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UniProtKB/Swiss-Prot P04792: Variant p.Ser135Phe

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

Variant position:  135
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 Serine (S) to Phenylalanine (F) at position 135 (S135F, p.Ser135Phe).
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 small size and polar (S) to large size and aromatic (F)
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:  Charcot-Marie-Tooth disease 2F (CMT2F) [MIM:606595]: A dominant axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. Onset of Charcot-Marie-Tooth disease type 2F is between 15 and 25 years with muscle weakness and atrophy usually beginning in feet and legs (peroneal distribution). Upper limb involvement occurs later. {ECO:0000269|PubMed:15122254, ECO:0000269|PubMed:20178975, ECO:0000269|PubMed:22176143, ECO:0000269|PubMed:22206013, ECO:0000269|PubMed:23728742}. 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.

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 CMT2F and HMN2B; decreased homodimerization; increased client proteins binding; increased function in chaperone-mediated protein folding; alters CDK5-mediated phosphorylation of neurofilament proteins; alters CDK5-mediated phosphorylation of neurofilament proteins and indirectly impairs their anterograde axonal transport.
Any additional useful information about the variant.

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



Sequence information

Variant position:  135
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:   DGVVEITGKHEERQDEHGYI  S RCFTRKYTLPPGVDPTQVSS
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                         DGVVEITGKHEERQDEHGYISRCFTRKYTLPPGVDPTQVSS

                              DGVVEITGKHEERQDEHGYISRRLTPKYTLPPGVDPTLVSS

Mouse                         EGVVEITGKHEERQDEHGYISRCFTRKYTLPPGVDPTLVSS

Rat                           EGVVEITGKHEERQDEHGYISRCFTRKYTLPPGVDPTLVSS

Pig                           DGVVEITGKHEERQDEHGFISRCFTRKYTLPPGVDPTQVSS

Bovine                        DGVVEITGKHEERQDEHGYISRCFTRKYTLPPGVDPTLVSS

Chicken                       DNIVEITGKHEEKQDEHGFISRCFTRKYTLPPGVEATAVRS

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 123 – 123 N6-acetyllysine


Literature citations

Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy.
Evgrafov O.V.; Mersiyanova I.; Irobi J.; Van Den Bosch L.; Dierick I.; Leung C.L.; Schagina O.; Verpoorten N.; Van Impe K.; Fedotov V.; Dadali E.; Auer-Grumbach M.; Windpassinger C.; Wagner K.; Mitrovic Z.; Hilton-Jones D.; Talbot K.; Martin J.-J.; Vasserman N.; Tverskaya S.; Polyakov A.; Liem R.K.H.; Gettemans J.; Robberecht W.; De Jonghe P.; Timmerman V.;
Nat. Genet. 36:602-606(2004)
Cited for: VARIANTS CMT2F PHE-135 AND TRP-136; VARIANTS HMN2B TRP-127; PHE-135; ILE-151 AND LEU-182;

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;

Increased monomerization of mutant HSPB1 leads to protein hyperactivity in Charcot-Marie-Tooth neuropathy.
Almeida-Souza L.; Goethals S.; de Winter V.; Dierick I.; Gallardo R.; Van Durme J.; Irobi J.; Gettemans J.; Rousseau F.; Schymkowitz J.; Timmerman V.; Janssens S.;
J. Biol. Chem. 285:12778-12786(2010)
Cited for: VARIANT TYR-156; CHARACTERIZATION OF VARIANT TYR-156; CHARACTERIZATION OF VARIANTS HMN2B TRP-127; PHE-135; ILE-151 AND LEU-182; CHARACTERIZATION OF VARIANT CMT2F TRP-136; FUNCTION; SUBUNIT;

Charcot-Marie-Tooth causing HSPB1 mutations increase Cdk5-mediated phosphorylation of neurofilaments.
Holmgren A.; Bouhy D.; De Winter V.; Asselbergh B.; Timmermans J.P.; Irobi J.; Timmerman V.;
Acta Neuropathol. 126:93-108(2013)
Cited for: FUNCTION; CHARACTERIZATION OF VARIANTS HMN2B TRP-127 AND LEU-182; CHARACTERIZATION OF VARIANT CMT2F PHE-135;

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.