Human Disease Model Report: Charcot-Marie-Tooth disease, axonal, type 2DD

General Information

Name

Charcot-Marie-Tooth disease, axonal, type 2DD

FlyBase ID

FBhh0001579

Disease Ontology Term

Charcot-Marie-Tooth disease type 2DD

Parent Disease

Charcot-Marie-Tooth disease

OMIM

CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2DD; CMT2DD

Overview

This report describes Charcot-Marie-Tooth disease, axonal, type 2DD, a subtype of Charcot-Marie-Tooth disease type 2; CMT2 is characterized by abnormalities in the axons of peripheral nerve cells. The human gene implicated is ATP1A1, which encodes the alpha-1 isoform of the Na(+),K(+)-ATPase. There is one high-scoring fly ortholog, Dmel\Atpα, for which multiple genetic reagents, including classical alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

Human ATP1A1 has not been introduced into flies.

A number missense mutations analogous to those implicated in this disease have been introduced into the Dmel\Atpα gene by homologous recombination; see the 'Disease-Implicated Variants' table below. In addition, a single gene carrying four such disease-implicated missense variants has been generated. Flies bearing disease-implicated variant-analogous alleles of Atpα display motor and sensory defects, and have an abnormal circadian neuron dendritic morphology. Mutant flies have significantly decreased Na+/K+-ATPase activity, and a decreased lifespan when fed a high Na+ diet.

Several other human diseases associated with the related human genes ATP1A2 and ATP1A3 have been studied in flies using the Dmel\Atpα gene; see the Human Disease Model report 'neurological disorders, ATPα-related' (FBhh0000547).

[updated Oct. 2024 by FlyBase; FBrf0222196]

Disease Summary Information

Parent Disease Summary: Charcot-Marie-Tooth disease

Symptoms and phenotype

Charcot-Marie-Tooth disease (CMT) constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. CMT is divided into several major types: Type 1 is characterized by demyelination and by a significantly slowed motor median nerve conduction velocity (NCV). Type 2 is characterized by axonal abnormalities and a normal or slightly reduced NCV. "Intermediate" types describe CMT families with nerve conduction velocities, in different affected individuals, that overlap the division between Type 1 and Type 2. Additional types are defined on the basis inheritance patterns. [from MIM:609260 and MIM:606482; 2015.12.15]

(OMIM, 2013-)

Symptoms typically include progressive distal muscle weakness and atrophy, often associated with mild to moderate sensory loss, depressed tendon reflexes, and high-arched feet. [from Gene Reviews, http://www.ncbi.nlm.nih.gov/books/NBK1358 2015.12.15]

(FlyBase Curators, 2013-)

Specific Disease Summary: Charcot-Marie-Tooth disease, axonal, type 2DD

OMIM report

[CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2DD; CMT2DD](https://omim.org/entry/618036)

Human gene(s) implicated

[ATPase, Na+/K+ TRANSPORTING, ALPHA-1 POLYPEPTIDE; ATP1A1](https://omim.org/entry/182310)

Symptoms and phenotype

Charcot-Marie-Tooth disease type 2DD is an autosomal dominant peripheral sensorimotor neuropathy mainly affecting the lower limbs. Affected individuals have gait impairment due to distal muscle weakness and atrophy. Some patients may also have involvement of the distal upper limbs, resulting in atrophy of the intrinsic hand muscles. The age at onset and severity of the disorder is highly variable, even within families, and those with earlier onset in late childhood or the teenage years tend to have a more severe disease course. Patients remain ambulatory even late in the disease, although some may require orthotic devices (summary by Lassuthova et al., 2018, pubmed:29499166) [from MIM:618036; 2024.05.31]

(OMIM, 2013-)

Genetics

Autosomal dominant axonal Charcot-Marie-Tooth disease type 2DD (CMT2DD) is caused by heterozygous mutation in the ATP1A1 gene on chromosome 1p13. [from MIM:618036; 2024.05.31]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

The ATP1A1 gene encodes the alpha-1 isoform of the Na(+),K(+)-ATPase, an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. As these gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle, the enzyme plays an essential role in cellular physiology. It is composed of at least 2 subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta) (ATP1B1. ATP1A1 and ATP1A2 are isoforms of the catalytic subunit. Kidney contains predominantly ATP1A1, whereas both subunits are found in brain, adipose tissue, and skeletal muscle (summary by Shull and Lingrel, 1987, pubmed:3035563). [from MIM:182310; 2024.05.31]

(OMIM, 2013-)

External links

Gene2Function (human gene): ATP1A1
Gene Cards: ATP1A1
MedlinePlus (gene): ATP1A1 gene
MedlinePlus (gene): ATP1A1
MARRVEL (human gene): ATP1A1
NCBI (Entrez) gene: ATP1A1; ATPase Na+/K+ transporting subunit alpha 1

Disease synonyms

Charcot-Marie-Tooth neuropathy, type 2DD

CMT2DD

Related Diseases

Related human health report(s)

Charcot-Marie-Tooth disease

neurological disorders, ATPα-related

Related Specific Diseases

OMIM phenotypic series

Charcot-Marie-Tooth disease

Disease

Associated Human gene(s)

Drosophila model

Human transgene in Drosophila

[CMT1B](https://omim.org/entry/118200)

[MPZ](https://omim.org/entry/159440)

[CMT2A2A](https://omim.org/entry/609260)

[MFN2](https://omim.org/entry/608507)

Charcot-Marie-Tooth disease, axonal, type 2A2A

[CMT2A2B](https://omim.org/entry/617087)

[MFN2](https://omim.org/entry/608507)

Charcot-Marie-Tooth disease, axonal, type 2A2B

[CMT2B](https://omim.org/entry/600882)

[RAB7A](https://omim.org/entry/602298)

Charcot-Marie-Tooth disease, type 2B

[CMT2D](https://omim.org/entry/601472)

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

Charcot-Marie-Tooth disease, type 2D

[CMT2DD](https://omim.org/entry/618036)

[ATP1A1](https://omim.org/entry/182310)

Charcot-Marie-Tooth disease, axonal, type 2DD

[CMT2EE](https://omim.org/entry/618400)

[MPV17](https://omim.org/entry/137960)

Charcot-Marie-Tooth disease, axonal, type 2EE

[CMT2K](https://omim.org/entry/607831)

[GDAP1](https://omim.org/entry/606598)

Charcot-Marie-Tooth disease, type 2K

[CMT2K](https://omim.org/entry/607831)

[JPH1](https://omim.org/entry/605266)

Charcot-Marie-Tooth disease, type 2K

[CMT2O](https://omim.org/entry/614228)

[DYNC1H1](https://omim.org/entry/600112)

Charcot-Marie-Tooth disease, axonal, type 2O

[CMT2T](https://omim.org/entry/617017)

[MME](https://omim.org/entry/120520)

Charcot-Marie-Tooth disease, type 2T

[CMT4A](https://omim.org/entry/214400)

[GDAP1](https://omim.org/entry/606598)

Charcot-Marie-Tooth disease, type 4A

[CMT4J](https://omim.org/entry/611228)

[FIG4](https://omim.org/entry/609390)

Charcot-Marie-Tooth disease, type 4J

[CMTDIB](https://omim.org/entry/606482)

[DNM2](https://omim.org/entry/602378)

Charcot-Marie-Tooth disease, dominant intermediate B

[CMTDIC](https://omim.org/entry/608323)

[YARS1](https://omim.org/entry/603623)

Charcot-Marie-Tooth disease, dominant intermediate C

[CMTDIE](https://omim.org/entry/614455)

[INF2](https://omim.org/entry/610982)

Charcot-Marie-Tooth disease, dominant intermediate E

[CMTRIA](https://omim.org/entry/608340)

[GDAP1](https://omim.org/entry/606598)

Charcot-Marie-Tooth disease, recessive intermediate A

[CMTRID](https://omim.org/entry/616039)

[COX6A1](https://omim.org/entry/602072)

Charcot-Marie-Tooth disease, recessive intermediate D

[GDAP1](https://omim.org/entry/607706)

[GDAP1](https://omim.org/entry/606598)

Charcot-Marie-Tooth disease, axonal, with vocal cord paresis

[HMSN2C](https://omim.org/entry/606071)

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

neuropathy, hereditary motor and sensory, type IIC

[HMSN6A](https://omim.org/entry/601152)

[MFN2](https://omim.org/entry/608507)

neuropathy, hereditary motor and sensory, type VIA

Ortholog Information

Human gene(s) in FlyBase

Human gene (HGNC)

Symbol / Name

ATP1A1; ATPase Na+/K+ transporting subunit alpha 1

D. melanogaster ortholog (based on DIOPT)

Dmel\Atpα

(DIOPT, 2013-)

Dmel\JYalpha

(DIOPT, 2013-)

Comments on ortholog(s)

Many to many (many human to many Drosophila); ATP1A1 has one high-scoring Drosophila ortholog, Atpα, and one moderate scoring ortholog, JYalpha

Other mammalian ortholog(s) used

D. melanogaster Gene Information (2)

Dmel\JYalpha

Gene Snapshot

JYalpha (JYalpha) is a gene essential for male fertility as mutants produce immotile sperm. [Date last reviewed: 2019-03-14]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

ATPIIC

Comments on ortholog(s)

Moderate-scoring ortholog of human ATP1A1, ATP12A, ATP1A2, ATP1A3, ATP1A4, and ATP4A (many Drosophila to many human).

Orthologs and Alignments from DRSC

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

H. sapiens (Human)

Dmel\Atpα

Gene Snapshot

Na pump α subunit (Atpα) encodes an integral membrane cation antiporter protein that utilizes ATP to shuttle Na[+] and K[+] across the plasma membrane to maintain ion homeostasis. [Date last reviewed: 2019-03-07]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

ATPIIC

Comments on ortholog(s)

High-scoring ortholog of human ATP1A3, ATP1A1, ATP1A2, ATP1A4; moderate scoring ortholog of human ATP12A and ATP4A (many Drosophila to many human).

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)

Atpα

protein-protein

Interacting group

Assay

References

Atpα - Akt

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Atpα - Chc

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - gig

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Atpα - Hel25E

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Ipo9

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Kap-α3

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Karyβ3

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - mats

anti tag coimmunoprecipitation, peptide massfingerprinting

(Kwon et al., 2013)

Atpα - Mcad

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Mec2

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - MRP

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - nrv2

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Ost1

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Ost48

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - OstΔ

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Past1

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Rab1

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Scamp

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Sec61α

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - SERCA

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - spidey

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Tctp

pull down, molecular weight estimation by staining, anti tag coimmunoprecipitation, anti tag western blot

(Lee et al., 2020)

Atpα - Tecr

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Ube3a

enzymatic study, western blot

(Jensen et al., 2013)

Atpα - UQCR-C2

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Vha68-2

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - wal

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - yki

anti tag coimmunoprecipitation, peptide massfingerprinting

(Kwon et al., 2013)

Atpα - ZnT63C

experimental knowledge based

(Guruharsha et al., 2011)

Alleles Reported to Model Human Disease (Disease Ontology) (16 alleles)

Atpα

Models Based on Experimental Evidence ( 16 )

Allele

Disease

Evidence

References

Atpα^HMS00703

model of epilepsy

CEA

(Hope et al., 2020)

Atpα²²⁰⁶

model of nervous system disease

CEA

(Palladino et al., 2003)

Atpα^DTS1

model of nervous system disease

CEA

(Talsma et al., 2014, Fergestad et al., 2006, Palladino et al., 2003)

model of epilepsy

CEA

(Fergestad et al., 2006)

Atpα^DTS1R1

model of familial hemiplegic migraine

CEA

(Ashmore et al., 2009)

Atpα^DTS2

model of nervous system disease

CEA

(Palladino et al., 2003)

Atpα^CJ5

model of familial hemiplegic migraine

CEA

(Ashmore et al., 2009)

model of nervous system disease

CEA

(Talsma et al., 2014)

Atpα^CJ6

model of familial hemiplegic migraine

CEA

(Ashmore et al., 2009)

Atpα^CJ7

model of familial hemiplegic migraine

CEA

(Ashmore et al., 2009)

Atpα^CJ10

model of familial hemiplegic migraine

CEA

(Ashmore et al., 2009)

model of nervous system disease

CEA

(Talsma et al., 2014)

Atpα^CJ13

model of familial hemiplegic migraine

CEA

(Ashmore et al., 2009)

Atpα^I571T

model of Charcot-Marie-Tooth disease type 2DD

CEA

(Yuan et al., 2025)

Atpα^A576T

model of Charcot-Marie-Tooth disease type 2DD

CEA

(Yuan et al., 2025)

Atpα^P579T

model of Charcot-Marie-Tooth disease type 2DD

CEA

(Yuan et al., 2025)

Atpα^D580F

model of Charcot-Marie-Tooth disease type 2DD

CEA

(Yuan et al., 2025)

Atpα^TTTF

model of Charcot-Marie-Tooth disease type 2DD

CEA

(Yuan et al., 2025)

Atpα^mut

model of Charcot-Marie-Tooth disease type 2DD

CEA

(Yuan et al., 2025)

Modifiers Based on Experimental Evidence ( 3 )

Allele

Disease

Interaction

References

Atpα^DTS1

model of nervous system disease

is exacerbated by CG5888^MB00188

(Talsma et al., 2014)

is exacerbated by Cyt-c1L^G9163

(Talsma et al., 2014)

is exacerbated by Dyrk2¹

(Talsma et al., 2014)

is exacerbated by Gαo^MB04922

(Talsma et al., 2014)

is exacerbated by Glt^EY22126

(Talsma et al., 2014)

is exacerbated by Nadk1b^MB05931

(Talsma et al., 2014)

is exacerbated by RpL19^k03704

(Talsma et al., 2014)

is exacerbated by SLO2^MB04544

(Talsma et al., 2014)

is exacerbated by aly¹

(Talsma et al., 2014)

is exacerbated by galectin^DG25505

(Talsma et al., 2014)

is ameliorated by ppk11^MB02012

(Talsma et al., 2014)

is exacerbated by rasp^m47

(Talsma et al., 2014)

is exacerbated by scramb2^EY01180

(Talsma et al., 2014)

exacerbates epilepsy

modeled by eag¹

(Fergestad et al., 2006)

modeled by Sh¹⁴

(Fergestad et al., 2006)

modeled by Sh¹⁴, eag¹

(Fergestad et al., 2006)

modeled by sei¹

(Fergestad et al., 2006)

modeled by para^ts1

(Fergestad et al., 2006)

Atpα^CJ5

model of nervous system disease

is ameliorated by CG5888^MB00188

(Talsma et al., 2014)

is ameliorated by Fkbp59^EY03538

(Talsma et al., 2014)

is ameliorated by Pde1c^c04487

(Talsma et al., 2014)

is ameliorated by Rbp9^Δ1

(Talsma et al., 2014)

is ameliorated by nAChRα6^MB06675

(Talsma et al., 2014)

is ameliorated by ppk11^MB02012

(Talsma et al., 2014)

is ameliorated by rasp^m47

(Talsma et al., 2014)

Atpα^CJ10

model of nervous system disease

is ameliorated by Pu^r1

(Talsma et al., 2014)

is ameliorated by Cyt-c1L^G9163

(Talsma et al., 2014)

is ameliorated by Dyrk2¹

(Talsma et al., 2014)

is ameliorated by Fkbp59^EY03538

(Talsma et al., 2014)

is ameliorated by Gαo^MI00833

(Talsma et al., 2014)

is ameliorated by Sec15²

(Talsma et al., 2014)

is ameliorated by cact⁷

(Talsma et al., 2014)

is ameliorated by pain^EP2451

(Talsma et al., 2014)

is ameliorated by scramb2^EY01180

(Talsma et al., 2014)

is ameliorated by slmb⁰⁰²⁹⁵

(Talsma et al., 2014)

is ameliorated by spz5^e03444

(Talsma et al., 2014)

Alleles Representing Disease-Implicated Variants

Genetic Tools, Stocks and Reagents

Sources of Stocks

Contact lab of origin for a reagent not available from a public stock center.

Bloomington Stock Center Disease Page

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

Atpα^GD3093

P{GD3093}

w¹¹¹⁸; P{GD3093}v12330

y¹ v¹; P{TRiP.JF02910}attP2

Atpα^HMS00047

P{TRiP.HMS00047}

y¹ v¹; P{TRiP.HMS00047}attP2/TM3, Sb¹

Atpα^HMS00703

P{TRiP.HMS00703}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00703}attP2

y¹ v¹; P{TRiP.GLC01778}attP40/CyO

JYalpha^GD1823

P{GD1823}

w¹¹¹⁸; P{GD1823}v3976

y¹ v¹; P{TRiP.HMJ23836}attP40/CyO

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Atpα²²⁰⁶

P-element activity

CRISPR/Cas9

CRISPR/Cas9

CRISPR/Cas9

CRISPR/Cas9

CRISPR/Cas9

CRISPR/Cas9

loss of function allele

gamma ray

Atpα^DTS1R2

loss of function allele

gamma ray

Atpα^DTS2R1

loss of function allele

gamma ray

Atpα^DTS2

ethyl methanesulfonate

Atpα^DTS2R3

loss of function allele

gamma ray

Atpα^DTS1

ethyl methanesulfonate

Atpα^CJ5

ethyl methanesulfonate

Atpα^CJ6

ethyl methanesulfonate

Atpα^CJ7

ethyl methanesulfonate

Atpα^CJ10

ethyl methanesulfonate

Atpα^CJ13

ethyl methanesulfonate

References (6)

Report Sections

Open Close