Details for: LRSAM1

Gene ID: 90678

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: LRSAM1

Ensembl ID: ENSG00000148356

Description: leucine rich repeat and sterile alpha motif containing 1

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • vascular leptomeningeal cell CL4023051
    CSI 7.5
    rCSI 13.15%
    PRS 88.75
  • lung ciliated cell CL1000271
    CSI 5.97
    rCSI 6.9%
    PRS 86.84
  • cerebral cortex endothelial cell CL1001602
    CSI 5.04
    rCSI 8.72%
    PRS 86.98
  • GABAergic neuron CL0000617
    CSI 4.61
    rCSI 15.46%
    PRS 79.48
  • mucosal invariant T cell CL0000940
    CSI 3.51
    rCSI 2.84%
    PRS 95.74
  • melanocyte CL0000148
    CSI 3.4
    rCSI 2.52%
    PRS 88.63
  • interneuron CL0000099
    CSI 3.05
    rCSI 6.12%
    PRS 86.33
  • sst GABAergic cortical interneuron CL4023017
    CSI 3.04
    rCSI 3.92%
    PRS 81.21
  • neural crest cell CL0011012
    CSI 3.02
    rCSI 2.39%
    PRS 85.63
  • retinal bipolar neuron CL0000748
    CSI 2.91
    rCSI 5.46%
    PRS 84.24
  • pulmonary alveolar type 1 cell CL0002062
    CSI 2.91
    rCSI 16.78%
    PRS 89.43
  • cerebellar granule cell CL0001031
    CSI 2.85
    rCSI 4.18%
    PRS 87.27
  • CD14-low, CD16-positive monocyte CL0002396
    CSI 2.69
    rCSI 2.07%
    PRS 94.42
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 2.64
    rCSI 6.84%
    PRS 89.63
  • Kupffer cell CL0000091
    CSI 2.62
    rCSI 5.99%
    PRS 92.69
  • hepatic stellate cell CL0000632
    CSI 2.6
    rCSI 9.74%
    PRS 88.03
  • choroid plexus epithelial cell CL0000706
    CSI 2.53
    rCSI 4.15%
    PRS 85.61
  • chondrocyte CL0000138
    CSI 2.5
    rCSI 3.97%
    PRS 87.75
  • kidney loop of Henle thin descending limb epithelial cell CL1001111
    CSI 2.47
    rCSI 3.51%
    PRS 90.04
  • Mueller cell CL0000636
    CSI 2.37
    rCSI 5.41%
    PRS 85.96
  • differentiation-committed oligodendrocyte precursor CL4023059
    CSI 2.33
    rCSI 4.23%
    PRS 86.03
  • intestinal tuft cell CL0019032
    CSI 2.29
    rCSI 3.49%
    PRS 93.24
  • lung neuroendocrine cell CL1000223
    CSI 2.28
    rCSI 3.37%
    PRS 93.02
  • Bergmann glial cell CL0000644
    CSI 2.27
    rCSI 3.1%
    PRS 85.08
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 2.22
    rCSI 2.76%
    PRS 77.92
  • VIP GABAergic cortical interneuron CL4023016
    CSI 2.17
    rCSI 2.59%
    PRS 80.14
  • alveolar macrophage CL0000583
    CSI 2.12
    rCSI 3.48%
    PRS 93.39
  • conjunctival epithelial cell CL1000432
    CSI 2.05
    rCSI 3.13%
    PRS 90.78
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 2.04
    rCSI 3.6%
    PRS 79.56
  • CD14-positive monocyte CL0001054
    CSI 2.01
    rCSI 2.5%
    PRS 96.42
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 1.95
    rCSI 7.03%
    PRS 78.2
  • lung secretory cell CL1000272
    CSI 1.91
    rCSI 4.74%
    PRS 92.53
  • cardiac neuron CL0010022
    CSI 1.91
    rCSI 6.13%
    PRS 90.71
  • cardiac muscle cell CL0000746
    CSI 1.81
    rCSI 2.6%
    PRS 84.51
  • astrocyte of the cerebral cortex CL0002605
    CSI 1.71
    rCSI 3.83%
    PRS 80.44
  • regular atrial cardiac myocyte CL0002129
    CSI 1.48
    rCSI 4.77%
    PRS 88.49
  • parietal epithelial cell CL1000452
    CSI 1.46
    rCSI 3.91%
    PRS 87.23
  • sncg GABAergic cortical interneuron CL4023015
    CSI 1.46
    rCSI 2.34%
    PRS 81.11
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 1.34
    rCSI 2.26%
    PRS 80.09
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 1.24
    rCSI 4.68%
    PRS 80.3
  • L6b glutamatergic cortical neuron CL4023038
    CSI 1.18
    rCSI 3.67%
    PRS 81.4
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.16
    rCSI 2.83%
    PRS 77.97
  • serotonergic neuron CL0000850
    CSI 1.12
    rCSI 4.99%
    PRS 78.11
  • retinal ganglion cell CL0000740
    CSI 1.11
    rCSI 2.44%
    PRS 82.38
  • neural progenitor cell CL0011020
    CSI 1.07
    rCSI 4.7%
    PRS 82.01
  • kidney connecting tubule epithelial cell CL1000768
    CSI 1.04
    rCSI 2.64%
    PRS 86.49
  • regular ventricular cardiac myocyte CL0002131
    CSI 1.02
    rCSI 6.36%
    PRS 86.03
  • dopaminergic neuron CL0000700
    CSI 0.86
    rCSI 4.86%
    PRS 81.88
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 0.78
    rCSI 2.43%
    PRS 83.06
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 0.73
    rCSI 4.29%
    PRS 80.54
  • cerebellar neuron CL1001611
    CSI 0.66
    rCSI 5.79%
    PRS 79.86
  • central nervous system neuron CL2000029
    CSI 0.59
    rCSI 4.35%
    PRS 84.35
  • ON parasol ganglion cell CL4033052
    CSI 0.4
    rCSI 5.69%
    PRS 84.99
  • ON midget ganglion cell CL4033046
    CSI 0.29
    rCSI 5.91%
    PRS 83.92
  • direct pathway medium spiny neuron CL4023026
    CSI 0.27
    rCSI 6.35%
    PRS 77.91
  • OFF midget ganglion cell CL4033047
    CSI 0.26
    rCSI 5.32%
    PRS 84.59
  • indirect pathway medium spiny neuron CL4023029
    CSI 0.24
    rCSI 5.88%
    PRS 78.04

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Analyzed for its expression specificity (CSI Z-Score), [LRSAM1](/details-gene/90678) is characterized as a broadly expressed E3 ubiquitin ligase rather than a specific cell type marker. Its expression across diverse cell lineages, including neuronal, immune, and epithelial cells, is consistent with its fundamental role in essential cellular processes such as autophagy, protein ubiquitination, and endocytosis. Functionally, it is crucial for cellular defense against intracellular pathogens and maintaining protein homeostasis. Mutations in [LRSAM1](/details-gene/90678) are clinically associated with Charcot-Marie-Tooth disease, a form of hereditary polyneuropathy, highlighting its critical, albeit widespread, importance in neuronal health. ## Cellular Roles and Expression Landscape The expression profile of [LRSAM1](/details-gene/90678), when evaluated for cell-type specificity, reveals a ubiquitous rather than a selective pattern. In the **Overall** context, the CSI (Z-SCORE) is 0.00 across all top-ranked cell types, with corresponding high p-values (p > 0.4) that indicate a lack of statistically significant enrichment in any single population. This suggests that [LRSAM1](/details-gene/90678) serves a conserved, housekeeping, or general defense function required by a multitude of cells. Its expression is noted in functionally disparate cell types, including: * **Nervous System:** [GABAergic neuron](/details-cell/CL0000617), [interneuron](/details-cell/CL0000099), and [cerebellar granule cell](/details-cell/CL0001031). This is consistent with the neurological phenotype observed in Charcot-Marie-Tooth disease patients with [LRSAM1](/details-gene/90678) mutations ([Guernsey et al., 2010](https://doi.org/10.1371/journal.pgen.1001081)). * **Immune System:** [Kupffer cell](/details-cell/CL0000091), [CD14-low, CD16-positive monocyte](/details-cell/CL0002396), and [mucosal invariant T cell](/details-cell/CL0000940). This aligns with its role in xenophagy and antigen processing. * **Epithelial and Endothelial Tissues:** [vascular leptomeningeal cell](/details-cell/CL4023051), [pulmonary alveolar type 1 cell](/details-cell/CL0002062), and [cerebral cortex endothelial cell](/details-cell/CL1001602). This broad expression in barrier tissues may indicate a role in cellular surveillance and defense. The lack of specificity suggests that while [LRSAM1](/details-gene/90678) is functionally critical, its expression level alone does not define the identity of these cells. Instead, its presence underscores the universal importance of ubiquitin-mediated protein degradation and autophagy for cellular maintenance and defense across the human body. ## Pathways and Molecular Function The broad expression of [LRSAM1](/details-gene/90678) is directly reflective of its involvement in fundamental cellular pathways. As an E3 ubiquitin ligase, it possesses [ubiquitin-protein transferase activity](/details-go/GO:0004842), a key function for tagging proteins for degradation or altering their function. This activity is central to several interconnected processes: * **Autophagy and Xenophagy:** [LRSAM1](/details-gene/90678) plays a crucial role in autophagy ([GO:0006914](https://www.ebi.ac.uk/QuickGO/term/GO:0006914)), particularly in the positive regulation of autophagosome assembly ([GO:2000786](https://www.ebi.ac.uk/QuickGO/term/GO:2000786)). Research has demonstrated its importance in ubiquitin-dependent autophagy of intracellular pathogens like *Salmonella Typhimurium*, a process known as xenophagy ([Huett et al., 2012](https://doi.org/10.1016/j.chom.2012.10.019)). This provides a molecular basis for its expression in immune cells like [Kupffer cells](/details-cell/CL0000091). * **Endocytosis and Viral Budding:** The gene is implicated in the negative regulation of endocytosis ([GO:0045806](https://www.ebi.ac.uk/QuickGO/term/GO:0045806)) and viral budding ([GO:0046755](https://www.ebi.ac.uk/QuickGO/term/GO:0046755)). It was shown to interact with the ESCRT machinery component TSG101 to regulate receptor endocytosis and retrovirus budding ([Amit et al., 2004](https://doi.org/10.1101/gad.294904)). * **Antigen Processing:** Its function aligns with the [Class I MHC mediated antigen processing & presentation](/details-pathway/R-HSA-983169) pathway. By ubiquitinating intracellular proteins (both self and foreign), [LRSAM1](/details-gene/90678) likely contributes to the generation of peptides for presentation on MHC class I molecules, a cornerstone of the [adaptive immune system](/details-pathway/R-HSA-1280218). The clinical link to Charcot-Marie-Tooth disease, a peripheral neuropathy, suggests that neurons are particularly sensitive to disruptions in these [LRSAM1](/details-gene/90678)-mediated pathways, potentially due to their extreme polarity, length, and high demand for protein quality control. ## Research Directions The widespread expression of [LRSAM1](/details-gene/90678) juxtaposed with its association with a specific peripheral neuropathy raises compelling questions about cell-type-specific vulnerabilities and functions. ### Testable Hypotheses 1. **Neuronal-Specific Susceptibility to LRSAM1 Dysfunction:** The manifestation of Charcot-Marie-Tooth disease from mutations in the broadly expressed [LRSAM1](/details-gene/90678) gene suggests that peripheral motor and sensory neurons possess a unique dependency on its function. This vulnerability may arise from the immense logistical challenge of maintaining protein homeostasis along their long axons, making them exquisitely sensitive to defects in autophagic clearance of protein aggregates. * **Experimental Approach:** Generate iPSC-derived motor neurons and a control cell line (e.g., fibroblasts) harboring patient-derived [LRSAM1](/details-gene/90678) mutations using CRISPR-Cas9. Perform quantitative proteomics to identify ubiquitinated protein aggregates and use live-cell imaging with fluorescently tagged autophagy markers (e.g., LC3) to measure autophagic flux and axonal transport defects. 2. **Context-Dependent Substrate Specificity in Xenophagy:** While [LRSAM1](/details-gene/90678) is a general factor in xenophagy, its ubiquitination targets may be tailored to specific pathogens or cell types. Its expression in both professional phagocytes like [Kupffer cells](/details-cell/CL0000091) and non-professional phagocytes like [pulmonary alveolar type 1 cells](/details-cell/CL0002062) suggests it might recognize different pathogen-associated molecular patterns or recruit distinct downstream effectors depending on the cellular context. * **Experimental Approach:** Perform proximity-dependent biotinylation (BioID) or APEX2-labeling mass spectrometry in different cell types (e.g., macrophages vs. epithelial cells) infected with various intracellular pathogens (e.g., *Salmonella*, *Mycobacterium tuberculosis*) to identify the cell-type and pathogen-specific interactome and ubiquitination substrates of [LRSAM1](/details-gene/90678). 3. **Role in Blood-Brain Barrier Maintenance:** The expression of [LRSAM1](/details-gene/90678) in [cerebral cortex endothelial cells](/details-cell/CL1001602) and its involvement in endocytosis suggest a potential role in regulating the integrity of the blood-brain barrier (BBB). Dysfunctional [LRSAM1](/details-gene/90678) could disrupt the endocytic trafficking of tight junction proteins, leading to increased BBB permeability and contributing to neuroinflammatory or neurodegenerative conditions. * **Experimental Approach:** Utilize an *in vitro* BBB model with human cerebral microvascular endothelial cells. Knock down [LRSAM1](/details-gene/90678) using siRNA and measure changes in trans-endothelial electrical resistance (TEER) and paracellular flux of fluorescently labeled dextrans. Analyze the localization and expression levels of key tight junction proteins like claudin-5 and ZO-1 via immunofluorescence microscopy. ### Therapeutic Potential As an E3 ligase, [LRSAM1](/details-gene/90678) is a theoretically druggable enzyme. Small molecule modulators that either enhance or inhibit its ligase activity could be developed. Enhancing its activity might be a strategy to promote the clearance of toxic protein aggregates in neurodegenerative diseases or to boost the elimination of intracellular pathogens. However, its ubiquitous expression poses a significant challenge for therapeutic development, as systemic modulation could lead to widespread, unpredictable side effects. Future therapeutic strategies would likely require tissue-specific delivery mechanisms (e.g., lipid nanoparticles targeted to the peripheral nervous system) to mitigate off-target toxicity and safely harness its therapeutic potential.

Genular Protein ID: 3917662083

Symbol: LRSM1_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q6UWE0 Q5VVV0 Q8NB40 Q96GT5 Q96MX5 Q96MZ7

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 2 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EC 1 ELM 1 EMBL 6 Ensembl 6 ExpressionAtlas 1 GO 15 Gene3D 3 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 8 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 MetOSite 1 MoonDB 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 3 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 Pumba 1 RNAct 1 Reactome 1 RefSeq 5 SIGNOR 1 SMART 3 SMR 1 STRING 1 SUPFAM 3 SignaLink 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 12975309

Title: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.

PubMed ID: 12975309

DOI: 10.1101/gr.1293003

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15164053

Title: DNA sequence and analysis of human chromosome 9.

PubMed ID: 15164053

DOI: 10.1038/nature02465

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 15256501

Title: Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding.

PubMed ID: 15256501

DOI: 10.1101/gad.294904

PubMed ID: 17556548

Title: Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery.

PubMed ID: 17556548

DOI: 10.1126/science.1143422

PubMed ID: 18669648

Title: A quantitative atlas of mitotic phosphorylation.

PubMed ID: 18669648

DOI: 10.1073/pnas.0805139105

PubMed ID: 20865121

Title: Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients with Charcot-Marie-Tooth disease.

PubMed ID: 20865121

DOI: 10.1371/journal.pgen.1001081

PubMed ID: 20068231

Title: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.

PubMed ID: 20068231

DOI: 10.1126/scisignal.2000475

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 23245322

Title: The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella Typhimurium.

PubMed ID: 23245322

DOI: 10.1016/j.chom.2012.10.019

PubMed ID: 22012984

Title: A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy.

PubMed ID: 22012984

DOI: 10.1093/hmg/ddr471

PubMed ID: 25484098

Title: PHF23 (plant homeodomain finger protein 23) negatively regulates cell autophagy by promoting ubiquitination and degradation of E3 ligase LRSAM1.

PubMed ID: 25484098

DOI: 10.4161/auto.36439

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 27615052

Title: A novel missense mutation of CMT2P alters transcription machinery.

PubMed ID: 27615052

DOI: 10.1002/ana.24776

PubMed ID: 27686364

Title: Charcot-Marie-Tooth disease type 2G redefined by a novel mutation in LRSAM1.

PubMed ID: 27686364

DOI: 10.1002/ana.24775

Sequence Information:

  • Length: 723
  • Mass: 83594
  • Checksum: 4A59461C92467BB1
  • Sequence:
    • MPLFFRKRKP SEEARKRLEY QMCLAKEAGA DDILDISKCE LSEIPFGAFA TCKVLQKKVL 
IVHTNHLTSL LPKSCSLLSL ATIKVLDLHD NQLTALPDDL GQLTALQVLN VERNQLMQLP 
RSIGNLTQLQ TLNVKDNKLK ELPDTVGELR SLRTLNISGN EIQRLPQMLA HVRTLEMLSL 
DASAMVYPPR EVCGAGTAAI LQFLCKESGL EYYPPSQYLL PILEQDGIEN SRDSPDGPTD 
RFSREELEWQ NRFSDYEKRK EQKMLEKLEF ERRLELGQRE HTQLLQQSSS QKDEILQTVK 
EEQSRLEQGL SEHQRHLNAE RQRLQEQLKQ TEQNISSRIQ KLLQDNQRQK KSSEILKSLE 
NERIRMEQLM SITQEETESL RRRDVASAMQ QMLTESCKNR LIQMAYESQR QNLVQQACSS 
MAEMDERFQQ ILSWQQMDQN KAISQILQES AMQKAAFEAL QVKKDLMHRQ IRSQIKLIET 
ELLQLTQLEL KRKSLDTESL QEMISEQRWA LSSLLQQLLK EKQQREEELR EILTELEAKS 
ETRQENYWLI QYQRLLNQKP LSLKLQEEGM ERQLVALLEE LSAEHYLPIF AHHRLSLDLL 
SQMSPGDLAK VGVSEAGLQH EILRRVQELL DAARIQPELK PPMGEVVTPT APQEPPESVR 
PSAPPAELEV QASECVVCLE REAQMIFLNC GHVCCCQQCC QPLRTCPLCR QDIAQRLRIY 
HSS