Home  |  Contact

UniProtKB/Swiss-Prot Q9HBA0: Variant p.Arg269His

Transient receptor potential cation channel subfamily V member 4
Gene: TRPV4
Chromosomal location: 12q24.1
Variant information

Variant position:  269
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 269 (R269H, p.Arg269His).
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:  Charcot-Marie-Tooth disease 2C (CMT2C) [MIM:606071]: An 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. {ECO:0000269|PubMed:20037586, ECO:0000269|PubMed:20037587, ECO:0000269|PubMed:20037588, ECO:0000269|PubMed:21115951, ECO:0000269|PubMed:21288981, ECO:0000269|PubMed:22702953, ECO:0000269|PubMed:25256292}. 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, 8 (HMN8) [MIM:600175]: A clinically variable, neuromuscular disorder characterized by congenital lower motor neuron disorder restricted to the lower part of the body. Clinical manifestations include non-progressive muscular atrophy, thigh muscle atrophy, weak thigh adductors, weak knee and foot extensors, minimal jaw muscle and neck flexor weakness, flexion contractures of knees and pes equinovarus. Tendon reflexes are normal. {ECO:0000269|PubMed:20037588, ECO:0000269|PubMed:22526352, ECO:0000269|PubMed:22702953}. 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 HMN8 and CMT2C; increased agonist-induced channel activity and increased basal intracellular calcium concentration; slightly decreased protein stability and ATP-binding; decreases binding to membranes enriched in phosphatidylinositol-2,4-bisphosphate; causes increased cell death.
Any additional useful information about the variant.

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



Sequence information

Variant position:  269
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  871
The length of the canonical sequence.

Location on the sequence:   RCKHYVELLVAQGADVHAQA  R GRFFQPKDEGGYFYFGELPL
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                         RCKHYVELLVAQGADVHAQARGRFFQPKDEGGYFYFGELPL

Mouse                         RCKHYVELLVAQGADVHAQARGRFFQPKDEGGYFYFGELPL

Rat                           RCKHYVELLVAQGADVHAQARGRFFQPKDEGGYFYFGELPL

Chicken                       RCKHYVELLVEKGADVHAQARGRFFQPKDEGGYFYFGELPL

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 – 871 Transient receptor potential cation channel subfamily V member 4
Topological domain 1 – 469 Cytoplasmic
Modified residue 253 – 253 Phosphotyrosine
Alternative sequence 239 – 285 Missing. In isoform 4 and isoform 6.
Mutagenesis 251 – 251 K -> E. No effect on channel activity. No effect on interaction with membranes enriched in phosphatidylinositol-2,4-bisphosphate.


Literature citations

TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P.
Takahashi N.; Hamada-Nakahara S.; Itoh Y.; Takemura K.; Shimada A.; Ueda Y.; Kitamata M.; Matsuoka R.; Hanawa-Suetsugu K.; Senju Y.; Mori M.X.; Kiyonaka S.; Kohda D.; Kitao A.; Mori Y.; Suetsugu S.;
Nat. Commun. 5:4994-4994(2014)
Cited for: FUNCTION; ACTIVITY REGULATION; SUBCELLULAR LOCATION; DOMAIN; MUTAGENESIS OF LYS-251; ASN-296; HIS-299 AND LYS-344; CHARACTERIZATION OF VARIANTS CMT2C CYS-232; HIS-269; TRP-315 AND HIS-316;

Structural and biochemical consequences of disease-causing mutations in the ankyrin repeat domain of the human TRPV4 channel.
Inada H.; Procko E.; Sotomayor M.; Gaudet R.;
Biochemistry 51:6195-6206(2012)
Cited for: X-RAY CRYSTALLOGRAPHY (2.85 ANGSTROMS) OF 149-397 ALONE AND IN COMPLEX WITH ATP; MUTAGENESIS OF PHE-231; CHARACTERIZATION OF VARIANTS MTD ARG-197; PHE-199; ALA-295; PHE-331; THR-331 AND PHE-342; CHARACTERIZATION OF VARIANTS SMDK LYS-278 AND GLY-333; CHARACTERIZATION OF VARIANTS CMT2C CYS-232; HIS-269; TRP-315 AND CYS-316; CHARACTERIZATION OF VARIANT SPSMA CYS-316; CHARACTERIZATION OF VARIANT LYS-183; CHARACTERIZATION OF VARIANTS HMN8 CYS-232 AND HIS-269;

Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C.
Auer-Grumbach M.; Olschewski A.; Papic L.; Kremer H.; McEntagart M.E.; Uhrig S.; Fischer C.; Frohlich E.; Balint Z.; Tang B.; Strohmaier H.; Lochmuller H.; Schlotter-Weigel B.; Senderek J.; Krebs A.; Dick K.J.; Petty R.; Longman C.; Anderson N.E.; Padberg G.W.; Schelhaas H.J.; van Ravenswaaij-Arts C.M.; Pieber T.R.; Crosby A.H.; Guelly C.;
Nat. Genet. 42:160-164(2010)
Cited for: VARIANTS CMT2C TRP-315 AND CYS-316; VARIANT HMN8 HIS-269; SUBCELLULAR LOCATION;

Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4.
Deng H.X.; Klein C.J.; Yan J.; Shi Y.; Wu Y.; Fecto F.; Yau H.J.; Yang Y.; Zhai H.; Siddique N.; Hedley-Whyte E.T.; Delong R.; Martina M.; Dyck P.J.; Siddique T.;
Nat. Genet. 42:165-169(2010)
Cited for: VARIANT CMT2C HIS-269; VARIANT SPSMA CYS-316; SUBCELLULAR LOCATION;

Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C.
Landoure G.; Zdebik A.A.; Martinez T.L.; Burnett B.G.; Stanescu H.C.; Inada H.; Shi Y.; Taye A.A.; Kong L.; Munns C.H.; Choo S.S.; Phelps C.B.; Paudel R.; Houlden H.; Ludlow C.L.; Caterina M.J.; Gaudet R.; Kleta R.; Fischbeck K.H.; Sumner C.J.;
Nat. Genet. 42:170-174(2010)
Cited for: VARIANTS CMT2C CYS-269 AND HIS-269; CHARACTERIZATION OF VARIANTS CMT2C CYS-269 AND HIS-269; FUNCTION;

TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies.
Klein C.J.; Shi Y.; Fecto F.; Donaghy M.; Nicholson G.; McEntagart M.E.; Crosby A.H.; Wu Y.; Lou H.; McEvoy K.M.; Siddique T.; Deng H.X.; Dyck P.J.;
Neurology 76:887-894(2011)
Cited for: VARIANTS CMT2C CYS-232 AND HIS-316; CHARACTERIZATION OF VARIANTS CMT2C CYS-232; CYS-269; HIS-269 AND HIS-316;

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.