Human Disease Model Report: neuronopathy, distal hereditary motor, autosomal dominant 14

General Information

Name

neuronopathy, distal hereditary motor, autosomal dominant 14

FlyBase ID

FBhh0000147

Disease Ontology Term

autosomal dominant distal hereditary motor neuronopathy 14

Parent Disease

neuronopathy, distal hereditary motor, autosomal dominant

OMIM

NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 14; HMND14

Overview

This report describes neuronopathy, distal hereditary motor, autosomal dominant 14 (HMND14), which is a subtype of distal hereditary motor neuronopathy. 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 the diseases Perry syndrome (MIM:168605, FBhh0000114) 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 HMN7B. 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 (FBhh0000114) have been compared to those associated with HMND14.

Homozygous amorphic mutations of Dmel\DCTN1-p150 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

Parent Disease Summary: neuronopathy, distal hereditary motor, autosomal dominant

Symptoms and phenotype

Distal hereditary motor neuronopathy (dHMN or HMN) is a heterogeneous group of neuromuscular disorders caused by anterior horn cell degeneration and characterized by progressive distal motor weakness and muscular atrophy of the peripheral nervous system without sensory impairment. Distal HMN is also referred to as spinal Charcot-Marie-Tooth disease (spinal CMT). Distal HMN is often referred to as a 'neuronopathy' instead of a 'neuropathy' based on the hypothesis that the primary pathologic process resides in the neuron cell body and not in the axons (Irobi et al., 2006, pubmed:16775372). [From MIM:607641, 2016.01.11]

(OMIM, 2013-)

Specific Disease Summary: neuronopathy, distal hereditary motor, autosomal dominant 14

OMIM report

[NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 14; HMND14](https://omim.org/entry/607641)

Human gene(s) implicated

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

Symptoms and phenotype

Autosomal dominant distal hereditary motor neuronopathy-14 (HMND14) is a slowly progressive form of motor neuron disease without sensory symptoms. Onset of the disorder was in early adulthood with breathing difficulty due to vocal fold paralysis, progressive facial weakness, and weakness and muscle atrophy in the hands. Weakness and muscle atrophy in the distal lower extremities developed later (Puls, et al., 2003, pubmed:12627231). There is some phenotypic overlap between this disorder and amyotrophic lateral sclerosis (ALS; MIM:105400, FBhh0000002). [from MIM:607641; 2024.02.20]

(OMIM, 2013-)

Genetics

Autosomal dominant distal hereditary motor neuronopathy-14 (HMND14) is caused by heterozygous mutation in the DCTN1 gene.

(OMIM, 2013-)

[from MIM:607641; 2024.02.20]

(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
MedlinePlus (gene): DCTN1
MARRVEL (human gene): DCTN1
NCBI MedGen: Distal hereditary motor neuronopathy type 7B (HMN7B)
NCBI (Entrez) gene: DCTN1; dynactin subunit 1

Disease synonyms

DHMN7B

distal hereditary motor neuronopathy, type VIIB

distal hereditary motor neuropathy, type VIIB

distal hereditary motor neuropathy with vocal cord paralysis, type VIIB

HMN7B

HMND14

HMN VIIB

lower motor neuron disease, dynactin type

neuronopathy, distal hereditary motor, autosomal dominant 14

neuronopathy, distal hereditary motor, Harding type VIIB

neuronopathy, distal hereditary motor, type VIIB

neuropathy, distal hereditary motor, Harding type VIIB

Neuropathy, distal hereditary motor, type VIIB; HMN7B

neuropathy, distal hereditary motor, with vocal cord paralysis, Harding type VIIB

Related Diseases

Related human health report(s)

amyotrophic lateral sclerosis

neuromuscular disease, DCTN1-related

Perry syndrome

Related Specific Diseases

OMIM phenotypic series

Neuronopathy, distal hereditary motor, autosomal dominant

Disease

Associated Human gene(s)

Drosophila model

Human transgene in Drosophila

[HMND1](https://omim.org/entry/182960)

[HMND2](https://omim.org/entry/158590)

[HSPB8](https://omim.org/entry/608014)

neuronopathy, distal hereditary motor, autosomal dominant 2

[HMND3](https://omim.org/entry/608634)

[HSPB1](https://omim.org/entry/602195)

neuronopathy, distal hereditary motor, autosomal dominant 3

[HMND4](https://omim.org/entry/613376)

[HSPB3](https://omim.org/entry/604624)

neuronopathy, distal hereditary motor, autosomal dominant 4

[HMND5](https://omim.org/entry/600794)

[GARS1](https://omim.org/entry/600287)

neuronopathy, distal hereditary motor, autosomal dominant 5

[HMND6](https://omim.org/entry/615575)

[FBXO38](https://omim.org/entry/608533)

[HMND7](https://omim.org/entry/158580)

[SLC5A7](https://omim.org/entry/608761)

[HMND8](https://omim.org/entry/600175)

[TRPV4](https://omim.org/entry/605427)

neuronopathy, distal hereditary motor, autosomal dominant 8

[HMND9](https://omim.org/entry/617721)

[WARS1](https://omim.org/entry/191050)

[HMND10](https://omim.org/entry/620080)

[EMILIN1](https://omim.org/entry/130660)

[HMND11](https://omim.org/entry/620528)

[SPTAN1](https://omim.org/entry/182810)

[HMND13](https://omim.org/entry/619112)

[BSCL2](https://omim.org/entry/606158)

[HMND14](https://omim.org/entry/607641)

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

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

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

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

(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

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

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

(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

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

(Sakuma et al., 2014)

DCTN1-p150 - sw

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

(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