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>
<td class="label">Cell Type</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Motor neurons</td>
<td>High</td>
</tr>
<tr>
<td class="label">Cortical neurons</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Glial cells</td>
<td>Low to moderate</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
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
See Also
- [ANKZF1 Protein](/proteins/ankzf1-protein)
- [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
- [Motor Neuron Disease](/mechanisms/motor-neuron-disease)
- [Protein Aggregation](/mechanisms/protein-aggregation)
- [Nuclear Envelope Dysfunction](/mechanisms/nuclear-envelope-dysfunction)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
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