LRSAM1

Summary

LRSAM1 (leucine rich repeat and sterile alpha motif containing 1, HGNC:25135) is a protein-coding gene on chromosome 9q33.3-q34.11, encoding E3 ubiquitin-protein ligase LRSAM1 (Q6UWE0). E3 ubiquitin-protein ligase that mediates monoubiquitination of TSG101 at multiple sites, leading to inactivate the ability of TSG101 to sort endocytic (EGF receptors) and exocytic (HIV-1 viral proteins) cargos.

This gene encodes a ring finger protein involved in a variety of functions, including regulation of signaling pathways and cell adhesion, mediation of self-ubiquitylation, and involvement in cargo sorting during receptor endocytosis. Mutations in this gene have been associated with Charcot-Marie-Tooth disease. Multiple transcript variants encoding different isoforms have been identified for this gene.

Source: NCBI Gene 90678 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease axonal type 2P (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 1,028 total — 45 pathogenic, 46 likely-pathogenic
• Phenotypes (HPO): 20
• MANE Select transcript: NM_001005373

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25135
Approved symbol	LRSAM1
Name	leucine rich repeat and sterile alpha motif containing 1
Location	9q33.3-q34.11
Locus type	gene with protein product
Status	Approved
Aliases	FLJ31641, CMT2P, RIFLE, TAL
Ensembl gene	ENSG00000148356
Ensembl biotype	protein_coding
OMIM	610933
Entrez	90678

Gene structure

Transcript identifiers

Ensembl transcripts: 76 — 46 protein_coding, 16 retained_intron, 14 nonsense_mediated_decay

ENST00000300417, ENST00000323301, ENST00000373322, ENST00000373324, ENST00000472068, ENST00000483302, ENST00000485704, ENST00000486587, ENST00000498513, ENST00000674511, ENST00000674516, ENST00000674621, ENST00000674771, ENST00000674784, ENST00000674970, ENST00000675012, ENST00000675141, ENST00000675198, ENST00000675213, ENST00000675224, ENST00000675253, ENST00000675364, ENST00000675445, ENST00000675448, ENST00000675521, ENST00000675558, ENST00000675572, ENST00000675641, ENST00000675657, ENST00000675662, ENST00000675789, ENST00000675883, ENST00000675945, ENST00000676014, ENST00000676035, ENST00000676106, ENST00000676137, ENST00000676170, ENST00000676318, ENST00000676336, ENST00000676349, ENST00000676399, ENST00000676409, ENST00000870573, ENST00000870574, ENST00000870575, ENST00000870576, ENST00000870577, ENST00000870578, ENST00000870579, ENST00000870580, ENST00000870581, ENST00000923145, ENST00000923146, ENST00000923147, ENST00000923148, ENST00000923149, ENST00000923150, ENST00000942472, ENST00000942473, ENST00000942474, ENST00000942475, ENST00000942476, ENST00000942477, ENST00000942478, ENST00000942479, ENST00000942480, ENST00000942481, ENST00000942482, ENST00000942483, ENST00000942484, ENST00000942485, ENST00000942486, ENST00000942487, ENST00000942488, ENST00000942489

RefSeq mRNA: 7 — MANE Select: NM_001005373 NM_001005373, NM_001005374, NM_001190723, NM_001384142, NM_001384143, NM_001384144, NM_138361

CCDS: CCDS55347, CCDS6873, CCDS94485

Canonical transcript exons

ENST00000300417 — 26 exons

Exon	Start	End
ENSE00000984635	127462252	127462373
ENSE00001036832	127473801	127473931
ENSE00001036836	127459003	127459071
ENSE00001036838	127457316	127457393
ENSE00001036844	127461173	127461257
ENSE00001036845	127467740	127467830
ENSE00001036860	127455576	127455620
ENSE00001431700	127451929	127452084
ENSE00003461099	127481183	127481227
ENSE00003462130	127454998	127455054
ENSE00003467801	127479839	127479978
ENSE00003538683	127478934	127478963
ENSE00003599821	127495320	127495418
ENSE00003614879	127495964	127496095
ENSE00003630900	127482950	127483020
ENSE00003646596	127485736	127485835
ENSE00003650361	127454496	127454599
ENSE00003660770	127487676	127487763
ENSE00003662561	127479383	127479505
ENSE00003663798	127489444	127489518
ENSE00003665327	127501010	127501143
ENSE00003665358	127502774	127503499
ENSE00003667855	127491215	127491295
ENSE00003688311	127492802	127492897
ENSE00003692193	127497253	127497334
ENSE00003900059	127451510	127451669

Expression profiles

Bgee: expression breadth ubiquitous, 192 present calls, max score 93.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.8807 / max 130.0447, expressed in 1812 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98609	18.3986	1811
98610	1.0802	774
98608	0.4019	179

Top tissues by expression

248 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	93.83	gold quality
sural nerve	UBERON:0015488	91.65	gold quality
skin of leg	UBERON:0001511	90.54	gold quality
skin of abdomen	UBERON:0001416	90.53	gold quality
heart left ventricle	UBERON:0002084	89.58	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.43	gold quality
right frontal lobe	UBERON:0002810	89.19	gold quality
cerebellar hemisphere	UBERON:0002245	89.17	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.14	gold quality
cerebellar cortex	UBERON:0002129	89.06	gold quality
cardiac ventricle	UBERON:0002082	88.99	gold quality
anterior cingulate cortex	UBERON:0009835	88.31	gold quality
lower esophagus mucosa	UBERON:0035834	87.88	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.76	gold quality
cerebellum	UBERON:0002037	87.47	gold quality
zone of skin	UBERON:0000014	86.93	gold quality
right adrenal gland	UBERON:0001233	86.90	gold quality
hypothalamus	UBERON:0001898	86.75	gold quality
right adrenal gland cortex	UBERON:0035827	86.63	gold quality
granulocyte	CL:0000094	86.58	gold quality
right atrium auricular region	UBERON:0006631	86.46	gold quality
ectocervix	UBERON:0012249	86.37	gold quality
prefrontal cortex	UBERON:0000451	86.35	gold quality
right ovary	UBERON:0002118	86.33	gold quality
heart	UBERON:0000948	86.28	gold quality
left ovary	UBERON:0002119	86.19	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	86.08	gold quality
metanephros cortex	UBERON:0010533	85.85	gold quality
left adrenal gland	UBERON:0001234	85.61	gold quality
cardiac atrium	UBERON:0002081	85.60	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.87

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

27 targeting LRSAM1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-4252	98.45	66.37	987
HSA-MIR-6881-5P	98.16	67.38	665
HSA-MIR-4494	97.86	64.93	850
HSA-MIR-1914-5P	97.83	66.21	807
HSA-MIR-8089	97.74	66.21	1698
HSA-MIR-4667-5P	97.61	66.67	1683
HSA-MIR-939-5P	97.10	65.80	1579
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-3126-5P	96.87	65.83	912
HSA-MIR-6875-5P	96.87	65.49	958
HSA-MIR-1343-5P	96.48	66.06	1506
HSA-MIR-6874-5P	95.73	64.94	545
HSA-MIR-4524B-3P	95.52	64.12	964

Literature-anchored findings (GeneRIF, showing 25)

• Results suggest that RIFLE represents a novel signaling protein that mediates components of the Wnt/wingless signaling pathway and cell adhesion in PC12 cells [RIFLE protein]. (PMID:14635195)
• Tal regulates a Tsg101-associated complex responsible for the sorting of cargo into cytoplasm-containing vesicles that bud at the multivesicular body and at the plasma membrane (PMID:15256501)
• Tal polyubiquitinates lysine residues in the C-terminus of uncomplexed Tsg101, resulting in proteasomal degradation. (PMID:18077552)
• LRSAM1 as a component of the antibacterial autophagic response. (PMID:20616063)
• LRSAM1 is a strong candidate for the causal gene for the Charcot-Marie-Tooth disease. (PMID:20865121)
• homozygous mutation in LRSAM1 was proposed as a strong candidate for the disease in a family with recessive axonal polyneuropathy (PMID:22012984)
• Our data further confirms that LRSAM1 mutations are associated with CMT2 of AD inheritance. (PMID:22781092)
• Authors identify LRSAM1 as the E3 ligase responsible for anti-Salmonella autophagy-associated ubiquitination. (PMID:23245322)
• disruption of the C-terminal RING domain confers dominant negative properties to LRSAM1 (PMID:24894446)
• Plant homeodomain finger protein 23 negatively regulates cell autophagy by promoting ubiquitination and degradation of E3 ligase LRSAM1 (PMID:25484098)
• findings suggest that the mutant LRSAM1 may aberrantly affect the formation of transcription machinery. (PMID:27615052)
• findings demonstrate that the isolated genetic entity Charcot-Marie-Tooth type 2G is caused by a missense mutation in LRSAM1. (PMID:27686364)
• LRSAM1 exhibited self-association in vitro and in vivo. The study found the self-association of LRSAM1 promotes intermolecular ubiquitination and proved a potential N-terminal ubiquitination. (PMID:28189685)
• We identified a novel LRSAM1 missense mutation (c.2120C > T, p.Pro707Leu) mapping to the RING domain. The identified missense mutation, as well as of another recently reported pathogenic missense mutation (c.2081G > A, p.Cys694Tyr), revealed that in vitro ubiquitylation activity was largely abrogated. (PMID:28335037)
• Our study shows the potential function of mir-939 through regulating LRSAM1 in Hirschsprung’s disease (PMID:29253842)
• We report a novel LRSAM1 mutation c.2021-2024del (p.E674VfsX11) in 4 members of a Chinese autosomal dominant Charcot-Marie-Tooth disease type 2 family (PMID:29341362)
• The article systematically represents the molecular functions, nature and detailed characterization of LRSAM1 E3 ubiquitin ligase, which are linked to molecular mechanisms of neurodegeneration. (Review) (PMID:30826859)
• Our results confirm the localization of variants in its catalytic C-terminal RING domain and broaden the phenotypic spectrum of LRSAM1-related neuropathies, including painful and predominantly sensory ataxic forms. (PMID:30996334)
• Identification of novel pathogenic copy number variations in Charcot-Marie-Tooth disease. (PMID:31852984)
• Ubiquitin ligase LRSAM1 suppresses neurodegenerative diseases linked aberrant proteins induced cell death. (PMID:31982566)
• LRSAM1 E3 ubiquitin ligase promotes proteasomal clearance of E6-AP protein. (PMID:33207262)
• Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P. (PMID:33414056)
• C698R mutation in Lrsam1 gene impairs nerve regeneration in a CMT2P mouse model. (PMID:35842440)
• [Novel MFN2, BSCL2 and LRSAM1 variants in a cohort of Chinese patients with Charcot-Marie-Tooth disease]. (PMID:35922214)
• A novel mutation in the LRSAM1 gene in a family with early onset autosomal dominant Charcot-Marie-Tooth type 2P. (PMID:38330802)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrsam1	ENSDARG00000060683
mus_musculus	Lrsam1	ENSMUSG00000026792
rattus_norvegicus	Lrsam1	ENSRNOG00000022312

Protein

Protein identifiers

E3 ubiquitin-protein ligase LRSAM1 — Q6UWE0 (reviewed: Q6UWE0)

Alternative names: Leucine-rich repeat and sterile alpha motif-containing protein 1, RING-type E3 ubiquitin transferase LRSAM1, Tsg101-associated ligase

All UniProt accessions (18): Q6UWE0, A0A6Q8PEU7, A0A6Q8PF55, A0A6Q8PFI6, A0A6Q8PFL1, A0A6Q8PFL5, A0A6Q8PFT9, A0A6Q8PFW1, A0A6Q8PG02, A0A6Q8PG90, A0A6Q8PGB2, A0A6Q8PGF7, A0A6Q8PGH9, A0A6Q8PGT8, A0A6Q8PGW1, A0A6Q8PGZ2, A0A6Q8PH70, A0A6Q8PHH6

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that mediates monoubiquitination of TSG101 at multiple sites, leading to inactivate the ability of TSG101 to sort endocytic (EGF receptors) and exocytic (HIV-1 viral proteins) cargos. Bacterial recognition protein that defends the cytoplasm from invasive pathogens. Localizes to several intracellular bacterial pathogens and generates the bacteria-associated ubiquitin signal leading to autophagy-mediated intracellular bacteria degradation (xenophagy).

Subunit / interactions. Interacts with TSG101. Interacts with PHF23. Interacts with FUS.

Subcellular location. Cytoplasm.

Tissue specificity. Highly expressed in adult spinal cord motoneurons as well as in fetal spinal cord and muscle tissue.

Post-translational modifications. Ubiquitination promoted by PHF23 leads to proteasomal degradation.

Disease relevance. Charcot-Marie-Tooth disease, axonal, type 2P (CMT2P) [MIM:614436] An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The coiled coil domains interact with the SB domain of TSG101. The PTAP motifs mediate the binding to UEV domains. The LRR domain is necessary and sufficient for localization to bacterial targets. The RING domain is required for ubiquitination.

Pathway. Protein modification; protein ubiquitination.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6UWE0-1	1	yes
Q6UWE0-2	2
Q6UWE0-3	3

RefSeq proteins (7): NP_001005373, NP_001005374, NP_001177652, NP_001371071, NP_001371072, NP_001371073, NP_612370 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR001660	SAM	Domain
IPR001841	Znf_RING	Domain
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR050216	LRR_domain-containing	Family
IPR055414	LRR_R13L4/SHOC2-like	Domain

Pfam: PF07647, PF13920, PF23598

UniProt features (28 total): repeat 6, sequence variant 3, mutagenesis site 3, region of interest 2, coiled-coil region 2, short sequence motif 2, modified residue 2, splice variant 2, sequence conflict 2, chain 1, compositionally biased region 1, domain 1, zinc finger region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UWE0-F1	78.47	0.26

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 234, 604

Mutagenesis-validated functional residues (3):

Position	Phenotype
649–664	abolishes interaction with tsg101.
675	abolishes ubiquitination of tsg101.
692	abolishes ubiquitination of tsg101.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 181 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, GOBP_VACUOLE_ORGANIZATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_POSITIVE_REGULATION_OF_VACUOLE_ORGANIZATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_VACUOLE_ORGANIZATION, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_XENOPHAGY, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_MACROAUTOPHAGY

GO Biological Process (11): protein polyubiquitination (GO:0000209), autophagy (GO:0006914), protein catabolic process (GO:0030163), negative regulation of endocytosis (GO:0045806), viral budding (GO:0046755), protein autoubiquitination (GO:0051865), ubiquitin-dependent endocytosis (GO:0070086), positive regulation of xenophagy (GO:1904417), positive regulation of autophagosome assembly (GO:2000786), protein transport (GO:0015031), protein ubiquitination (GO:0016567)

GO Molecular Function (6): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein ubiquitination	2
endocytosis	2
positive regulation of macroautophagy	2
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
macromolecule catabolic process	1
protein metabolic process	1
regulation of endocytosis	1
negative regulation of transport	1
negative regulation of cellular component organization	1
viral process	1
virion assembly	1
protein transport	1
protein localization to organelle	1
establishment of protein localization to organelle	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
xenophagy	1
regulation of xenophagy	1
autophagosome assembly	1
positive regulation of vacuole organization	1
positive regulation of organelle assembly	1
regulation of autophagosome assembly	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
protein modification by small protein conjugation	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

1848 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRSAM1	TSG101	Q99816	905
LRSAM1	CALCOCO2	Q13137	874
LRSAM1	VPS28	Q9UK41	786
LRSAM1	CEP55	Q53EZ4	711
LRSAM1	RNF166	Q96A37	699
LRSAM1	LGALS8	O00214	644
LRSAM1	SH3TC2	Q8TF17	623
LRSAM1	GDAP1	Q8TB36	620
LRSAM1	IGHMBP2	P38935	599
LRSAM1	FGD4	Q96M96	589
LRSAM1	SBF2	Q86WG5	555
LRSAM1	NAIP	Q13075	544
LRSAM1	MTMR2	Q13614	544
LRSAM1	LITAF	Q99732	533
LRSAM1	RDX	P35241	531

IntAct

130 interactions, top by confidence:

A	B	Type	Score
TSG101	LRSAM1	psi-mi:“MI:0915”(physical association)	0.830
LRSAM1	TSG101	psi-mi:“MI:0915”(physical association)	0.830
CNOT6L	CNOT1	psi-mi:“MI:0914”(association)	0.810
FUS	TARDBP	psi-mi:“MI:0914”(association)	0.750
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
UBE2N	LRSAM1	psi-mi:“MI:0915”(physical association)	0.690
LRSAM1	UBE2N	psi-mi:“MI:0915”(physical association)	0.690
ATXN1	LRSAM1	psi-mi:“MI:0915”(physical association)	0.670
LRRC46	TFPT	psi-mi:“MI:0914”(association)	0.640
LRSAM1	DMAP1	psi-mi:“MI:0915”(physical association)	0.560
CCDC6	LRSAM1	psi-mi:“MI:0915”(physical association)	0.560
LRSAM1	ZMAT4	psi-mi:“MI:0915”(physical association)	0.560
LRSAM1	UBE2I	psi-mi:“MI:0915”(physical association)	0.560
XAF1	LRSAM1	psi-mi:“MI:0915”(physical association)	0.560
PAPOLG	ZFC3H1	psi-mi:“MI:0914”(association)	0.530
TERF1	LRSAM1	psi-mi:“MI:0915”(physical association)	0.510
LRSAM1	Fus	psi-mi:“MI:0915”(physical association)	0.500
LIPF	LRSAM1	psi-mi:“MI:0915”(physical association)	0.500
Tsg101	LRSAM1	psi-mi:“MI:0915”(physical association)	0.400
LRSAM1	G3BP1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (117): LRSAM1 (Biochemical Activity), TSG101 (Biochemical Activity), LRSAM1 (Affinity Capture-Western), LRSAM1 (Two-hybrid), LRSAM1 (Affinity Capture-Western), TSG101 (Co-localization), LRSAM1 (Affinity Capture-Western), LRSAM1 (Affinity Capture-MS), LRSAM1 (Affinity Capture-MS), LRSAM1 (Two-hybrid), LRSAM1 (Affinity Capture-Western), PHF23 (Affinity Capture-Western), LRSAM1 (Reconstituted Complex), LRSAM1 (Affinity Capture-Western), LRSAM1 (Reconstituted Complex)

ESM2 similar proteins: A0A8M2BID5, A2AL36, A2CG49, A6PWD2, B1WBU8, B2RPU2, D3ZEY0, D3ZHV2, E9Q1U1, E9Q557, E9Q8Q6, E9Q9R9, F1LMV6, F1M0Z1, G3V7L1, O15068, O35550, O60229, O60437, O75962, O97592, P10911, P11530, P11531, P11532, P11533, P15924, P46939, P97924, Q0KL02, Q1LUA6, Q4FZC9, Q5GN48, Q63406, Q64096, Q6UWE0, Q6ZMZ3, Q6ZP82, Q6ZWQ0, Q6ZWR6

Diamond homologs: A1E2V0, A1L020, A1L3F4, A5D8Q0, A9JTP3, A9ULZ2, D3ZDI6, E3SCZ8, O08863, O10296, O10324, O14064, O15392, O62640, O70201, O88738, P40629, P41435, P41436, P41437, P41454, P47732, P98170, Q05AK5, Q0WPJ7, Q13489, Q13490, Q28ER3, Q28H51, Q50L39, Q557E7, Q5BKL8, Q5R881, Q5RAH9, Q60989, Q62210, Q69Z36, Q6I6F4, Q6J1J1, Q6NTT6

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	LRSAM1	ubiquitination
LRSAM1	“down-regulates quantity”	TSG101	monoubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 129 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	7	28.3×	2e-06
E3 ubiquitin ligases ubiquitinate target proteins	6	12.8×	5e-04
mRNA Polyadenylation	9	8.7×	1e-04
mRNA Splicing	6	7.2×	8e-03
Processing of Capped Intron-Containing Pre-mRNA	8	7.2×	8e-04
Dengue Virus-Host Interactions	12	6.0×	1e-04
mRNA Splicing - Major Pathway	10	6.0×	5e-04
Antigen processing: Ubiquitination & Proteasome degradation	14	5.7×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein K11-linked ubiquitination	5	17.0×	1e-03
negative regulation of TORC1 signaling	5	14.1×	3e-03
protein polyubiquitination	11	11.0×	4e-06
protein K48-linked ubiquitination	7	10.3×	9e-04
ubiquitin-dependent protein catabolic process	11	7.1×	2e-04
mRNA processing	9	6.2×	2e-03
DNA repair	11	6.1×	5e-04
protein ubiquitination	13	4.7×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

1028 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	45
Likely pathogenic	46
Uncertain significance	454
Likely benign	327
Benign	54

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1000445	NM_001005373.4(LRSAM1):c.382C>T (p.Gln128Ter)	Pathogenic
1046625	NM_001005373.4(LRSAM1):c.1956_1957dup (p.Gln653fs)	Pathogenic
1073788	NM_001005373.4(LRSAM1):c.988C>T (p.Gln330Ter)	Pathogenic
1076638	NM_001005373.4(LRSAM1):c.1144C>T (p.Arg382Ter)	Pathogenic
1076924	NM_001005373.4(LRSAM1):c.602dup (p.Leu201fs)	Pathogenic
1445717	NM_001005373.4(LRSAM1):c.1135_1136del (p.Ser379fs)	Pathogenic
1458236	NM_001005373.4(LRSAM1):c.2089C>T (p.Gln697Ter)	Pathogenic
1460311	NC_000009.11:g.(?130265033)(130265178_?)del	Pathogenic
1512430	NM_001005373.4(LRSAM1):c.352C>T (p.Gln118Ter)	Pathogenic
1762915	NM_001005373.4(LRSAM1):c.831del (p.Gln278fs)	Pathogenic
1764498	NM_001005373.4(LRSAM1):c.1267G>T (p.Glu423Ter)	Pathogenic
204301	NM_001005373.4(LRSAM1):c.1913-1G>A	Pathogenic
2107035	NM_001005373.4(LRSAM1):c.2108_2114del (p.Leu703fs)	Pathogenic
2427228	NC_000009.11:g.(?130245209)(130245319_?)del	Pathogenic
2427229	NC_000009.11:g.(?130229999)(130230129_?)del	Pathogenic
268046	NM_001005373.4(LRSAM1):c.2081G>A (p.Cys694Tyr)	Pathogenic
2706775	NM_001005373.4(LRSAM1):c.428_435dup (p.Val146fs)	Pathogenic
2735340	NM_001005373.4(LRSAM1):c.2075_2087del (p.His692fs)	Pathogenic
2737762	NM_001005373.4(LRSAM1):c.940C>T (p.Gln314Ter)	Pathogenic
2743863	NM_001005373.4(LRSAM1):c.1717C>T (p.Gln573Ter)	Pathogenic
2820235	NM_001005373.4(LRSAM1):c.1911del (p.Glu638fs)	Pathogenic
2887131	NM_001005373.4(LRSAM1):c.1606_1609dup (p.Glu537fs)	Pathogenic
2913480	NM_001005373.4(LRSAM1):c.1546C>T (p.Gln516Ter)	Pathogenic
30859	NM_001005373.4(LRSAM1):c.1914G>A (p.Glu638=)	Pathogenic
30860	NM_001005373.4(LRSAM1):c.2121_2122dup (p.Leu708fs)	Pathogenic
3341092	NM_001005373.4(LRSAM1):c.1190del (p.Cys397fs)	Pathogenic
3648191	NM_001005373.4(LRSAM1):c.304C>T (p.Gln102Ter)	Pathogenic
3648651	NM_001005373.4(LRSAM1):c.996_1015dup (p.Ile339fs)	Pathogenic
3699419	NM_001005373.4(LRSAM1):c.166C>T (p.Gln56Ter)	Pathogenic
3727854	NM_001005373.4(LRSAM1):c.1573C>T (p.Arg525Ter)	Pathogenic

SpliceAI

3983 predictions. Top by Δscore:

Variant	Effect	Δscore
9:127454494:AG:A	acceptor_gain	1.0000
9:127454495:GG:G	acceptor_gain	1.0000
9:127454581:G:GT	donor_gain	1.0000
9:127454591:A:G	donor_gain	1.0000
9:127454607:A:T	donor_gain	1.0000
9:127454610:G:GG	donor_gain	1.0000
9:127455574:A:AG	acceptor_gain	1.0000
9:127455575:G:GG	acceptor_gain	1.0000
9:127458999:GCA:G	acceptor_loss	1.0000
9:127459000:CAG:C	acceptor_loss	1.0000
9:127459001:A:AG	acceptor_gain	1.0000
9:127459001:AG:A	acceptor_gain	1.0000
9:127459002:G:GG	acceptor_gain	1.0000
9:127459002:GG:G	acceptor_gain	1.0000
9:127459068:CCAGG:C	donor_loss	1.0000
9:127459072:GTA:G	donor_loss	1.0000
9:127462248:GCAGA:G	acceptor_loss	1.0000
9:127462250:A:AG	acceptor_gain	1.0000
9:127462250:A:T	acceptor_loss	1.0000
9:127462251:G:GA	acceptor_gain	1.0000
9:127462251:GA:G	acceptor_gain	1.0000
9:127462251:GAC:G	acceptor_gain	1.0000
9:127462251:GACA:G	acceptor_gain	1.0000
9:127462251:GACAA:G	acceptor_gain	1.0000
9:127462371:G:GT	donor_gain	1.0000
9:127462371:GAGGT:G	donor_loss	1.0000
9:127462372:AG:A	donor_loss	1.0000
9:127462373:GG:G	donor_loss	1.0000
9:127462375:T:G	donor_loss	1.0000
9:127467826:CAAAG:C	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000007078 (9:127465034 C>T), RS1000061236 (9:127465332 C>G), RS1000114635 (9:127488943 G>A), RS1000216841 (9:127482235 C>G,T), RS1000228584 (9:127450305 C>G), RS1000230930 (9:127465569 C>T), RS1000297195 (9:127459335 C>T), RS1000377300 (9:127471668 T>A), RS1000436981 (9:127488599 C>T), RS1000450232 (9:127490248 T>A), RS1000507262 (9:127484823 T>G), RS1000620691 (9:127489836 T>C), RS1000632610 (9:127501038 C>G,T), RS1000644696 (9:127483976 T>C), RS1000690452 (9:127495767 T>C)

Disease associations

OMIM: gene MIM:610933 | disease phenotypes: MIM:608591, MIM:614436, MIM:118220, MIM:615670, MIM:612164

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease axonal type 2P	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease axonal type 2P	Definitive	AD

Mondo (6): Charcot-Marie-Tooth disease axonal type 2P (MONDO:0013753), Charcot-Marie-Tooth disease (MONDO:0015626), LZTR1-related schwannomatosis (MONDO:0014299), developmental and epileptic encephalopathy, 4 (MONDO:0012812), Charcot-Marie-Tooth disease type 1 (MONDO:0019011), Charcot-Marie-Tooth disease type 4 (MONDO:0018995)

Orphanet (9): Charcot-Marie-Tooth disease type 2P (Orphanet:300319), Autosomal dominant Charcot-Marie-Tooth disease type 2G (Orphanet:99941), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Full schwannomatosis (Orphanet:93921), Early infantile developmental and epileptic encephalopathy (Orphanet:1934), Dravet syndrome (Orphanet:33069), STXBP1-related encephalopathy (Orphanet:599373), Charcot-Marie-Tooth disease type 1 (Orphanet:65753), Charcot-Marie-Tooth disease type 4 (Orphanet:64749)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000764	Peripheral axonal degeneration
HP:0001265	Hyporeflexia
HP:0001284	Areflexia
HP:0001761	Pes cavus
HP:0001765	Hammertoe
HP:0002380	Fasciculations
HP:0002460	Distal muscle weakness
HP:0002936	Distal sensory impairment
HP:0003376	Steppage gait
HP:0003378	Axonal degeneration/regeneration
HP:0003431	Decreased motor nerve conduction velocity
HP:0003677	Slowly progressive
HP:0003693	Distal amyotrophy
HP:0003829	Typified by incomplete penetrance
HP:0006886	Impaired distal vibration sensation
HP:0009027	Foot dorsiflexor weakness
HP:0030051	Tip-toe gait
HP:0040078	Axonal degeneration

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002392_596	Mean corpuscular volume	2.000000e-09

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
C567404	Epileptic Encephalopathy, Early Infantile, 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
abrine	increases expression	1
jinfukang	increases expression	1
Sunitinib	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Dexamethasone	affects cotreatment, increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Indomethacin	increases expression, affects cotreatment	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Ribonucleotides	affects binding	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Sodium Selenite	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Lactic Acid	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SW05	HAP1 LRSAM1 (-) 1	Cancer cell line	Male
CVCL_SW06	HAP1 LRSAM1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

59 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease
NCT01289704	PHASE2/PHASE3	UNKNOWN	Treadmill, Stretching and Proprioceptive Exercise (TreSPE) Rehabilitation Program for Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)
NCT00541164	PHASE1/PHASE2	COMPLETED	Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease
NCT05361031	PHASE1/PHASE2	COMPLETED	The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)
NCT07223632	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S) in an Individual Patient
NCT00149045	Not specified	COMPLETED	Follow up and Observation of Charcot Marie Tooth Disease in Families
NCT01193075	Not specified	RECRUITING	Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others
NCT01203085	Not specified	COMPLETED	Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale for Children With CMT
NCT01455623	Not specified	COMPLETED	Development and Validation of a Disability Severity Index for CMT
NCT01918826	Not specified	UNKNOWN	Evaluation of the Analgesic Efficiency of the Transcutaneous Neurostimulation in the Charcot Syndrome Marie Tooth on the Pains of Lower Limbs
NCT02001038	Not specified	COMPLETED	Survey of Current Management of Orthopaedic Complications in CMT Patients
NCT02011204	Not specified	COMPLETED	Study of Electrical Impedance Myography (EIM) in ALS
NCT02194010	Not specified	COMPLETED	Disability Severity Scale (DSI) and Hereditary Motor and Sensory Neuropathy Overall Disability Scale (HMSN-R-ODS)
NCT02429947	Not specified	COMPLETED	An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients
NCT02532244	Not specified	COMPLETED	Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02788734	Not specified	COMPLETED	Patient Reported Outcomes Measures (PROM) in Carpal Tunnel Therapies in Patients With Inherited Neuropathies
NCT02979145	Not specified	UNKNOWN	Charcot-Marie-Tooth Disease (CMT) Infant Scale (INC-6611)
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03460951	Not specified	COMPLETED	Diffusion Tensor Imaging in Chronic Inflammatory Demyelinating Polyneuropathy (PIDC)
NCT03715283	Not specified	COMPLETED	Change in MUNIX in Patients With CMT1A Undergoing a Home Ankle Strengthening Program Versus Standard of Care
NCT03782883	Not specified	COMPLETED	The Impact of Charcot-Marie-Tooth Disease in the Real World
NCT03810508	Not specified	TERMINATED	A Natural History Study of Charcot-Marie-Tooth 4J (CMT4J)
NCT03966287	Not specified	COMPLETED	Analysis of Pain and Quality of Life in Patients With Charcot-Marie-Tooth Neuropathy (CMT)
NCT04010188	Not specified	RECRUITING	A Registered Cohort Study on Charcot-Marie-Tooth Disease
NCT04283175	Not specified	COMPLETED	Validation Study of Posturology Platforms for Evaluating Postural Control of Hemiparetic and Neuro-muscular Patients
NCT04461613	Not specified	UNKNOWN	Physical Activity in Persons With Charcot-Marie-Tooth: Developing a Measurement Instrument
NCT04786522	Not specified	COMPLETED	Irisin Levels in Patients With Charcot-Marie-Tooth (CMT) Disease
NCT04967716	Not specified	UNKNOWN	Genetics of Charcot-Marie-Tooth Dystrophy and Related Diseases
NCT04980807	Not specified	COMPLETED	Observational Study of Neuromuscular Function in CMT Type 1&2 and Healthy Controls