA transporter. Northern blot analysis revealed that AT1 was expressed as 3.3- and 4.3-kb mRNAs in all tissues tested.
In various cellular studies, Huppke et al. (2012) found that the SLC33A1 protein showed a perinuclear cytoplasmic distribution and localized to the Golgi apparatus.
Lin et al. (2008) reported that the SLC33A1 gene has 6 coding exons.
Lin et al. (2008) reported that the SLC33A1 gene maps to chromosome 3q25.1.
By fluorescence in situ hybridization, Bora et al. (1998) mapped the Acatn gene to mouse chromosome 3E1-E3.
Kanamori et al. (1997) concluded that AT1 is an acetyl-CoA transporter that is involved in the process of O-acetylation.
Spastic Paraplegia 42, Autosomal Dominant
In affected members of a Chinese family with autosomal dominant spastic paraplegia-42 (SPG42; 612539), Lin et al. (2008) identified a heterozygous mutation in the SLC33A1 gene (603690.0001). The authors postulated haploinsufficiency as the disease mechanism.
In a cohort of 29 Polish patients with hereditary ataxia who did not have a molecular diagnosis, Radziwonik et al. (2022) identified 2 unrelated patients with a heterozygous mutation in the SLC33A1 gene (I520T; 603690.0007). The mutations were identified by next-generation sequencing of a panel of 152 genes associated with hereditary ataxias and spastic paraplegias and were confirmed by Sanger sequencing.
Huppke-Brendel Syndrome
By linkage analysis followed by candidate gene sequencing in 3 consanguineous families with Huppke-Brendel syndrome (HPBDS; 614482), Huppke et al. (2012) identified 5 different pathogenic mutations in the SLC33A1 gene in homozygous or compound heterozygous state (603690.0002-603690.0006). The patients presented at birth with congenital cataracts and later showed severe psychomotor retardation with hearing loss and variable nystagmus. Laboratory studies showed decreased serum ceruloplasmin and copper, and brain MRI showed cerebral and cerebellar atrophy and hypomyelination. All patients died of various causes by age 6 years. The patients did not show evidence of total body copper deficiency or copper toxicity. Knockdown of SLC33A1 in hepatic cells caused a 30% reduction of ceruloplasmin secretion, indicating that SLC33A1 expression and ceruloplasmin secretion are connected. None of the parents who were heterozygous carriers showed signs of spastic paraplegia.
By exome sequencing in a 7-month-old male infant, born to first-cousin Indian parents, with HPGDS, Chiplunkar et al. (2016) identified a homozygous 2-bp deletion in the SLC33A1 gene (603690.0008). The unaffected parents were heterozygous for the deletion.
In 2 brothers, born to consanguineous parents from Tunisia, with HPBDS, Monastiri et al. (2021) identified homozygosity for the c.1267-1G-A mutation (603690.0003) identified by Huppke et al. (2012) in Tunisian sibs. Monastiri et al. (2021) suggested the possibility of a founder effect for this mutation.
In a 3-year-old girl, born to nonconsanguineous Croatian parents, with HPBDS, Sikic et al. (2022) identified a homozygous nonsense mutation (Y377X; 603690.0009) in the SLC33A1 gene. Both unaffected parents were heterozygous for the mutation.
By exome sequencing in a 53-year-old Danish woman with a mild form of HPBDS, who was previously diagnosed with Wilson disease (277900), Kirk et al. (2022) identified compound heterozygosity for mutations in the SLC33A1 gene. One variant was a T-to-C transition (c.1331T-C), resulting in an ile444-to-thr (I444T) substitution, and the other was a 3-bp deletion at position 817 (c.817_819del), resulting in deletion of threonine at codon 273. The first variant was not found in gnomAD, while the second was found 3 times in heterozygous state only. Both affected amino acids were highly evolutionarily conserved. No clinical information on the deceased parents was available. Kirk et al. (2022) classified these variants as variants of uncertain significance.
Lin et al. (2008) observed that knockdown of the slc33a1 gene in zebrafish resulted in a curved-tail phenotype. Spinal motoneuron axons in the mutant fish were scarce and poorly organized compared to wildtype fish. The phenotype was corrected by coinjection of human wildtype SLC33A1, but not S113R mutant SLC33A1. The findings were consistent with a loss-of-function mechanism.
Bone morphogenetic proteins (see BMP1, 112264) act in a gradient to dictate neuronal cell fate, guidance, and differentiation. Mao et al. (2015) found that Slc33a1-knockdown zebrafish showed elevated Bmp signaling, as measured by phosphorylated nuclear Smad1 (601595)/Smad5 (603110)/Smad8 (SMAD9; 603295) and elevated Bmpr1a (601299). Expression of wildtype human SLC33A1, but not loss-of-function mutant SLC33A1, attenuated the increase in phosphorylated Smad1/5/8 and the morphologic abnormalities, including curved tail, in Slc33a1-knockdown zebrafish. Coinjection of S113R mutant human SLC33A1 reduced the rescue effect of wildtype human SLC33A1, suggesting that the S113R mutation has a dominant-negative effect. In culture, Slc33a1-morphant spinal motor neurons showed shortened axons and increased axon branching compared with wildtype spinal neuron axons.
In affected members of a large Chinese family with pure autosomal dominant spastic paraplegia-42 (SPG42; 612539), Lin et al. (2008) identified a heterozygous 339T-G transversion in exon 1 of the SLC33A1 gene, resulting in a ser113-to-arg (S113R) substitution in the beginning of the second transmembrane domain, which was predicted to reverse the orientation of all the descending domains. Residue 113 is highly conserved in evolution, and the mutation was not present in 200 controls. Lin et al. (2008) postulated functional haploinsufficiency.
Variant Function
Mao et al. (2015) found that S113R mutant patient fibroblasts showed elevated BMP signaling. Expression of S113R mutant and wildtype human SLC33A1 in slc33a1-knockdown zebrafish indicated that the S113R mutation functions in a dominant-negative manner.
In a boy, born of consanguineous Arab parents, with Huppke-Brendel syndrome (HPBDS; 614482), who was originally reported by Horvath et al. (2005), Huppke et al. (2012) identified a homozygous 328G-C transversion in exon 1 of the SLC33A1 gene, resulting in an ala110-to-pro (A110P) substitution in a highly conserved residue. The substitution was predicted to cause a structural change in the first and second transmembrane domains. The mutation was not found in 122 controls. RT-PCR of patient fibroblasts showed that the mutant protein was present at normal levels. However, the mutant protein failed to localize normally to the Golgi apparatus and instead showed punctate staining in the cytoplasm.
In a Tunisian brother and sister, born of consanguineous parents, with Huppke-Brendel syndrome (HPBDS; 614482), Huppke et al. (2012) identified a homozygous G-to-A transition in intron 5 of the SLC33A1 gene (c.1267-1G-A), resulting in partial or complete loss of exon 5.
In 2 brothers with HPBDS born to consanguineous Tunisian parents, Monastiri et al. (2021) found homozygosity for the c.1267-1G-A mutation identified by Huppke et al. (2012) in Tunisian sibs. Monastiri et al. (2021) suggested the possibility of a founder effect for this mutation.
In a Turkish boy, born of consanguineous parents, with Huppke-Brendel syndrome (HPBDS; 614482), Huppke et al. (2012) identified a homozygous 1098C-G transversion in exon 3 of the SLC33A1 gene, resulting in a tyr366-to-ter (Y366X) substitution. There was significantly reduced gene expression in patient fibroblasts, likely due to nonsense-mediated mRNA decay. However, a shortened protein was detected in the cytoplasm, where it colocalized with markers for the endoplasmic reticulum.
In the Turkish boy reported by Huppke et al. (2012), Huppke et al. (2012) identified a homozygous variation in the CCS gene (R163W; 603864.0001) that resulted in decreased CCS and SOD1 (147450) activity. Patient fibroblasts also showed evidence of the unfolded protein response, which may reflect cellular oxidative stress. Huppke et al. (2012) suggested that a defect in copper homeostasis or SOD1 deficiency may have contributed to the phenotype. This patient had additional symptoms not present in the other patients with SLC33A1 mutations, including neonatal hypotonia, hypoglycemia, and a pericardial effusion. At age 18 months, he had rapid developmental regression and epilepsy with persistent bilateral thalamic lesions on brain MRI.
In a boy from New Zealand with Huppke-Brendel syndrome (HPBDS; 614482), Huppke et al. (2012) identified compound heterozygosity for 2 mutations in the SLC33A1 gene: a 1-bp insertion (614_615insT) in exon 1, resulting in premature termination, and an 18-bp deletion (1474_1482+9del) leading to the loss of 3 amino acids and 9 bp in intron 5, including the donor splice site (603690.0006). RT-PCR of patient fibroblasts showed about 20% SLC33A1 mRNA levels.
For discussion of the 18-bp deletion in the SLC33A1 gene (1474_1482+9del) that was found in compound heterozygous state in a patient with Huppke-Brendel syndrome (HPBDS; 614482) by Huppke et al. (2012), see 603690.0005.
In 2 unrelated Polish patients (patients SA and BJ) with autosomal dominant spastic paraplegia-42 (SPG42; 612539), Radziwonik et al. (2022) identified heterozygosity for a c.1559T-C transition (c.1559T-C, NM_004733.3) in the SLC33A1 gene, resulting in an ile520-to-thr (I520T) substitution. The mutation was identified by next-generation sequencing of a panel of 152 genes associated with hereditary ataxias and spastic paraplegias and was confirmed by Sanger sequencing. Functional testing in patient cells was not performed.
In a 7-month-old boy, born to first-cousin Indian parents, with Huppke-Brendel syndrome (HPBDS; 614482), Chiplunkar et al. (2016) identified homozygosity for a 2-bp deletion at position 542 (c.542_543delTG) in exon 1 of the SLC33A1 gene. The mutation was identified by exome sequencing and was present in heterozygosity in both unaffected parents. The mutation was predicted to result in a frameshift and premature termination (Val181GlyfsTer6). Functional studies of the mutation were not performed.
In a 3-year-old girl, born to nonconsanguineous Croatian parents, with Huppke-Brendel syndrome (HPBDS; 614482), Sikic et al. (2022) identified homozygosity for a c.1131C-G transversion in the SLC33A1 gene, resulting in a tyr377-to-ter (Y377X) substitution. The mutation was identified by targeted sequencing. Both unaffected parents were heterozygous for the mutation. Functional studies of the mutation were not performed. Although N-terminal protein acetylation and acetyl-CoA levels in fibroblasts appeared normal, the authors found decreased levels of many N-acetylated amino acids in the cerebrospinal fluid and suggested that these could be potential biomarkers for the condition.
Bora, R. S., Kanamori, A., Hirabayashi, Y. Assignment of a putative acetyl-CoA transporter gene (Acatn) to mouse chromosome band 3E1-E3 by in situ hybridization. Cytogenet. Cell Genet. 83: 78-79, 1998. [PubMed: 9925934] [Full Text: https://doi.org/10.1159/000015132]
Chiplunkar, S., Bindu, P. S., Nagappa, M., Bineesh, C., Govindaraj, P., Gayathri, N., Bharath, M. M., Arvinda, H. R., Mathuranath, P. S., Sinha, S., Taly, A. B. Huppke-Brendel syndrome in a seven months old boy with a novel 2-bp deletion in SLC33A1. Metab. Brain Dis. 31: 1195-1198, 2016. [PubMed: 27306358] [Full Text: https://doi.org/10.1007/s11011-016-9854-6]
Horvath, R., Freisinger, P., Rubio, R., Merl, T., Bax, R., Mayr, J. A., Shawan, Muller-Hocker, J., Pongratz, D., Moller, L. B., Horn, N., Jaksch, M. Congenital cataract, muscular hypotonia, developmental delay and sensorineural hearing loss associated with a defect in copper metabolism. J. Inherit. Metab. Dis. 28: 479-492, 2005. [PubMed: 15902551] [Full Text: https://doi.org/10.1007/s10545-005-0479-x]
Huppke, P., Brendel, C., Kalscheuer, V., Korenke, G. C., Marquardt, I., Freisinger, P., Christodoulou, J., Hillebrand, M., Pitelet, G., Wilson, C., Gruber-Sedlmayr, U., Ullmann, R., Haas, S., Elpeleg, O., Nurnberg, G., Nurnberg, P., Dad, S., Moller, L. B., Kaler, S. G., Gartner, J. Mutations in SLC33A1 cause a lethal autosomal-recessive disorder with congenital cataracts, hearing loss, and low serum copper and ceruloplasmin. Am. J. Hum. Genet. 90: 61-68, 2012. Note: Erratum: Am. J. Hum. Genet. 90: 378 only, 2012. [PubMed: 22243965] [Full Text: https://doi.org/10.1016/j.ajhg.2011.11.030]
Huppke, P., Brendel, C., Korenke, G. C., Marquardt, I., Donsante, A., Yi, L., Hicks, J. D., Steinbach, P. J., Wilson, C., Elpeleg, O., Moller, L. B., Christodoulou, J., Kaler, S. G., Gartner, J. Molecular and biochemical characterization of a unique mutation in CCS, the human copper chaperone to superoxide dismutase. Hum. Mutat. 33: 1207-1215, 2012. [PubMed: 22508683] [Full Text: https://doi.org/10.1002/humu.22099]
Kanamori, A., Nakayama, J., Fukuda, M. N., Stallcup, W. B., Sasaki, K., Fukuda, M., Hirabayashi, Y. Expression cloning and characterization of a cDNA encoding a novel membrane protein required for the formation of O-acetylated ganglioside: a putative acetyl-CoA transporter. Proc. Nat. Acad. Sci. 94: 2897-2902, 1997. [PubMed: 9096318] [Full Text: https://doi.org/10.1073/pnas.94.7.2897]
Kirk, F. T., Munk, D. E., Ek, J., Birk Moller, L., Bendixen Thorup, M., Hvid Danielsen, E., Vilstrup, H., Ott, P., Damgaard Sandahl, T. Case report: Huppke-Brendel syndrome in an adult, mistaken for and treated as Wilson disease for 25 years. Front. Neurol. 13: 957794, 2022. [PubMed: 36119696] [Full Text: https://doi.org/10.3389/fneur.2022.957794]
Lin, P., Li, J., Liu, Q., Mao, F., Li, J., Qiu, R., Hu, H., Song, Y., Yang, Y., Gao, G., Yan, C., Yang, W., Shao, C., Gong, Y. A missense mutation in SLC33A1, which encodes the acetyl-CoA transporter, causes autosomal-dominant spastic paraplegia (SPG42). Am. J. Hum. Genet. 83: 752-759, 2008. [PubMed: 19061983] [Full Text: https://doi.org/10.1016/j.ajhg.2008.11.003]
Mao, F., Li, Z., Zhao, B., Lin, P., Liu, P., Zhai, M., Liu, Q., Shao, C., Sun, W., Gong, Y. Identification and functional analysis of a SLC33A1: c.339T-G (p.Ser113Arg) variant in the original SPG42 family. Hum. Mutat. 36: 240-249, 2015. [PubMed: 25402622] [Full Text: https://doi.org/10.1002/humu.22732]
Monastiri, K., Chioukh, F. Z., Besbes, H., Ben Hmida, H. Huppke-Brendel syndrome: two new Tunisian cases. (Abstract) J. Inher. Metab. Dis. 44: 335 only, 2021.
Radziwonik, W., Elert-Dobkowska, E., Klimkowicz-Mrowiec, A., Ziora-Jakutowicz, K., Stepniak, I., Zaremba, J., Sulek, A. Application of a custom NGS gene panel revealed a high diagnostic utility for molecular testing of hereditary ataxias. J. Appl. Genet. 63: 513-525, 2022. [PubMed: 35588347] [Full Text: https://doi.org/10.1007/s13353-022-00701-3]
Sikic, K., Peters, T. M. A., Marusic, E., Cagalj, I. C., Ramadza, D. P., Zigman, T., Fumic, K., Fernandez, E., Gevaert, K., Debeljak, Z., Wevers, R. A., Baric, I. Abnormal concentrations of acetylated amino acids in cerebrospinal fluid in acetyl-CoA transporter deficiency. J. Inherit. Metab. Dis. 45: 1048-1058, 2022. [PubMed: 35999711] [Full Text: https://doi.org/10.1002/jimd.12549]