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UniProtKB/Swiss-Prot O95278: Variant p.Gln293Leu

Laforin
Gene: EPM2A
Chromosomal location: 6q24
Variant information

Variant position:  293
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 Glutamine (Q) to Leucine (L) at position 293 (Q293L, p.Gln293Leu).
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 polar (Q) to medium size and hydrophobic (L)
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:  Epilepsy, progressive myoclonic 2 (EPM2) [MIM:254780]: An autosomal recessive and severe form of adolescent-onset progressive epilepsy. Typically, as seizures increase in frequency, cognitive function declines towards dementia, and affected individuals die usually within 10 years after onset. EPM2 occurs worldwide, but it is particularly common in the mediterranean countries of southern Europe and northern Africa, in southern India and in the Middle East. At the cellular level, it is characterized by accumulation of starch-like polyglucosans called Lafora bodies (LBs) that are most abundant in organs with the highest glucose metabolism: brain, heart, liver and skeletal muscle. Among other conditions involving polyglucosans, EPM2 is unique in that the inclusions are in neuronal dendrites but not axons and the forming polyglucosan fibrils are associated with the endoplasmic reticulum. {ECO:0000269|PubMed:11001928, ECO:0000269|PubMed:11175283, ECO:0000269|PubMed:11739371, ECO:0000269|PubMed:12019207, ECO:0000269|PubMed:12560877, ECO:0000269|PubMed:14532330, ECO:0000269|PubMed:14706656, ECO:0000269|PubMed:14722920, ECO:0000269|PubMed:15009235, ECO:0000269|PubMed:18311786, ECO:0000269|PubMed:25544560, ECO:0000269|PubMed:26231210, ECO:0000269|PubMed:9771710, ECO:0000269|PubMed:9931343}. 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 EPM2; results in ubiquitin-positive perinuclear aggregates; may affect proper folding; loss of phosphatase activity; affects glycogen binding; disrupts the interaction with PPP1R3C.
Any additional useful information about the variant.

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



Sequence information

Variant position:  293
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  331
The length of the canonical sequence.

Location on the sequence:   STAAVCGWLQYVMGWNLRKV  Q YFLMAKRPAVYIDEEALARA
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                         STAAVCGWLQYVMGWNLRKVQYFLMAKRPAVYIDEEALARA

                              STAAVCGWLQYVMGWNLRKVQYFLMAKRPAVYIDEDALARA

Mouse                         STAAVCGWLHYVIGWNLRKVQYFIMAKRPAVYIDEDALAQA

Rat                           STAAVCGWLHYVIGWSLRKVQYFIMAKRPAVYIDEEALAQA

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 – 331 Laforin
Domain 243 – 311 Tyrosine-protein phosphatase
Binding site 304 – 304 Substrate
Alternative sequence 160 – 293 Missing. In isoform 5.
Alternative sequence 200 – 331 Missing. In isoform 4.
Helix 289 – 296


Literature citations

Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.
Minassian B.A.; Lee J.R.; Herbrick J.-A.; Huizenga J.; Soder S.; Mungall A.J.; Dunham I.; Gardner R.; Fong C.G.; Carpenter S.; Jardim L.; Satishchandra P.; Andermann E.; Snead O.C. III; Lopes-Cendes I.; Tsui L.-C.; Delgado-Escueta A.V.; Rouleau G.A.; Scherer S.W.;
Nat. Genet. 20:171-174(1998)
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2); ALTERNATIVE SPLICING; TISSUE SPECIFICITY; VARIANTS EPM2 CYS-108; SER-279 AND LEU-293; VARIANT ASP-114;

Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes.
Ganesh S.; Agarwala K.L.; Ueda K.; Akagi T.; Shoda K.; Usui T.; Hashikawa T.; Osada H.; Delgado-Escueta A.V.; Yamakawa K.;
Hum. Mol. Genet. 9:2251-2261(2000)
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1); FUNCTIONAL CHARACTERIZATION; CATALYTIC ACTIVITY; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANTS EPM2 HIS-171 AND LEU-293;

Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation.
Fernandez-Sanchez M.E.; Criado-Garcia O.; Heath K.E.; Garcia-Fojeda B.; Medrano-Fernandez I.; Gomez-Garre P.; Sanz P.; Serratosa J.M.; Rodriguez de Cordoba S.;
Hum. Mol. Genet. 12:3161-3171(2003)
Cited for: FUNCTION; CATALYTIC ACTIVITY; SELF-INTERACTION; SUBCELLULAR LOCATION; GLYCOGEN-BINDING; INTERACTION WITH PPP1R3C; TISSUE SPECIFICITY; MUTAGENESIS OF ASP-235 AND CYS-266; ACTIVE SITE; CHARACTERIZATION OF VARIANTS EPM2 GLY-32; LEU-84; CYS-108; ILE-194; SER-240; SER-279; LEU-293; ASN-294 AND LEU-301;

Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype.
Ganesh S.; Delgado-Escueta A.V.; Suzuki T.; Francheschetti S.; Riggio C.; Avanzini G.; Rabinowicz A.; Bohlega S.; Bailey J.; Alonso M.E.; Rasmussen A.; Thomson A.E.; Ochoa A.; Prado A.J.; Medina M.T.; Yamakawa K.;
Hum. Mol. Genet. 11:1263-1271(2002)
Cited for: VARIANTS EPM2 PRO-25; CYS-108; HIS-171 AND LEU-293; CHARACTERIZATION OF VARIANTS EPM2 GLY-32; CYS-108; ILE-194; SER-279 AND ASN-294;

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.