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UniProtKB/Swiss-Prot P08559: Variant p.Arg288His

Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial
Gene: PDHA1
Variant information

Variant position:  288
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 Arginine (R) to Histidine (H) at position 288 (R288H, p.Arg288His).
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 (R) to medium size and polar (H)
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:  Pyruvate dehydrogenase E1-alpha deficiency (PDHAD) [MIM:312170]: An enzymatic defect causing primary lactic acidosis in children. It is associated with a broad clinical spectrum ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis. {ECO:0000269|PubMed:1293379, ECO:0000269|PubMed:1338114, ECO:0000269|PubMed:1551669, ECO:0000269|PubMed:1909401, ECO:0000269|PubMed:27864847, ECO:0000269|PubMed:7545958, ECO:0000269|PubMed:7573035, ECO:0000269|PubMed:7757088, ECO:0000269|PubMed:7887409, ECO:0000269|PubMed:7967473, ECO:0000269|PubMed:8032855, ECO:0000269|PubMed:8199595, ECO:0000269|PubMed:8498846, ECO:0000269|PubMed:8504306, ECO:0000269|PubMed:8664900, ECO:0000269|PubMed:8844217, ECO:0000269|PubMed:9266390, ECO:0000269|PubMed:9671272}. 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 PDHAD.
Any additional useful information about the variant.

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



Sequence information

Variant position:  288
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  390
The length of the canonical sequence.

Location on the sequence:   FAAAYCRSGKGPILMELQTY  R YHGHSMSDPGVSYRTREEIQ
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                         FAAAYCRSGKGPILMELQTYRYHGHSMSDPGVSYRTREEIQ

Chimpanzee                    FAAAYCRSGKGPILMELQTYRYHGHSMSGPGVSYRTREEIQ

Mouse                         FAAAYCRSGKGPILMELQTYRYHGHSMSDPGVSYRTREEIQ

Rat                           FAAAYCRSGKGPILMELQTYRYHGHSMSDPGVSYRTREEIQ

Bovine                        FAAAYCRSGKGPILMELQTYRYHGHSMSDPGVSYRTREEIQ

Caenorhabditis elegans        WAKEYCDSGKGPLMMEMATYRYHGHSMSDPGTSYRTREEIQ

Slime mold                    YAAEWCRAGNGPIILEMDTYRYVGHSMSDPGITYRTREEVN

Baker's yeast                 FAKDWCLSGKGPLVLEYETYRYGGHSMSDPGTTYRTRDEIQ

Fission yeast                 FAKKYTVENSQPLLMEFVTYRYGGHSMSDPGTTYRSREEVQ

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 31 – 390 Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial
Modified residue 277 – 277 N6-succinyllysine
Modified residue 293 – 293 Phosphoserine; by PDK1, PDK2, PDK3 and PDK4
Modified residue 295 – 295 Phosphoserine
Modified residue 300 – 300 Phosphoserine; by PDK1, PDK2, PDK3 and PDK4
Modified residue 301 – 301 Phosphotyrosine
Mutagenesis 293 – 293 S -> A. Reduces enzyme activity. Abolishes inactivation by phosphorylation; when associated with A-232 and A-300.
Mutagenesis 293 – 293 S -> E. Interferes with substrate binding.
Mutagenesis 300 – 300 S -> A. Abolishes inactivation by phosphorylation; when associated with A-232 and A-293.


Literature citations

Mutation analysis of the pyruvate dehydrogenase E1 alpha gene in eight patients with a pyruvate dehydrogenase complex deficiency.
Lissens W.; de Meirleir L.; Seneca S.; Benelli C.; Marsac C.; Poll-The B.T.; Briones P.; Ruitenbeek W.; van Diggelen O.; Chaigne D.; Ramaekers V.; Liebaers I.;
Hum. Mutat. 7:46-51(1996)
Cited for: VARIANTS PDHAD CYS-72; ASP-113; ARG-162; GLY-263; HIS-288 AND CYS-302;

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.