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UniProtKB/Swiss-Prot P04792: Variant p.Leu99Met

Heat shock protein beta-1
Gene: HSPB1
Chromosomal location: 7q11.2-q22
Variant information

Variant position:  99
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 Leucine (L) to Methionine (M) at position 99 (L99M, p.Leu99Met).
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:  2
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:  Neuronopathy, distal hereditary motor, 2B (HMN2B) [MIM:608634]: A neuromuscular disorder. Distal hereditary motor neuronopathies constitute a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. {ECO:0000269|PubMed:15122254, ECO:0000269|PubMed:18832141, ECO:0000269|PubMed:18952241, ECO:0000269|PubMed:20178975, ECO:0000269|PubMed:20870250, ECO:0000269|PubMed:22176143, ECO:0000269|PubMed:23643870, ECO:0000269|PubMed:23728742, ECO:0000269|PubMed:23948568, ECO:0000269|PubMed:25965061, ECO:0000269|PubMed:28144995}. 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 HMN2B; decreased homooligomerization; decreased heterooligomerization with HSPB6; no effect on phosphorylation by MAPKAPK2; decreased function in chaperone-mediated protein folding.
Any additional useful information about the variant.

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



Sequence information

Variant position:  99
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  205
The length of the canonical sequence.

Location on the sequence:   RQLSSGVSEIRHTADRWRVS  L DVNHFAPDELTVKTKDGVVE
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                         RQLSSGVSEIRHTADRWRVSLDVNHFAPDELTVKTKDGVVE

                              RQLSSGVSEIRQTADRWRVSLDVNHFAPEELTVKTKDGVVE

Mouse                         RQLSSGVSEIRQTADRWRVSLDVNHFAPEELTVKTKEGVVE

Rat                           RQLSSGVSEIRQTADRWRVSLDVNHFAPEELTVKTKEGVVE

Pig                           RQLSSGVSEIQQTADRWRVSLDVNHFAPEELTVKTKDGVVE

Bovine                        RQLSSGVSEIQQTADRWRVSLDVNHFAPEELTVKTKDGVVE

Chicken                       -ELSSGISEIRQSADSWKVTLDVNHFAPEELVVKTKDNIVE

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 – 205 Heat shock protein beta-1
Domain 76 – 184 sHSP
Region 70 – 205 Interaction with TGFB1I1
Modified residue 82 – 82 Phosphoserine; by MAPKAPK2, MAPKAPK3 and MAPKAPK5
Modified residue 83 – 83 Phosphoserine
Modified residue 86 – 86 Phosphoserine
Modified residue 98 – 98 Phosphoserine
Mutagenesis 82 – 82 S -> D. Mimicks phosphorylation state, leading to dreased ability to act as molecular chaperones; when associated with D-15 and D-78.
Beta strand 94 – 100


Literature citations

Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporadic distal HMN/CMT type 2.
Houlden H.; Laura M.; Wavrant-De Vrieze F.; Blake J.; Wood N.; Reilly M.M.;
Neurology 71:1660-1668(2008)
Cited for: VARIANTS HMN2B LEU-39; ARG-84; MET-99; PHE-135 AND GLY-140;

Structure and properties of G84R and L99M mutants of human small heat shock protein HspB1 correlating with motor neuropathy.
Nefedova V.V.; Sudnitsyna M.V.; Strelkov S.V.; Gusev N.B.;
Arch. Biochem. Biophys. 538:16-24(2013)
Cited for: CHARACTERIZATION OF VARIANTS HMN2B ARG-84 AND MET-99; INTERACTION WITH HSPB6;

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.