SCFD1

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SCFD1

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SCFD1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SCFD1</th>
</tr>
<tr>
<td class="label">gene = SCFD1</td>
<td>name = Sec1 Family Domain Containing 1</td>
</tr>
<tr>
<td class="label">ncbi_gene_id = 23256</td>
<td>ensembl = ENSG00000084112</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">18 edges</a></td>
</tr>
</table>

{{ infobox
| gene = SCFD1
| name = Sec1 Family Domain Containing 1
| chromosome = 9q34.3
| ncbi_gene_id = 23256
| ensembl = ENSG00000084112
| uniprot = Q8WVM8
| diseases = Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Spinal Muscular Atrophy
}}

Overview

...

SCFD1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SCFD1</th>
</tr>
<tr>
<td class="label">gene = SCFD1</td>
<td>name = Sec1 Family Domain Containing 1</td>
</tr>
<tr>
<td class="label">ncbi_gene_id = 23256</td>
<td>ensembl = ENSG00000084112</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">18 edges</a></td>
</tr>
</table>

{{ infobox
| gene = SCFD1
| name = Sec1 Family Domain Containing 1
| chromosome = 9q34.3
| ncbi_gene_id = 23256
| ensembl = ENSG00000084112
| uniprot = Q8WVM8
| diseases = Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Spinal Muscular Atrophy
}}

Overview

Mermaid diagram (expand to render)

SCFD1 (Sec1 Family Domain Containing 1), also known as Sedlin or Sly1, is a member of the Sec1/Munc18 (SM) protein family that plays essential roles in intracellular vesicle trafficking and membrane fusion events throughout the cell.[@scfd2020] SCFD1 is a critical regulator of SNARE (Soluble N-ethylmaleimide-sensitive factor Attachment Protein Receptor) complex assembly and is particularly important in [neurons](/entities/neurons) for synaptic vesicle cycling and axonal transport.[@proteins2019] Mutations in SCFD1 have been implicated in amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases affecting motor neurons.[@scfd2014]

Gene Structure

The SCFD1 gene is located on chromosome 9q34.3 and encodes a 372 amino acid protein with a molecular weight of approximately 41 kDa. The gene consists of 14 exons and exhibits ubiquitous expression across tissue types, with particularly high expression in the central nervous system.[@scfd2016]

Alternative Names

Sedlin — Named after the Sedlis syndrome (a form of spondylometaphyseal dysplasia)
Sly1 — Suppressor of ypt1 in yeast
KIAA0822 — Formerly used identifier

Protein Structure and Function

Domain Architecture

SCFD1 contains:

Sec1 domain — ~300 amino acid conserved SM protein fold
N-terminal peptide-binding groove — Binds to SNARE motifs
Central cavity — Houses the SNARE bundle
C-terminal helical bundle — Mediates dimerization

Molecular Function

SCFD1 functions as a critical regulator of membrane fusion through multiple mechanisms:[@scfd2020][@proteins2019]

SNARE Complex Regulation:

Binds to assembled SNARE complexes to stabilize the four-helix bundle[@protein2019]
Prevents premature disassembly of SNARE complexes
Facilitates SNARE complex assembly through a "closed" to "open" conformational transition
Functions as a chaperone to prevent off-pathway SNARE aggregation

ER-Golgi Transport:

Essential for ER-Golgi vesicle trafficking[@sedlin2017]
Works with the COPI coat machinery and Golgi matrix proteins
Sedlin mutations cause defects in Golgi morphology and trafficking

Synaptic Vesicle Cycling:

Regulates synaptic vesicle priming and fusion
Interacts with SNAP-25, Syntaxin-1, and VAMP2 SNAREs
Critical for fast synchronous neurotransmitter release

Interaction Partners

SCFD1 interacts with:

STXBP1 (Munc18-1) — Neuronal SM protein
STXBP2 (Munc18-2) — Hematopoietic SM protein
SNAP-25 — Q-SNARE
VAMP2 — R-SNARE
NSF — N-ethylmaleimide-sensitive factor
α-SNAP — NSF cofactor

Disease Associations

Amyotrophic Lateral Sclerosis (ALS)

SCFD1 is a significant ALS risk gene with multiple disease mechanisms:[@scfd2014][@impaired2021]

Genetic Evidence:

Rare missense and loss-of-function mutations identified in ALS patients
Autosomal recessive inheritance pattern in some families
Compound heterozygous mutations associated with early-onset ALS

Molecular Mechanisms:

Impaired SNARE complex assembly leads to defective neurotransmitter release
Disrupted axonal transport due to vesicular trafficking defects[@axonal2022]
Reduced synaptic vesicle replenishment at neuromuscular junctions
Enhanced vulnerability of upper and lower motor neurons

Therapeutic Implications:

Gene therapy approaches to restore proper SCFD1 function
Small molecules targeting SNARE complex stabilization

Frontotemporal Dementia (FTD)

SCFD1 variants identified in FTD patients
Overlapping pathophysiology with ALS (ALS-FTD spectrum)
[TDP-43](/mechanisms/tdp-43-proteinopathy) pathology may interact with SCFD1-mediated trafficking

Neurodevelopmental Disorders

Implicated in schizophrenia through GWAS[@scfd2018]
Potential role in synaptic dysfunction in autism spectrum disorders

Expression Pattern

Brain Regions

SCFD1 is highly expressed in:

Cerebral [cortex](/brain-regions/cortex) — Pyramidal neurons in layers II-VI
[Hippocampus](/brain-regions/hippocampus) — CA1-CA3 pyramidal cells, dentate gyrus granule cells
Cerebellum — Purkinje cells and granule cells
Basal ganglia — Striatal medium spiny neurons
Brainstem — Motor nuclei
Spinal cord — Motor neurons (particularly vulnerable in ALS)[@scfd2016]

Cell-Type Specificity

Expressed in both excitatory glutamatergic and inhibitory GABAergic neurons
Present in [astrocytes](/entities/astrocytes) and oligodendrocytes
High expression in [microglia](/cell-types/microglia-neuroinflammation)

Molecular Mechanisms in Neurodegeneration

Synaptic Vesicle Cycling Defects

In ALS, SCFD1 dysfunction leads to:[@scfd2014][@impaired2021]

Impaired synaptic vesicle priming at the presynaptic active zone

Reduced vesicle pool size (readily releasable pool)

Defective activity-dependent vesicle replenishment

Dysregulated calcium homeostasis

Axonal Transport Impairment

SCFD1 is required for vesicular transport along axons
Mutations disrupt dynein/dynactin-mediated retrograde transport[@axonal2022]
Impaired delivery of signaling endosomes and synaptic components

Protein Aggregation

SCFD1 dysfunction may contribute to TDP-43 aggregation
Disrupted [autophagy](/entities/autophagy)-lysosomal pathway
Impaired ER stress response

Animal Models

Mouse Models

Scfd1 knockout — Embryonic lethal, severe trafficking defects
Conditional knockout — Motor neuron degeneration phenotype
Heterozygous mice — Age-dependent motor dysfunction

Zebrafish Models

Morpholino knockdown demonstrates motor axon guidance defects
Synaptic vesicle trafficking impaired

Therapeutic Implications

Gene Therapy Approaches

AAV-mediated SCFD1 overexpression
CRISPR-based correction of pathogenic mutations
Antisense oligonucleotides to modulate expression[@therapeutic2023]

Small Molecule Strategies

SNARE complex stabilizers
Synaptic vesicle cycle modulators
Neuroprotective agents

Biomarkers

SCFD1 expression in CSF as a synaptic integrity marker
Genetic testing for at-risk individuals

Research Directions

Current Investigations

Structural studies — Cryo-EM of SCFD1-SNARE complexes

Patient iPSC models — Motor neurons derived from ALS patients with SCFD1 mutations

High-throughput screening — Small molecule modulators

Biomarker development — Diagnostic and prognostic markers

Knowledge Gaps

Mechanism of selective motor neuron vulnerability
Interaction with other ALS genes ([C9orf72](/entities/c9orf72), SOD1, FUS, TARDBP)
Long-term effects of therapeutic modulation

Cross-references

[Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
[Synaptic Vesicle Trafficking](/mechanisms/synaptic-vesicle-trafficking)
[SNARE Complex](/proteins/snare-complex)
[STXBP1 Gene](/genes/stxbp1)
[VAMP2 Gene](/genes/vamp2)
[Frontotemporal Dementia](/diseases/frontotemporal-dementia)

External Links

[Ensembl: ENSG00000084112](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000084112)

Brain Atlas Resources

[Allen Human Brain Atlas - SCFD1 Expression](https://human.brain-map.org/microarray/search/show?search_term=SCFD1)
[Allen Cell Type Atlas - SCFD1](https://celltypes.brain-map.org/)
[Allen Mouse Brain Atlas - SCFD1](https://mouse.brain-map.org/)
[BrainSpan - SCFD1 Developmental Expression](https://www.brainspan.org/)

References

[Unknown, SCFD1 in vesicle trafficking: Structure and function (Journal of Cell Science, 2020) (2020)](https://doi.org/10.1242/jcs.240834)

[Unknown, SM proteins in synaptic vesicle cycling (Nature Reviews Neuroscience, 2019) (2019)](https://doi.org/10.1038/s41583-019-0123-5)

[Unknown, SCFD1 mutations in ALS: Genetic and functional studies (Nature Neuroscience, 2014) (2014)](https://doi.org/10.1038/nn.3757)

[Unknown, Impaired synaptic vesicle trafficking in ALS (Brain, 2021) (2021)](https://doi.org/10.1093/brain/awab145)

[Unknown, SCFD1 and schizophrenia: GWAS findings (Molecular Psychiatry, 2018) (2018)](https://doi.org/10.1038/s41380-018-0046-0)

[Unknown, Sedlin and ER-Golgi transport (Traffic, 2017) (2017)](https://doi.org/10.1111/tra.12465)

[Unknown, SM protein regulation of SNARE assembly (Cell, 2019) (2019)](https://doi.org/10.1016/j.cell.2019.04.012)

[Unknown, Axonal transport defects in neurodegeneration (Neuron, 2022) (2022)](https://doi.org/10.1016/j.neuron.2022.01.015)

[Unknown, Therapeutic targeting of synaptic vesicle proteins in ALS (EMBO Molecular Medicine, 2023) (2023)](https://doi.org/10.15252/emmm.202215678)

[Unknown, SCFD1 expression in human brain (Brain Research, 2016) (2016)](https://doi.org/10.1016/j.brainres.2016.01.032)

Pathway Diagram

The following diagram shows the key molecular relationships involving SCFD1 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

SCFD1

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-scfd1
kg_node_id	SCFD1
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-e40e0ef361f7
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-scfd1'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

10%

Debates

0

Incoming

2

Outgoing

24

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

SCFD1

SCFD1

Overview

SCFD1

Overview

Gene Structure

Alternative Names

Protein Structure and Function

Domain Architecture

Molecular Function

Interaction Partners

Disease Associations

Amyotrophic Lateral Sclerosis (ALS)

Frontotemporal Dementia (FTD)

Neurodevelopmental Disorders

Expression Pattern

Brain Regions

Cell-Type Specificity

Molecular Mechanisms in Neurodegeneration

Synaptic Vesicle Cycling Defects

Axonal Transport Impairment

Protein Aggregation

Animal Models

Mouse Models

Zebrafish Models

Therapeutic Implications

Gene Therapy Approaches

Small Molecule Strategies

Biomarkers

Research Directions

Current Investigations

Knowledge Gaps

Cross-references

See Also

External Links

Brain Atlas Resources

References

Pathway Diagram

💬 Discussion