Human Disease Model Report: Perry syndrome

General Information

Name

Perry syndrome

FlyBase ID

FBhh0000114

Disease Ontology Term

Perry syndrome

Parent Disease

OMIM

PERRY SYNDROME

Overview

This report describes Perry syndrome, an autosomal dominant neurodegenerative disorder. The human gene implicated in this disease is DCTN1, which encodes dynactin 1 (p150, Glued (Drosophila) homolog), the largest polypeptide of the dynactin complex. There is one high-scoring fly ortholog, DCTN1-p150, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated. DCTN1 is also associated with neuronopathy, distal hereditary motor, autosomal dominant 14 (HMND14; MIM:607641; FBhh0000147) and with an increased susceptibility to amyotrophic lateral sclerosis (MIM:105400; FBhh0000002). There is a second, moderate-scoring, ortholog in flies, Dred.

Multiple UAS constructs of the human Hsap\DCTN1 gene have been introduced into flies, including wild-type and a gene carrying a mutational lesion implicated in Perry syndrome. See the 'Disease-Implicated Variants' table below. Strong pan-neuronal overexpression of the wild-type human gene is toxic; low-level expression allows heterologous rescue (functional complementation) of the larval lethal phenotype of DCTN1-p150 amorphic mutations, however, the rescued adults are sterile. Phenotypes of variants analogous to those associated with Perry syndrome have been compared to those associated with distal hereditary motor neuronopathy (HMND14, FBhh0000147).

Homozygous amorphic mutations of Dmel\Hsap\DCTN1 are lethal in the embryonic or early larval stages. Heterozygous animals exhibit neuroanatomy defects, neurophysiology defects, and small roughened eyes.

[updated Feb. 2024 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: Perry syndrome

OMIM report

[PERRY SYNDROME](https://omim.org/entry/168605)

Human gene(s) implicated

[DYNACTIN 1; DCTN1](https://omim.org/entry/601143)

Symptoms and phenotype

Perry syndrome is an autosomal dominant neurodegenerative disorder classically characterized by adult-onset parkinsonism and depression, followed by weight loss and respiratory hypoventilation (Perry et al., 1975, pubmed:1122713). The phenotype has subsequently been expanded to include features that overlap with other neurodegenerative conditions, including frontotemporal dementia (see, e.g., MIM:600274) and progressive supranuclear palsy (PSP; MIM:601104). There is intrafamilial variation in the manifestations of the disorder (summary by Caroppo et al., 2014, pubmed:24343258; review by Wider et al., 2010, pubmed:19732908). Mutation in the DCTN1 gene can also cause distal motor neuropathy type VIIB (HMN7B; MIM:607641, temp-HMN7B) and confer increased susceptibility to amyotrophic lateral sclerosis (ALS; see MIM:105400, FBhh0000002). [From MIM:168605, 2016.01.08]

(OMIM, 2013-)

Genetics

Perry syndrome is caused by heterozygous mutation in the DCTN1 gene. [From MIM:168605, 2016.01.08]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

The DCTN1 gene encodes p150(Glued), the largest polypeptide of the dynactin complex, which binds directly to microtubules and to cytoplasmic dynein (DYNC1H1; MIM:600112), a microtubule-based biologic motor protein (Holzbaur and Tokito, 1996, pubmed:8838327). [From MIM:601143, 2016.01.08]

(OMIM, 2013-)

External links

Gene2Function (human gene): DCTN1
Gene Cards: DCTN1
GeneReviews, NCBI Bookshelf: Perry Syndrome
MedlinePlus (condition): Perry syndrome
MedlinePlus (gene): DCTN1
MARRVEL (human gene): DCTN1
NCBI MedGen: Perry syndrome
NCBI (Entrez) gene: DCTN1; dynactin subunit 1

Disease synonyms

Parkinsonism with alveolar hypoventilation and mental depression

Related Diseases

Related human health report(s)

amyotrophic lateral sclerosis

neuromuscular disease, DCTN1-related

neuronopathy, distal hereditary motor, autosomal dominant 14

Ortholog Information

Human gene(s) in FlyBase

Hsap\DCTN1

Human gene (HGNC)

Symbol / Name

DCTN1; dynactin subunit 1

D. melanogaster ortholog (based on DIOPT)

Dmel\DCTN1-p150

(DIOPT, 2013-)

Dmel\Dred

(DIOPT, 2013-)

Comments on ortholog(s)

One to many: 1 human to 2 Drosophila.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\DCTN1-p150

Gene Snapshot

Dynactin 1, p150 subunit (DCTN1-p150) encodes the p150 subunit of the dynactin complex. Dynactin is thought to act as a dynein receptor that modulates binding of dynein to cellular cargoes and enhances the processivity of dynein movement. The roles of the product of DCTN1-p150 include oocyte polarity, mitotic cell division, embryonic development, neuronal transport and neurogenesis. [Date last reviewed: 2019-03-07]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

DYNA-C

Comments on ortholog(s)

High-scoring ortholog of human DCTN1 (2 Drosophila to 1 human); Dmel\DCTN1-p150 shares 34% identity and 55% similarity with the human gene.

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (29 groups)

DCTN1-p150

protein-protein

Interacting group

Assay

References

DCTN1-p150 - αTub67C

cosedimentation through density gradient, molecular weight estimation by staining

(Lloyd et al., 2012)

DCTN1-p150 - αTub84B

cosedimentation through density gradient, molecular weight estimation by staining

(Lloyd et al., 2012)

DCTN1-p150 - Arfip

cosedimentation, anti tag coimmunoprecipitation, western blot, anti tag western blot

(Chang et al., 2013)

DCTN1-p150 - Arp1

anti tag coimmunoprecipitation, anti tag western blot, experimental knowledge based

(Guruharsha et al., 2011, Kim et al., 2007)

DCTN1-p150 - Arp10

experimental knowledge based

(Guruharsha et al., 2011)

DCTN1-p150 - aurA

enzymatic study, autoradiography, anti bait coimmunoprecipitation, anti tag western blot, anti tag coimmunoprecipitation, western blot

(Romé et al., 2010)

DCTN1-p150 - βTub56D

cosedimentation through density gradient, molecular weight estimation by staining

(Lloyd et al., 2012)

DCTN1-p150 - βTub60D

cosedimentation through density gradient, molecular weight estimation by staining

(Lloyd et al., 2012)

DCTN1-p150 - DCTN2-p50

anti tag coimmunoprecipitation, western blot, anti tag western blot, experimental knowledge based

(Guruharsha et al., 2011, Kim et al., 2007, Basto et al., 2004)

DCTN1-p150 - DCTN3-p24

experimental knowledge based

(Guruharsha et al., 2011)

DCTN1-p150 - DCTN4-p62

experimental knowledge based

(Guruharsha et al., 2011)

DCTN1-p150 - Dhc64C

cosedimentation through density gradient, western blot, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, anti tag western blot

(Kim et al., 2007, Papoulas et al., 2005, Siller et al., 2005)

DCTN1-p150 - egl

anti tag coimmunoprecipitation, western blot

(McClintock et al., 2018)

DCTN1-p150 - γTub23C

cosedimentation through density gradient, molecular weight estimation by staining

(Lloyd et al., 2012)

DCTN1-p150 - Kap3

pull down, western blot

(Doodhi et al., 2009)

DCTN1-p150 - Lis-1

anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation

(Siller et al., 2005)

DCTN1-p150 - LRR

experimental knowledge based

(Guruharsha et al., 2011)

DCTN1-p150 - lva

pull down, anti tag western blot, western blot, anti bait coimmunoprecipitation

(Lin et al., 2015, Papoulas et al., 2005)

DCTN1-p150 - Nnf1a

anti tag coimmunoprecipitation, peptide massfingerprinting

(Przewloka et al., 2007)

DCTN1-p150 - nuf

pull down, western blot

(Calero-Cuenca et al., 2016)

DCTN1-p150 - PCID2

anti bait coimmunoprecipitation, western blot

(Glukhova et al., 2021)

DCTN1-p150 - rod

anti tag coimmunoprecipitation, western blot

(Basto et al., 2004)

DCTN1-p150 - Strip

anti bait coimmunoprecipitation, western blot, pull down, anti tag western blot, two hybrid

(Sakuma et al., 2014)

DCTN1-p150 - sw

pull down, western blot, nuclear magnetic resonance, anti bait coimmunoprecipitation, comigration in non denaturing gel electrophoresis, molecular weight estimation by staining

(Dix et al., 2013, Sanghavi et al., 2013, Nyarko et al., 2012, Reis et al., 2012, Morgan et al., 2011)

RNA-protein

Interacting group

Assay

References

DCTN1-p150 - bcd

anti bait coimmunoprecipitation, primer specific pcr

(Sanghavi et al., 2013)

DCTN1-p150 - fs(1)K10

pull down, peptide massfingerprinting, western blot

(Dix et al., 2013)

DCTN1-p150 - hry