UniProtKB/Swiss-Prot Q13501: Variant p.Gly425Arg

Gene: SQSTM1
Chromosomal location: 5q35
Variant information

Variant position:  425
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 have been found in patients and disease-association is reported in literature. However, this classification is not a definitive assessment of variant pathogenicity.
  • Polymorphism: No disease-association has been reported.
  • Unclassified: Variants have been found in patients but disease-association remains unclear.

Residue change:  From Glycine (G) to Arginine (R) at position 425 (G425R, p.Gly425Arg).
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 glycine (G) to large size and basic (R)
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:  Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (FTDALS3) [MIM:616437]: A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. Some FTDALS3 patients may also develop Paget disease of bone. {ECO:0000269|PubMed:22084127, ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140, ECO:0000269|PubMed:25114083}. 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:  Paget disease of bone 3 (PDB3) [MIM:167250]: A disorder of bone remodeling characterized by increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Osteoclastic overactivity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically weaker, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone. {ECO:0000269|PubMed:11992264, ECO:0000269|PubMed:12374763, ECO:0000269|PubMed:14584883, ECO:0000269|PubMed:15125799, ECO:0000269|PubMed:15146436, ECO:0000269|PubMed:15176995, ECO:0000269|PubMed:15207768}. 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 PDB3 and FTDALS3; loss of polyubiquitin-binding and increased activation of NF-kappa-B.
Any additional useful information about the variant.

Sequence information

Variant position:  425
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  440
The length of the canonical sequence.

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.




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.

Chain 2 – 440 Sequestosome-1
Domain 389 – 434 UBA
Region 269 – 440 Interaction with NTRK1
Mutagenesis 406 – 406 F -> V. Loss of polyubiquitin-binding.
Mutagenesis 409 – 409 E -> K. Decreased activation of NF-kappa-B.
Mutagenesis 410 – 410 G -> K. Decreased activation of NF-kappa-B.
Mutagenesis 413 – 413 L -> V. No effect on polyubiquitin-binding.
Mutagenesis 417 – 417 L -> V. Loss of polyubiquitin-binding.
Mutagenesis 431 – 431 I -> V. Partial loss of polyubiquitin-binding. Loss of localization to cytoplasmic inclusion bodies.
Helix 424 – 431

Literature citations

SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis.
Fecto F.; Yan J.; Vemula S.P.; Liu E.; Yang Y.; Chen W.; Zheng J.G.; Shi Y.; Siddique N.; Arrat H.; Donkervoort S.; Ajroud-Driss S.; Sufit R.L.; Heller S.L.; Deng H.X.; Siddique T.;
Arch. Neurol. 68:1440-1446(2011)
Cited for: INVOLVEMENT IN FTDALS3; VARIANTS FTDALS3 VAL-33; ILE-153; LEU-228; LYS-238 DEL; PRO-318; CYS-321; PRO-370; LEU-392; SER-411 AND ARG-425;

Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and regulates NF-kappaB signalling.
Long J.; Garner T.P.; Pandya M.J.; Craven C.J.; Chen P.; Shaw B.; Williamson M.P.; Layfield R.; Searle M.S.;
J. Mol. Biol. 396:178-194(2010)

Familial Paget's disease in The Netherlands: occurrence, identification of new mutations in the sequestosome 1 gene, and their clinical associations.
Eekhoff E.W.M.; Karperien M.; Houtsma D.; Zwinderman A.H.; Dragoiescu C.; Kneppers A.L.J.; Papapoulos S.E.;
Arthritis Rheum. 50:1650-1654(2004)
Cited for: VARIANTS PDB3 LEU-392; PRO-399; THR-404 AND ARG-425;

Two novel mutations at exon 8 of the Sequestosome 1 (SQSTM1) gene in an Italian series of patients affected by Paget's disease of bone (PDB).
Falchetti A.; Di Stefano M.; Marini F.; Del Monte F.; Mavilia C.; Strigoli D.; De Feo M.L.; Isaia G.; Masi L.; Amedei A.; Cioppi F.; Ghinoi V.; Maddali Bongi S.; Di Fede G.; Sferrazza C.; Rini G.B.; Melchiorre D.; Matucci-Cerinic M.; Brandi M.L.;
J. Bone Miner. Res. 19:1013-1017(2004)
Cited for: VARIANTS PDB3 LEU-392; VAL-404 AND ARG-425;

Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype phenotype correlation, functional analysis, and structural consequences.
Hocking L.J.; Lucas G.J.A.; Daroszewska A.; Cundy T.; Nicholson G.C.; Donath J.; Walsh J.P.; Finlayson C.; Cavey J.R.; Ciani B.; Sheppard P.W.; Searle M.S.; Layfield R.; Ralston S.H.;
J. Bone Miner. Res. 19:1122-1127(2004)

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.