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UniProtKB/Swiss-Prot Q9NUN7: Variant p.Glu33Gly

Alkaline ceramidase 3
Gene: ACER3
Variant information

Variant position:  33
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Glutamate (E) to Glycine (G) at position 33 (E33G, p.Glu33Gly).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from medium size and acidic (E) to glycine (G)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -2
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in disease:  Leukodystrophy, progressive, early childhood-onset (PLDECO) [MIM:617762]: A form of leukodystrophy, a disorder of myelin production or maintenance affecting the central nervous system. PELCO features include neurological regression between 6 and 13 months of age, truncal hypotonia, appendicular spasticity, dystonia, optic disk pallor, peripheral neuropathy and neurogenic bladder. Brain imaging shows progressive diffuse abnormal white matter signals, cerebral atrophy, and thin corpus callosum. Sural nerve biopsy shows decreased myelination. PLDECO inheritance is autosomal recessive. {ECO:0000269|PubMed:26792856, ECO:0000269|PubMed:30575723}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In PLDECO; impaired protein stability; strongly decreased enzyme activity; decreased ceramide catabolic process; in fibroblasts of patients homozygous for the mutation.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  33
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  267
The length of the canonical sequence.

Location on the sequence:   PTTSTLDWCEENYSVTWYIA  E FWNTVSNLIMIIPPMFGAVQ
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         PTTSTLDWCEENYSVTWYIAEFWNTVSNLIMIIPPMFGAVQ

Mouse                         PTTSTLDWCEENYVVTLFVAEFWNTVSNLIMIIPPIFGAIQ

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 1 – 267 Alkaline ceramidase 3
Topological domain 1 – 33 Cytoplasmic
Metal binding 19 – 19 Calcium
Metal binding 20 – 20 Calcium; via carbonyl oxygen
Metal binding 22 – 22 Calcium; via carbonyl oxygen
Metal binding 24 – 24 Calcium
Metal binding 33 – 33 Calcium
Alternative sequence 1 – 133 Missing. In isoform 2.
Mutagenesis 19 – 19 D -> G. Mildly decreased enzyme activity.
Mutagenesis 22 – 22 E -> G. Strongly decreased enzyme activity.
Mutagenesis 24 – 24 N -> G. Strongly decreased enzyme activity.
Beta strand 29 – 33


Literature citations

Deficiency of the alkaline ceramidase ACER3 manifests in early childhood by progressive leukodystrophy.
Edvardson S.; Yi J.K.; Jalas C.; Xu R.; Webb B.D.; Snider J.; Fedick A.; Kleinman E.; Treff N.R.; Mao C.; Elpeleg O.;
J. Med. Genet. 53:389-396(2016)
Cited for: FUNCTION; CATALYTIC ACTIVITY; INVOLVEMENT IN PLDECO; VARIANT PLDECO GLY-33; CHARACTERIZATION OF VARIANT PLDECO GLY-33;

Structure of a human intramembrane ceramidase explains enzymatic dysfunction found in leukodystrophy.
Vasiliauskaite-Brooks I.; Healey R.D.; Rochaix P.; Saint-Paul J.; Sounier R.; Grison C.; Waltrich-Augusto T.; Fortier M.; Hoh F.; Saied E.M.; Arenz C.; Basu S.; Leyrat C.; Granier S.;
Nat. Commun. 9:5437-5437(2018)
Cited for: X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 2-244 IN COMPLEX WITH CALCIUM AND ZINC IONS; FUNCTION; CATALYTIC ACTIVITY; COFACTOR; PATHWAY; CHARACTERIZATION OF VARIANT PLDECO GLY-33; SUBCELLULAR LOCATION; TOPOLOGY; MUTAGENESIS OF ASP-19; GLU-22; ASN-24; SER-99; TYR-149 AND SER-228;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.