UniProtKB/SwissProt variant VAR

Variant information

Variant position:

465

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 Phenylalanine (F) to Leucine (L) at position 465 (F465L, p.Phe465Leu).

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 aromatic (F) to medium size and hydrophobic (L)

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

BLOSUM score:

0

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:

Mucolipidosis 4 (ML4) [MIM:252650]: An autosomal recessive lysosomal storage disorder characterized by severe psychomotor retardation and ophthalmologic abnormalities, including corneal opacity, retinal degeneration and strabismus. Storage bodies of lipids and water-soluble substances are seen by electron microscopy in almost every cell type of the patients. Most patients are unable to speak or walk independently and reach a maximal developmental level of 1-2 years. All patients have constitutive achlorhydia associated with a secondary elevation of serum gastrin levels. {ECO:0000269|PubMed:10973263, ECO:0000269|PubMed:11013137, ECO:0000269|PubMed:11030752, ECO:0000269|PubMed:11317355, ECO:0000269|PubMed:12182165, ECO:0000269|PubMed:14749347, ECO:0000269|PubMed:15178326, ECO:0000269|PubMed:15523648, ECO:0000269|PubMed:16978393, ECO:0000269|PubMed:18794901, ECO:0000269|PubMed:21256127, ECO:0000269|PubMed:28112729}. 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 ML4; still localizes to late endosomes; fails to rescue defect of lactosylceramide traffic through the late endocytic pathway in ML4 patient cells; minor effect on formation and extrusion of tubulo-vesicular structures when overexpressed.

Any additional useful information about the variant.

Other resources:

Links to websites of interest for the variant.

Variant rs797044828 [ dbSNP | Ensembl ]

Sequence information

Variant position:

465

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

Protein sequence length:

580

The length of the canonical sequence.

Location on the sequence:

IVLGPYHVKFRSLSMVSECL F SLINGDDMFVTFAAMQAQQG

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                         IVLGPYHVKFRSLSMVSECLFSLINGDDMFVTFAAMQAQQG

Mouse                         IVLGPYHVKFRSLSMVSECLFSLINGDDMFVTFAAMQAQQG

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 – 580	Mucolipin-1
Intramembrane	457 – 477	Pore-forming
Mutagenesis	471 – 471	D -> A. Fails to rescue defect of lactosylceramide traffic through the late endocytic pathway in ML4 patient cells.
Helix	457 – 467

Literature citations

Overexpression of wild-type and mutant mucolipin proteins in mammalian cells: effects on the late endocytic compartment organization.
Manzoni M.; Monti E.; Bresciani R.; Bozzato A.; Barlati S.; Bassi M.T.; Borsani G.;
FEBS Lett. 567:219-224(2004)
Cited for: SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANTS ML4 PRO-232; PHE-408 DEL AND LEU-465;

Mucolipin-1 is a lysosomal membrane protein required for intracellular lactosylceramide traffic.
Pryor P.R.; Reimann F.; Gribble F.M.; Luzio J.P.;
Traffic 7:1388-1398(2006)
Cited for: FUNCTION; MUTAGENESIS OF ASP-471; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANT ML4 LEU-465;

The cation channel mucolipin-1 is a bifunctional protein that facilitates membrane remodeling via its serine lipase domain.
LaPlante J.M.; Falardeau J.L.; Brown E.M.; Slaugenhaupt S.A.; Vassilev P.M.;
Exp. Cell Res. 317:691-705(2011)
Cited for: FUNCTION; MUTAGENESIS OF TYR-109; CHARACTERIZATION OF VARIANTS ML4 PRO-106 AND LEU-465;

Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population.
Bargal R.; Avidan N.; Olender Z.; Ben-Asher E.; Zeigler M.; Raas-Rothschild A.; Frumkin A.; Ben-Yoseph O.; Friedlender Y.; Lancet D.; Bach G.;
Hum. Mutat. 17:397-402(2001)
Cited for: VARIANTS ML4 PRO-232; PHE-408 DEL AND LEU-465;

UniProtKB/Swiss-Prot Q9GZU1: Variant p.Phe465Leu