UniProtKB/SwissProt variant VAR

Variant information

Variant position:

255

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

Type of variant:

LP/P [Disclaimer]

The variants are classified into three categories: LP/P, LB/B and US.

LP/P: likely pathogenic or pathogenic.
LB/B: likely benign or benign.
US: uncertain significance

Residue change:

From Lysine (K) to Glutamate (E) at position 255 (K255E, p.Lys255Glu).

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 large size and basic (K) to medium size and acidic (E)

The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:

1

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

Variant description:

In FSGS1; no effect on protein abundance; no effect on homodimerization; loss of localization to the nucleus; prevents nuclear localization of the wild-type protein; decreased interaction with PPARG and RARA; loss of transcriptional coactivator activity; dominant negative effect on nuclear receptors-mediated transcription; increased actin-binding affinity.

Any additional useful information about the variant.

Other resources:

Links to websites of interest for the variant.

Variant rs121908415 [ dbSNP | Ensembl ]

Sequence information

Variant position:

255

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

Protein sequence length:

911

The length of the canonical sequence.

Location on the sequence:

LDIPKMLDAEDIVNTARPDE K AIMTYVSSFYHAFSGAQKAE

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                         LDIPKMLDAEDIVNTARPDEKAIMTYVSSFYHAFSGAQKAE

Mouse                         LDIPKMLDAEDIVNTARPDEKAIMTYVSSFYHAFSGAQKAE

Rat                           LDIPKMLDAEDIVNTARPDEKAIMTYVSSFYHAFSGAQKAE

Bovine                        LDIPKMLDAEDIVNTARPDEKAIMTYVSSFYHAFSGAQKAE

Chicken                       LDIPKMLDAEDIVNTARPDEKAIMTYVSSFYHAFSGAQKAE

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.

Type	Positions	Description
Chain	1 – 911	Alpha-actinin-4
Domain	163 – 269	Calponin-homology (CH) 2
Region	1 – 269	Actin-binding
Modified residue	249 – 249	Phosphothreonine
Alternative sequence	54 – 272	Missing. In isoform ACTN4ISO.
Alternative sequence	89 – 478	Missing. In isoform 3.
Helix	254 – 268

Literature citations

Crystal structure of the actin-binding domain of alpha-actinin-4 Lys255Glu mutant implicated in focal segmental glomerulosclerosis.
Lee S.H.; Weins A.; Hayes D.B.; Pollak M.R.; Dominguez R.;
J. Mol. Biol. 376:317-324(2008)
Cited for: X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 47-271; CHARACTERIZATION OF VARIANTS FSGS1 GLU-255; ILE-259 AND PRO-262;

Familial focal segmental glomerulosclerosis (FSGS)-linked alpha-actinin 4 (ACTN4) protein mutants lose ability to activate transcription by nuclear hormone receptors.
Khurana S.; Chakraborty S.; Lam M.; Liu Y.; Su Y.T.; Zhao X.; Saleem M.A.; Mathieson P.W.; Bruggeman L.A.; Kao H.Y.;
J. Biol. Chem. 287:12027-12035(2012)
Cited for: CHARACTERIZATION OF VARIANTS FSGS1 GLU-255; ILE-259 AND PRO-262; FUNCTION; INTERACTION WITH PPARG AND RARA; MUTAGENESIS OF 87-LEU-LEU-88; DOMAIN; SUBCELLULAR LOCATION;

Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis.
Kaplan J.M.; Kim S.H.; North K.N.; Rennke H.; Correia L.A.; Tong H.-Q.; Mathis B.J.; Rodriguez-Perez J.-C.; Allen P.G.; Beggs A.H.; Pollak M.R.;
Nat. Genet. 24:251-256(2000)
Cited for: VARIANTS FSGS1 GLU-255; ILE-259 AND PRO-262;

Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis.
Barua M.; Brown E.J.; Charoonratana V.T.; Genovese G.; Sun H.; Pollak M.R.;
Kidney Int. 83:316-322(2013)
Cited for: VARIANTS FSGS1 ARG-59; GLN-72; LEU-153; GLU-255; ILE-259 AND PRO-262;

UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot O43707: Variant p.Lys255Glu