UniProtKB/SwissProt variant VAR

Variant information

Variant position:

80

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 Valine (V) to Leucine (L) at position 80 (V80L, p.Val80Leu).

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:

Similar physico-chemical property. Both residues are medium size and hydrophobic.

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

Involvement in disease:

Autoimmune polyendocrine syndrome 1, with or without reversible metaphyseal dysplasia (APS1) [MIM:240300]: A rare disease characterized by the combination of chronic mucocutaneous candidiasis, hypoparathyroidism and Addison disease. Symptoms of mucocutaneous candidiasis manifest first, followed by hypotension or fatigue occurring as a result of Addison disease. APS1 is associated with other autoimmune disorders including diabetes mellitus, vitiligo, alopecia, hepatitis, pernicious anemia and primary hypothyroidism. {ECO:0000269|PubMed:10677297, ECO:0000269|PubMed:11274163, ECO:0000269|PubMed:11275943, ECO:0000269|PubMed:11524731, ECO:0000269|PubMed:11524733, ECO:0000269|PubMed:11600535, ECO:0000269|PubMed:11836330, ECO:0000269|PubMed:12050215, ECO:0000269|PubMed:12173302, ECO:0000269|PubMed:12625412, ECO:0000269|PubMed:14974083, ECO:0000269|PubMed:15649886, ECO:0000269|PubMed:15712268, ECO:0000269|PubMed:16114041, ECO:0000269|PubMed:18292755, ECO:0000269|PubMed:19446523, ECO:0000269|PubMed:26084028, ECO:0000269|PubMed:27426947, ECO:0000269|PubMed:9398839, ECO:0000269|PubMed:9888391}. Note=The disease is caused by mutations affecting the gene represented in this entry. Most of the mutations alter the nucleus-cytoplasm distribution of AIRE and disturb its association with nuclear dots and cytoplasmic filaments. Most of the mutations also decrease transactivation of the protein. The HSR domain is responsible for the homomultimerization activity of AIRE. All the missense mutations of the HSR and the SAND domains decrease this activity, but those in other domains do not. The AIRE protein is present in soluble high-molecular-weight complexes. Mutations in the HSR domain and deletion of PHD zinc fingers disturb the formation of these complexes (PubMed:14974083). Heterozygous mutations within the PHD1 domain have dominant-negatif effects and cause organ-specific autoimmune diseases (PubMed:26084028). Patients harbor extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines such as type I interferons which could protect them from some types of autoimmune diseases, like type I diabetes (PubMed:27426947). {ECO:0000269|PubMed:14974083, ECO:0000269|PubMed:26084028, ECO:0000269|PubMed:27426947}.

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 APS1.

Any additional useful information about the variant.

Other resources:

Links to websites of interest for the variant.

Variant rs179363881 [ dbSNP | Ensembl ]

Sequence information

Variant position:

80

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

Protein sequence length:

545

The length of the canonical sequence.

Location on the sequence:

HALLSWLLTQDSTAILDFWR V LFKDYNLERYGRLQPILDSF

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                         HALLSWLLTQDSTAILDFWRVLFKDYNLERYGRLQPILDSF

Mouse                         HALLSWLLTRDSGAILDFWRILFKDYNLERYSRLHSILDGF

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 – 545	Autoimmune regulator
Domain	1 – 105	HSR
Alternative sequence	1 – 292	MATDAALRRLLRLHRTEIAVAVDSAFPLLHALADHDVVPEDKFQETLHLKEKEGCPQAFHALLSWLLTQDSTAILDFWRVLFKDYNLERYGRLQPILDSFPKDVDLSQPRKGRKPPAVPKALVPPPRLPTKRKASEEARAAAPAALTPRGTASPGSQLKAKPPKKPESSAEQQRLPLGNGIQTMSASVQRAVAMSSGDVPGARGAVEGILIQQVFESGGSKKCIQVGGEFYTPSKFEDSGSGKNKARSSSGPKPLVRAKGAQGAAPGGGEARLGQQGSVPAPLALPSDPQLH -> MWLVYSSGAPGTQQPARNRVFFPIGMAPGGVCWRPDGWGTGGQGRISGPGSMGAGQRLGSSGTQRCCWGSCFGKEVALRRVLHPS. In isoform 2, isoform 3 and isoform 4.
Mutagenesis	97 – 97	L -> P. Loss of transactivation activity on target gene transcription; no dominant-negatif effect on target gene transcription. Loss of doted nuclear localization.

Literature citations

Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein.
Bjeorses P.; Halonen M.; Palvimo J.J.; Kolmer M.; Aaltonen J.; Ellonen P.; Perheentupa J.; Ulmanen I.; Peltonen L.;
Am. J. Hum. Genet. 66:378-392(2000)
Cited for: SUBCELLULAR LOCATION; VARIANTS APS1 LEU-80; CYS-85; TYR-311 AND GLN-326;

APECED-causing mutations in AIRE reveal the functional domains of the protein.
Halonen M.; Kangas H.; Rueppell T.; Ilmarinen T.; Ollila J.; Kolmer M.; Vihinen M.; Palvimo J.; Saarela J.; Ulmanen I.; Eskelin P.;
Hum. Mutat. 23:245-257(2004)
Cited for: SUBCELLULAR LOCATION; HOMOOLIGOMERIZATION; CHARACTERIZATION OF VARIANTS APS1 LEU-15; MET-16; VAL-21; PRO-28; PRO-29; ARG-78; LEU-80; GLU-83; CYS-90; ARG-93; TRP-228 AND GLN-326;

APECED mutations in the autoimmune regulator (AIRE) gene.
Heino M.; Peterson P.; Kudoh J.; Shimizu N.; Antonarakis S.E.; Scott H.S.; Krohn K.J.E.;
Hum. Mutat. 18:205-211(2001)
Cited for: VARIANTS APS1 LEU-15; MET-16; PRO-28; PR0-29; ARG-78; LEU-80; GLU-83; CYS-85; CYS-90; ARG-93; MET-301; TYR-311 AND GLN-326; VARIANT ARG-278;

UniProtKB/Swiss-Prot O43918: Variant p.Val80Leu