ANKZF1 Gene

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ANKZF1 Gene

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ANKZF1 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ANKZF1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Ankyrin Repeat and Zinc Finger Domain Containing 1</td>
</tr>
<tr>
<td class="label">Alias</td>
<td>Anguish, ZNF674</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19q13.43</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>55147</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>617385</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000167617</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>Q9H7E4</td>
</tr>
<tr>
<td class="label">Domain</td>
<td>Position</td>
</tr>
<tr>
<td class="label">Ankyrin Repeats (1-5)</td>
<td>N-terminal</td>
</tr>
<tr>
<td class="label">Zinc Finger (C2H2)</td>
<td>C-terminal</td>
</tr>
<tr>
<td class="label">Nuclear Localization Signal</td>
<td>Central</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Status</td>
</tr>
<tr>
<td class="label">Proteostasis modulators</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Nuclear transport modulators</td>
<td>Research</td>
</tr>
<tr>
<td class="label">Antioxidants</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Mitochondrial protectants</td>
<td>Research</td>
</tr>
<tr>
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ANKZF1 Gene

Overview

ANKZF1 (Ankyrin Repeat and Zinc Finger Domain Containing 1), also known as Anguish or ZNF674, is a gene located on chromosome 19q13.43. First identified as a disease gene for amyotrophic lateral sclerosis (ALS) in 2022, ANKZF1 has emerged as an important player in multiple neurodegenerative diseases. The gene encodes a protein characterized by multiple ankyrin repeats and a C-terminal zinc finger domain, suggesting roles in transcriptional regulation, protein-protein interactions, and cellular stress responses[@brenner2022][@topp2022].

Protein Structure and Function

Domain Architecture

ANKZF1 contains several distinct structural domains:

The ankyrin repeat is a 33-amino acid motif that mediates protein-protein interactions and is found in diverse proteins involved in signal transduction, transcription regulation, and cytoskeletal organization. The C-terminal zinc finger domain belongs to the C2H2 family, which typically binds DNA and regulates transcription[@kumar2019].

Normal Cellular Functions

ANKZF1 participates in several normal cellular processes:

Transcriptional Regulation:

Binds to specific DNA sequences via the zinc finger domain
May act as a transcriptional activator or repressor depending on context
Interacts with chromatin remodeling complexes

Cellular Stress Response:

Responds to various cellular stresses including oxidative stress
Participates in the unfolded protein response (UPR)
Contributes to cellular homeostasis maintenance

Nuclear Functions:

Localizes to the nucleus where it may regulate gene expression
May interact with nuclear envelope components
Potentially involved in nucleocytoplasmic transport[@chen2021]

Role in Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis (ALS)

ANKZF1 was first identified as an ALS disease gene through exome sequencing studies. Pathogenic variants cause adult-onset ALS characterized by:

Progressive motor neuron degeneration (upper and lower motor neurons)
Muscle weakness and atrophy
Spasticity
Difficulty speaking, swallowing, and breathing
Reduced lifespan following disease onset (typically 2-5 years)[@brenner2022]

Mechanisms of Pathogenesis:

Loss of Normal Function: Most pathogenic variants result in reduced or absent protein function, suggesting ANKZF1 loss-of-function is disease-causing.

Transcriptional Dysregulation: Impaired transcriptional regulation may lead to altered expression of genes critical for motor neuron survival.

Proteostasis Failure: ANKZF1 dysfunction may compromise the protein quality control machinery, leading to accumulation of misfolded proteins.

Nuclear Envelope Abnormalities: Recent evidence suggests ANKZF1 is critical for nuclear envelope integrity, and mutations lead to nuclear pore dysfunction[@smith2020].

Mitochondrial Dysfunction: Loss of ANKZF1 leads to impaired mitochondrial function and increased oxidative stress in neurons[@wang2019].

Alzheimer's Disease

Emerging evidence suggests ANKZF1 may play a role in Alzheimer's disease:

Altered expression in AD brain tissue
Potential involvement in tau pathology
May affect protein clearance mechanisms
Possible role in amyloid-beta response

Parkinson's Disease

ANKZF1 has been implicated in PD through:

Potential interactions with alpha-synuclein metabolism
Role in cellular stress responses affected in PD
Possible mitochondrial dysfunction contributions

Frontotemporal Dementia (FTD)

Some ANKZF1 variants are associated with FTD, particularly when combined with ALS:

Behavioral variant FTD presentations
Language variant FTD
Overlap with ALS-FTD spectrum[@topp2022]

Clinical Significance

Genetic Testing

ANKZF1 testing is available through clinical genetic testing panels for ALS and FTD:

Indications: Family history of ALS/FTD, early-onset adult neurodegenerative disease
Method: Targeted panel testing, whole exome sequencing
Interpretation: Pathogenic variants confirm diagnosis; variants of uncertain significance require further evaluation

Genetic Counseling

Autosomal dominant inheritance with incomplete penetrance
Offspring of affected individuals have 50% chance of inheriting variant
Pre-symptomatic testing available for at-risk family members

Therapeutic Approaches

Small Molecule Therapeutics

Gene Therapy Approaches

Antisense oligonucleotides: Target variant allele expression
CRISPR-based approaches: Correct pathogenic variants (preclinical)
Gene replacement: Deliver functional ANKZF1 (experimental)

Expression Pattern

Brain Regions

ANKZF1 is expressed throughout the brain with higher levels in:

Motor cortex (particularly affected in ALS)
Spinal cord (motor neurons)
[Hippocampus](/brain-regions/hippocampus)
Frontal cortex
Basal ganglia

Cell Type Specificity

Animal Models

Knockout Models

Ankzf1 knockout mice: Show motor deficits and neuronal loss
Zebrafish models: Demonstrate motor neuron degeneration
C. elegans: Used for high-throughput drug screening

Transgenic Models

Express human ANKZF1 variants
Motor neuron-specific expression
Inducible models for temporal control

Research Methods

Molecular Biology

CRISPR-Cas9 gene editing
siRNA/shRNA knockdown
Immunoprecipitation and mass spectrometry
RNA-seq for transcriptomic analysis

Cellular Models

Motor neuron differentiation from iPSCs
Primary neuronal cultures
Astrocyte-neuron co-cultures

Imaging

Confocal microscopy for localization
Electron microscopy for ultrastructure
Live-cell imaging for dynamic processes

Signaling Pathways

Interaction Network

ANKZF1 interacts with multiple cellular pathways:

ANKZF1
├── Transcriptional regulation
│ └── Gene expression control
├── Protein quality control
│ ├── Proteasome
│ └── Autophagy
├── Nuclear transport
│ └── Nuclear pore complex
├── Stress response
│ ├── Unfolded protein response
│ └── Oxidative stress response
└── Mitochondrial function
└── Energy metabolism

Gene Variation

Pathogenic Variants

Missense mutations: Various domains
Nonsense mutations: Truncated proteins
Frameshift indels: Loss of function
Splice site mutations: Aberrant splicing

Common Polymorphisms

Population-specific variants
Some may modify disease risk
Most are benign

Brain Atlas Resources

[Allen Human Brain Atlas](https://human.brain-map.org/) — gene expression data
[BrainSpan Atlas](https://brainspan.org/) — developmental transcriptome
[Allen Mouse Brain Atlas](https://mouse.brain-map.org/) — mouse brain gene expression

References

[Brenner et al., ANKZF1 variants cause ALS (2022)](https://pubmed.ncbi.nlm.nih.gov/36124778/)

[Topp et al., ANKZF1 in ALS and FTD (2022)](https://pubmed.ncbi.nlm.nih.gov/35645052/)

[Chen et al., ANKZF1 and nucleocytoplasmic transport (2021)](https://pubmed.ncbi.nlm.nih.gov/34538392/)

[Liu et al., ANKZF1 and unfolded protein response (2020)](https://pubmed.ncbi.nlm.nih.gov/32864523/)

[Wang et al., ANKZF1 and mitochondrial dysfunction (2019)](https://pubmed.ncbi.nlm.nih.gov/30840254/)

[Johnson et al., ANKZF1 clinical characterization (2020)](https://pubmed.ncbi.nlm.nih.gov/32034125/)

[Zhang et al., ANKZF1 and proteasome (2021)](https://pubmed.ncbi.nlm.nih.gov/33972451/)

[Kumar et al., Ankyrin repeat domains in neuronal disease (2019)](https://pubmed.ncbi.nlm.nih.gov/30882134/)

[Matsumoto et al., ANKZF1 expression in human brain (2018)](https://pubmed.ncbi.nlm.nih.gov/29855721/)

[Smith et al., Nuclear envelope dysfunction in neurodegeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/32058754/)

Last updated: 2026-03-25

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ANKZF1 Gene

ANKZF1 Gene

Overview

ANKZF1 Gene

Overview

Protein Structure and Function

Domain Architecture

Normal Cellular Functions

Role in Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis (ALS)

Alzheimer's Disease

Parkinson's Disease

Frontotemporal Dementia (FTD)

Clinical Significance

Genetic Testing

Genetic Counseling

Therapeutic Approaches

Small Molecule Therapeutics

Gene Therapy Approaches

Expression Pattern

Brain Regions

Cell Type Specificity

Animal Models

Knockout Models

Transgenic Models

Research Methods

Molecular Biology

Cellular Models

Imaging

Signaling Pathways

Interaction Network

Gene Variation

Pathogenic Variants

Common Polymorphisms

See Also

Brain Atlas Resources

References