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UniProtKB/Swiss-Prot P43026: Variant p.Leu441Pro

Growth/differentiation factor 5
Gene: GDF5
Chromosomal location: 20q11.2
Variant information

Variant position:  441
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 Proline (P) at position 441 (L441P, p.Leu441Pro).
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:  Brachydactyly A2 (BDA2) [MIM:112600]: A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. In brachydactyly type A2 shortening of the middle phalanges is confined to the index finger and the second toe, all other digits being more or less normal. Because of a rhomboid or triangular shape of the affected middle phalanx, the end of the second finger usually deviates radially. {ECO:0000269|PubMed:16127465, ECO:0000269|PubMed:18203755, ECO:0000269|PubMed:21976273}. 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:  Du Pan syndrome (DPS) [MIM:228900]: Rare autosomal recessive condition characterized by absence of the fibulae and severe acromesomelic limb shortening with small, non-functional toes. Although milder, the phenotype resembles the autosomal recessive Hunter-Thompson and Grebe types of acromesomelic chondrodysplasia. {ECO:0000269|PubMed:12121354, ECO:0000269|PubMed:16222676, ECO:0000269|PubMed:18629880}. 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:  Multiple synostoses syndrome 2 (SYNS2) [MIM:610017]: A bone disease characterized by multiple progressive joint fusions that commonly involve proximal interphalangeal, tarsal-carpal, humeroradial and cervical spine joints. Additional features can include progressive conductive deafness and facial dysmorphism. {ECO:0000269|PubMed:16532400, ECO:0000269|PubMed:19956691, ECO:0000269|PubMed:21976273, ECO:0000269|PubMed:24098149, ECO:0000269|Ref.18}. 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 DPS, SYNS2 and BDA2; the mutant is almost inactive; loss of binding to BMPR1A and BMPR1B ectodomains; no induction of SMAD1-SMAD5-SMAD8 protein complex phosphorylation; impairs nuclear translocation of phosphotylated SMAD1-SMAD5-SMAD8 protein complex; no ability to induce SMAD protein signal transduction; binds to NOG.
Any additional useful information about the variant.

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



Sequence information

Variant position:  441
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  501
The length of the canonical sequence.

Location on the sequence:   PLEYEAFHCEGLCEFPLRSH  L EPTNHAVIQTLMNSMDPEST
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                         PLEYEAFHCEGLCEFPLRSHLEPTNHAVIQTLMNSMDPEST

Mouse                         PLEYEAFHCEGLCEFPLRSHLEPTNHAVIQTLMNSMDPEST

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 382 – 501 Growth/differentiation factor 5
Disulfide bond 400 – 466
Disulfide bond 429 – 498
Disulfide bond 433 – 500
Helix 439 – 441


Literature citations

New insights into the molecular mechanism of multiple synostoses syndrome (SYNS): mutation within the GDF5 knuckle epitope causes noggin-resistance.
Schwaerzer G.K.; Hiepen C.; Schrewe H.; Nickel J.; Ploeger F.; Sebald W.; Mueller T.; Knaus P.;
J. Bone Miner. Res. 27:429-442(2012)
Cited for: INTERACTION WITH BMPR2; NOG; BMPR1A AND BMPR1B; FUNCTION; VARIANT BDA2 PRO-441; VARIANT SYNS2 ASN-475; CHARACTERIZATION OF VARIANT SYNS2 ASN-475; CHARACTERIZATION OF VARIANT BDA2 PRO-441;

Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome).
Faiyaz-Ul-Haque M.; Ahmad W.; Zaidi S.H.E.; Haque S.; Teebi A.S.; Ahmad M.; Cohn D.H.; Tsui L.-C.;
Clin. Genet. 61:454-458(2002)
Cited for: VARIANT DPS PRO-441;

Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2.
Seemann P.; Schwappacher R.; Kjaer K.W.; Krakow D.; Lehmann K.; Dawson K.; Stricker S.; Pohl J.; Ploeger F.; Staub E.; Nickel J.; Sebald W.; Knaus P.; Mundlos S.;
J. Clin. Invest. 115:2373-2381(2005)
Cited for: VARIANT SYM1B LEU-438; VARIANT BDA2 PRO-441; CHARACTERIZATION OF VARIANT SYM1B LEU-438; CHARACTERIZATION OF VARIANT BDA2 PRO-441;

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.