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UniProtKB/Swiss-Prot O43918: Variant p.Pro326Leu

Autoimmune regulator
Gene: AIRE
Variant information

Variant position:  326
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 Proline (P) to Leucine (L) at position 326 (P326L, p.Pro326Leu).
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:  -3
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; no significant effect on structure, but may alter protein interactions; no effect on doted nuclear localization; dominant-negatif effect on regulation of target gene transcription.
Any additional useful information about the variant.

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



Sequence information

Variant position:  326
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:   GELICCDGCPRAFHLACLSP  P LREIPSGTWRCSSCLQATVQ
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                         GELICCDGCPRAFHLACLSPPLREIPSGTWRCSSCLQATVQ

Mouse                         GELICCDGCPRAFHLACLSPPLQEIPSGLWRCSCCLQGRVQ

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 – 545 Autoimmune regulator
Zinc finger 296 – 343 PHD-type 1
Mutagenesis 307 – 307 E -> A. Reduces interaction with histone H3.
Mutagenesis 312 – 312 D -> A. Abolishes interaction with histone H3.
Mutagenesis 312 – 312 D -> N. No effect on doted nuclear localization. Dominant-negatif effect on target gene transcription.


Literature citations

Structure and site-specific recognition of histone H3 by the PHD finger of human autoimmune regulator.
Chakravarty S.; Zeng L.; Zhou M.-M.;
Structure 17:670-679(2009)
Cited for: STRUCTURE BY NMR OF 294-347 IN COMPLEX WITH ZINC IONS AND UNMETHYLATED HISTONE H3 N-TERMINUS; CHARACTERIZATION OF VARIANTS APS1 MET-301; TYR-311; LEU-326 AND GLN-326;

Identification of a novel mutation in the autoimmune regulator (AIRE-1) gene in a French family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Saugier-Veber P.; Drouot N.; Wolf L.M.; Kuhn J.M.; Frebourg T.; Lefebvre H.;
Eur. J. Endocrinol. 144:347-351(2001)
Cited for: VARIANT APS1 LEU-326;

Dominant mutations in the autoimmune regulator AIRE are associated with common organ-specific autoimmune diseases.
Oftedal B.E.; Hellesen A.; Erichsen M.M.; Bratland E.; Vardi A.; Perheentupa J.; Kemp E.H.; Fiskerstrand T.; Viken M.K.; Weetman A.P.; Fleishman S.J.; Banka S.; Newman W.G.; Sewell W.A.; Sozaeva L.S.; Zayats T.; Haugarvoll K.; Orlova E.M.; Haavik J.; Johansson S.; Knappskog P.M.; Loevaas K.; Wolff A.S.; Abramson J.; Husebye E.S.;
Immunity 42:1185-1196(2015)
Cited for: INVOLVEMENT IN APS1; FUNCTION; SUBCELLULAR LOCATION; VARIANTS APS1 PRO-28; CYS-90; MET-301; TYR-311 AND LEU-326; CHARACTERIZATION OF VARIANTS PRO-28; CYS-90; MET-301; TYR-311 AND LEU-326; MUTAGENESIS OF 28-LEU-LEU-29; LEU-97; ASP-297; ARG-303; ASP-312; CYS-446 AND ARG-471; VARIANTS LYS-298; TRP-299; TYR-302; GLN-303; TRP-303; SER-305; ARG-306; MET-309; GLN-316; TRP-316; PRO-319; GLN-328; TRP-328; ARG-332 AND ALA-484; CHARACTERIZATION OF VARIANTS LYS-298; TYR-302; SER-305 AND GLN-328;

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.