UniProtKB/SwissProt variant VAR

Variant information

Variant position:

74

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 Glutamine (Q) to Proline (P) at position 74 (Q74P, p.Gln74Pro).

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 medium size and polar (Q) to medium size and hydrophobic (P)

The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:

-1

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:

Perry syndrome (PERRYS) [MIM:168605]: A neuropsychiatric disorder characterized by mental depression not responsive to antidepressant drugs or electroconvulsive therapy, sleep disturbances, exhaustion and marked weight loss. Parkinsonism develops later and respiratory failure occurred terminally. {ECO:0000269|PubMed:19136952, ECO:0000269|PubMed:23874158, ECO:0000269|PubMed:24676999, ECO:0000269|PubMed:24881494, ECO:0000269|PubMed:25185702, ECO:0000269|PubMed:26972003}. 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 PERRYS; diminishes microtubule binding and lead to intracytoplasmic inclusions; significant decrease in motility of dynein-dynactin complex along microtubules; defective in inhibiting microtubule catastrophe in neurons.

Any additional useful information about the variant.

Other resources:

Links to websites of interest for the variant.

Variant rs72466487 [ dbSNP | Ensembl ]

Sequence information

Variant position:

74

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

Protein sequence length:

1278

The length of the canonical sequence.

Location on the sequence:

TGKWVGVILDEAKGKNDGTV Q GRKYFTCDEGHGIFVRQSQI

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                         TGKWVGVILDEAKGKNDGTVQGRKYFTCDEGHGIFVRQSQI

Mouse                         TGKWVGVILDEAKGKNDGTVQGRKYFTCDEGHGIFVRQSQI

Rat                           TGKWVGVILDEAKGKNDGTVQGRKYFTCDEGHGIFVRQSQI

Chicken                       TGKWVGVILDEAKGKNDGTVQGRKYFTCEENHGIFVRQSQI

Xenopus laevis                TGKWVGVILDDSKGKNDGTVQGRRYFTCEENHGIFVRQSQI

Drosophila                    VGKWVGVVLDEPKGKNSGSIKGQQYFQCDENCGMFVRPTQL

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.

Type	Positions	Description
Chain	1 – 1278	Dynactin subunit 1
Domain	48 – 90	CAP-Gly
Alternative sequence	1 – 138	MAQSKRHVYSRTPSGSRMSAEASARPLRVGSRVEVIGKGHRGTVAYVGATLFATGKWVGVILDEAKGKNDGTVQGRKYFTCDEGHGIFVRQSQIQVFEDGADTTSPETPDSSASKVLKREGTDTTAKTSKLRGLKPKK -> MMRQ. In isoform p135 and isoform 5.
Mutagenesis	68 – 68	K -> A. Abolishes interaction with CLIP1.
Mutagenesis	90 – 90	R -> E. Abolishes interaction with CLIP1.

Literature citations

DCTN1 mutations in Perry syndrome.
Farrer M.J.; Hulihan M.M.; Kachergus J.M.; Daechsel J.C.; Stoessl A.J.; Grantier L.L.; Calne S.; Calne D.B.; Lechevalier B.; Chapon F.; Tsuboi Y.; Yamada T.; Gutmann L.; Elibol B.; Bhatia K.P.; Wider C.; Vilarino-Gueell C.; Ross O.A.; Brown L.A.; Castanedes-Casey M.; Dickson D.W.; Wszolek Z.K.;
Nat. Genet. 41:163-165(2009)
Cited for: VARIANTS PERRYS ARG-71; GLU-71; ALA-71; PRO-72 AND PRO-74; CHARACTERIZATION OF VARIANTS PERRYS ARG-71 AND PRO-74; CHARACTERIZATION OF VARIANT HMN7B SER-59;

Dynactin subunit p150(Glued) is a neuron-specific anti-catastrophe factor.
Lazarus J.E.; Moughamian A.J.; Tokito M.K.; Holzbaur E.L.;
PLoS Biol. 11:E1001611-E1001611(2013)
Cited for: CHARACTERIZATION OF VARIANT PERRYS PRO-74; FUNCTION; SUBUNIT; INTERACTION WITH MAPRE1;

Dynactin functions as both a dynamic tether and brake during dynein-driven motility.
Ayloo S.; Lazarus J.E.; Dodda A.; Tokito M.; Ostap E.M.; Holzbaur E.L.;
Nat. Commun. 5:4807-4807(2014)
Cited for: CHARACTERIZATION OF VARIANTS PERRYS ARG-71 AND PRO-74; FUNCTION; INTERACTION WITH DYNEIN INTERMEDIATE CHAIN AND DYNEIN HEAVY CHAIN; DOMAIN CAP-GLY;

UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot Q14203: Variant p.Gln74Pro