LAMC2

Summary

LAMC2 (laminin subunit gamma 2, HGNC:6493) is a protein-coding gene on chromosome 1q25.3, encoding Laminin subunit gamma-2 (Q13753). Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.

Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins, composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively), have a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. Several isoforms of each chain have been described. Different alpha, beta and gamma chain isomers combine to give rise to different heterotrimeric laminin isoforms which are designated by Arabic numerals in the order of their discovery, i.e. alpha1beta1gamma1 heterotrimer is laminin 1. The biological functions of the different chains and trimer molecules are largely unknown, but some of the chains have been shown to differ with respect to their tissue distribution, presumably reflecting diverse functions in vivo. This gene encodes the gamma chain isoform laminin, gamma 2. The gamma 2 chain, formerly thought to be a truncated version of beta chain (B2t), is highly homologous to the gamma 1 chain; however, it lacks domain VI, and domains V, IV and III are shorter. It is expressed in several fetal tissues but differently from gamma 1, and is specifically localized to epithelial cells in skin, lung and kidney. The gamma 2 chain together with alpha 3 and beta 3 chains constitute laminin 5 (earlier known as kalinin), which is an integral part of the anchoring filaments that connect epithelial cells to the underlying basement membrane. The epithelium-specific expression of the gamma 2 chain implied its role as an epithelium attachment molecule, and mutations in this gene have been associated with junctional epidermolysis bullosa, a skin disease characterized by blisters due to disruption of the epidermal-dermal junction. Two transcript variants resulting from alternative splicing of the 3’ terminal exon, and encoding different isoforms of gamma 2 chain, have been described. The two variants are differentially expressed in embryonic tissues, however, the biological significance of the two forms is not known. Transcript variants utilizing alternative polyA_signal have also been noted in literature.

Source: NCBI Gene 3918 — RefSeq curated summary.

At a glance

• Gene–disease (curated): junctional epidermolysis bullosa (Definitive, GenCC) — +5 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 1,316 total — 98 pathogenic, 121 likely-pathogenic
• Phenotypes (HPO): 78
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_005562

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6493
Approved symbol	LAMC2
Name	laminin subunit gamma 2
Location	1q25.3
Locus type	gene with protein product
Status	Approved
Aliases	nicein-100kDa, kalinin-105kDa, BM600-100kDa
Ensembl gene	ENSG00000058085
Ensembl biotype	protein_coding
OMIM	150292
Entrez	3918

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 11 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000264144, ENST00000461729, ENST00000476255, ENST00000493293, ENST00000878925, ENST00000878926, ENST00000878927, ENST00000878928, ENST00000914498, ENST00000914499, ENST00000971655, ENST00000971656, ENST00000971657

RefSeq mRNA: 2 — MANE Select: NM_005562 NM_005562, NM_018891

CCDS: CCDS1352, CCDS44285

Canonical transcript exons

ENST00000264144 — 23 exons

Exon	Start	End
ENSE00001068737	183240292	183240391
ENSE00001068741	183243147	183245127
ENSE00001853846	183186264	183186431
ENSE00002090777	183225608	183225720
ENSE00002094180	183235575	183235730
ENSE00002095261	183227515	183227697
ENSE00002096146	183228374	183228619
ENSE00002101035	183236460	183236604
ENSE00002105971	183218390	183218488
ENSE00002106682	183222089	183222211
ENSE00002110930	183207881	183208069
ENSE00002113154	183240040	183240198
ENSE00002116027	183237352	183237504
ENSE00002120880	183239364	183239563
ENSE00002121650	183215453	183215588
ENSE00002122592	183220825	183220961
ENSE00002124182	183226698	183226916
ENSE00002125426	183230961	183231103
ENSE00002128613	183232652	183232857
ENSE00002129274	183238307	183238421
ENSE00002136578	183223135	183223324
ENSE00002137243	183232187	183232343
ENSE00002137245	183234367	183234446

Expression profiles

Bgee: expression breadth ubiquitous, 209 present calls, max score 96.14.

FANTOM5 (CAGE): breadth broad, TPM avg 64.2751 / max 8762.8859, expressed in 681 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
7075	63.3387	664
7111	0.1272	44
7105	0.1189	43
7107	0.1148	43
7119	0.0677	28
7117	0.0670	31
7104	0.0648	30
7113	0.0621	33
7103	0.0606	28
7102	0.0477	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	96.14	gold quality
hair follicle	UBERON:0002073	95.23	gold quality
periodontal ligament	UBERON:0008266	93.50	gold quality
right uterine tube	UBERON:0001302	91.82	gold quality
mammary duct	UBERON:0001765	89.91	gold quality
cartilage tissue	UBERON:0002418	89.77	gold quality
epithelium of mammary gland	UBERON:0003244	89.76	gold quality
epithelium of bronchus	UBERON:0002031	89.75	gold quality
pancreatic ductal cell	CL:0002079	89.54	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	89.49	gold quality
tongue squamous epithelium	UBERON:0006919	88.81	silver quality
bronchus	UBERON:0002185	88.80	gold quality
cervix squamous epithelium	UBERON:0006922	88.68	silver quality
bronchial epithelial cell	CL:0002328	88.61	gold quality
epithelial cell of pancreas	CL:0000083	87.99	gold quality
mucosa of paranasal sinus	UBERON:0005030	87.34	gold quality
gingival epithelium	UBERON:0001949	86.53	silver quality
oviduct epithelium	UBERON:0004804	85.92	gold quality
epithelium of nasopharynx	UBERON:0001951	85.57	gold quality
gingiva	UBERON:0001828	85.29	gold quality
visceral pleura	UBERON:0002401	84.40	gold quality
fallopian tube	UBERON:0003889	84.30	gold quality
cervix epithelium	UBERON:0004801	84.19	silver quality
nasal cavity epithelium	UBERON:0005384	84.13	silver quality
skin of abdomen	UBERON:0001416	84.12	gold quality
lung	UBERON:0002048	83.77	gold quality
skin of leg	UBERON:0001511	83.32	gold quality
vermiform appendix	UBERON:0001154	83.22	gold quality
upper lobe of left lung	UBERON:0008952	83.20	gold quality
gall bladder	UBERON:0002110	83.13	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-10596	yes	1551.71
E-MTAB-5061	yes	26.20
E-GEOD-81547	yes	23.04
E-ENAD-27	yes	6.72
E-GEOD-86618	no	5473.31
E-CURD-53	no	702.44
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CTNNB1, JUN, SMAD4, ZEB1

miRNA regulators (miRDB)

62 targeting LAMC2, 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-432-3P	100.00	67.86	705
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-12130	99.75	65.47	452
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-26A-1-3P	99.64	66.81	788
HSA-MIR-26A-2-3P	99.64	66.82	786
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-885-5P	99.59	68.59	879
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-106A-3P	99.53	67.58	995
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-6719-3P	99.29	67.78	1387
HSA-MIR-3978	99.24	68.39	2201

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• cytoplasmic expression represents high invasive potential of pancreatic ductal adenocarcinoma and is correlated with distant metastasis and poorer prognosis (PMID:11920553)
• laminin-gamma2 is frequently overexpressed in HNSCCs and derivative cell lines (PMID:11992550)
• level of circulating LN gamma2 NH(2)-terminal fragment (G2F) is a new, prognostic, tumor-characterizing marker for estimating the invasiveness and malignancy of epithelial carcinomas (PMID:12517801)
• Thus the synergistic activation of the LAMC2 gene is mediated via different cis-elements and results in an overproduction of the laminin gamma 2 chain relative to the other laminin-5 constituent chains. (PMID:12519076)
• Laminin-5 gamma2 chain expression may contribute to formation of budding tumor cells at the invasive front, and immunostaining of this adhesion molecule may be useful in identifying high-risk patients for locoregional failure in T1 colorectal carcinomas. (PMID:12643602)
• Results identify the point during neoplastic progression in epithelia when the tumor suppressor p16 and laminin 5 are expressed and suggest that normal epithelia may use the same mechanism to generate non-dividing, motile cells for wound repair. (PMID:12875969)
• proteolytic processing of laminin-5 influences its interaction with alpha3beta1 integrin (PMID:14612440)
• epidermis of the Lamc2-/- mice revealed induced apoptosis in the basal cells of the blistered skin (PMID:14632187)
• Laminin gamma 2 chain exhibits aberrant expression in a stepwise manner through different aggressive stages of tumor progression. (PMID:15105812)
• co-cultures of epithelial cells and fibroblasts were studied to analyse the processing of laminin 5 alpha3, beta3, and gamma2 chains (PMID:15149852)
• In squamous cell carcinoma of the tongue and colorectal carcinoma, laminin 5 gamma2 chain is important in the invasiveness of cancer cells. (PMID:15363037)
• Premature termination codon mutations in both alleles of LAMB3 or LAMC2 genes were found in nine of the 11 H junctional epidermolysis bullosa patients (PMID:15373767)
• Data show that the expression of laminin gamma2 chain and collagen type XVII is altered in endometrial adenocarcinomas. (PMID:15609083)
• up-regulation of Ang2, MMP-2, MT1-MMP, and LN 5 gamma 2 is associated with the invasiveness displayed by human gliomas (PMID:15743799)
• the absolute mRNA levels generated from the laminin 5 genes do not determine the translated protein levels of the laminin 5 chains in keratinocytes; the expression of the laminin 5 genes may be controlled by common regulation mechanisms (PMID:15854126)
• Ln-5 gamma2 chain regulates the secretion of the alpha3 and beta3 subunits. More importantly, suppression of Ln-5 results in a phenotype that is representative of invasive tumor cells (PMID:15963983)
• This study suggests that coexpression of LN-5 gamma2 and EGFR is closely related to the progression and poor prognosis of esophageal SCC. (PMID:16103736)
• The uncoordinated production of chains of ln-5 in allergic asthma could have a bearing on the poor epithelial cell anchorage in these patients. (PMID:16179086)
• Ln-5 and TGF-beta1 cooperatively induce epithelial to mesenchymal transition in hepatocellular carcinoma (PMID:16285938)
• Our results suggest that PAI-1 is a novel potential marker of initial invasion in oral SCC, and that the coordinated expression of PAI-1 with uPAR and lam-gamma2 sustain the features of the early invasive cancer cells. (PMID:16395714)
• tumor cell migration on laminin-5 is inhibited by HYD1, a biologically active integrin-targeting peptide (PMID:16537560)
• Ln-5 is an important regulator of ADPKD cell proliferation and cystogenesis; Ln-5 gamma(2) chain and Ln-5-alpha(6)beta(4) integrin interaction both contribute to these phenotypic changes (PMID:16870608)
• Laminin-5 alone stimulates global changes in gene/protein expression in mesenchymal stem cells that lead to commitment of these cells to the osteogenic phenotype, and this correlates with extracellular matrix production. (PMID:17137774)
• domain V of the gamma2 chain negatively regulates the integrin beta4 phosphorylation, probably through a syndecan-1-mediated signaling, leading to enhanced cell adhesion and suppressed cell motility (PMID:17314405)
• findings suggest that mesenchymal cells contribute to the promotion of tumour cell migration as well as vessel formation in oral squamous cell carcinoma by providing and organising promigratory Ln-5 fragments (PMID:17390227)
• Study summarizes recent progress concerning the molecular mechanisms of laminins in development and disease. (PMID:17426950)
• LM-332 is a crucial motility-promoting factor for B-CLL lymphocytes and is a potential constituent favoring the dissemination of B-CLL lymphocytes through vascular basement membranes and possibly lymph node compartments. (PMID:17482449)
• Overexpression of Laminin-5 gamma2 is associated with oral squamous cell carcinomas (PMID:17786338)
• The TP0136 protein was exposed on the surface of the bacterial outer membrane and bound to the host extracellular matrix glycoproteins fibronectin and laminin. (PMID:18332212)
• LAMC2 mRNA was overexpressed in 89% of esophageal squamous cell carcinoma cases. (PMID:18559558)
• the alpha3 chain can assemble with only beta3-gamma2 heterodimer to form a heterotrimer via disulfide bonds (PMID:18603785)
• The expression of LAMC2-COL4A1 genes were particularly effective in distinguishing OSCC from normal oral tissue. (PMID:18669583)
• Laminin isoforms containing the gamma3 chain are unable to bind to integrins due to the absence of the glutamic acid residue conserved in the C-terminal regions of the gamma1 and gamma2 chains (PMID:18697739)
• Results suggest that HIF1 contributes to keratinocyte migration and thus to the re-epithelialisation process by regulating laminin-332. (PMID:18713836)
• proteolytic processing of the LN-5 gamma 2 chain by MT1-MMP is involved in cell migration and subsequent architectural organization in ovarian clear cell carcinoma (PMID:19047908)
• LAMC2 is a novel biomarker of bladder cancer metastasis that reflects the propensity of cells to metastasize via either lymphatic or hematogenous routes. (PMID:19147813)
• laminin-5gamma2 chain expression is associated with the wall-invasion pattern of gallbladder adenocarcinoma (PMID:19265264)
• Higher laminin 332 levels are associated with aggressive features in breast cancers. (PMID:19351903)
• Ln-332 gamma2 may be a therapeutic target against metastatic colon cancer because a lowered beta3:gamma2 ratio would reduce expression of heterotrimeric Ln-332 and increase monomeric gamma2 secretion. (PMID:19383890)
• LAMC2, LAMA4, ITGB1, ITGB3, RSPA and MMP2) are overexpressed in angiotropic melanoma cells vs. non-angiotropic melanoma cells from the same tumor (PMID:19469865)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Lamc2	ENSMUSG00000026479
rattus_norvegicus	Lamc2	ENSRNOG00000002667

Paralogs (27): USH2A (ENSG00000042781), LAMC3 (ENSG00000050555), LAMA3 (ENSG00000053747), NTN1 (ENSG00000065320), NTN4 (ENSG00000074527), ATRN (ENSG00000088812), LAMB4 (ENSG00000091128), LAMB1 (ENSG00000091136), LAMA1 (ENSG00000101680), MEGF8 (ENSG00000105429), MEGF9 (ENSG00000106780), ATRNL1 (ENSG00000107518), LAMA4 (ENSG00000112769), LAMA5 (ENSG00000130702), LAMC1 (ENSG00000135862), NTN5 (ENSG00000142233), HSPG2 (ENSG00000142798), TMEFF2 (ENSG00000144339), NTN3 (ENSG00000162068), NTNG1 (ENSG00000162631), EGFLAM (ENSG00000164318), LAMB2 (ENSG00000172037), AGRN (ENSG00000188157), NTNG2 (ENSG00000196358), LAMA2 (ENSG00000196569), LAMB3 (ENSG00000196878), TMEFF1 (ENSG00000241697)

Protein

Protein identifiers

Laminin subunit gamma-2 — Q13753 (reviewed: Q13753)

Alternative names: Cell-scattering factor 140 kDa subunit, Epiligrin subunit gamma, Kalinin subunit gamma, Kalinin/nicein/epiligrin 100 kDa subunit, Ladsin 140 kDa subunit, Laminin B2t chain, Laminin-5 subunit gamma, Large adhesive scatter factor 140 kDa subunit, Nicein subunit gamma

All UniProt accessions (1): Q13753

UniProt curated annotations — full annotation on UniProt →

Function. Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. Ladsin exerts cell-scattering activity toward a wide variety of cells, including epithelial, endothelial, and fibroblastic cells.

Subunit / interactions. Laminin is a complex glycoprotein, consisting of three different polypeptide chains (alpha, beta, gamma), which are bound to each other by disulfide bonds into a cross-shaped molecule comprising one long and three short arms with globules at each end. Gamma-2 is a subunit of laminin-5 (laminin-332 or epiligrin/kalinin/nicein).

Subcellular location. Secreted. Extracellular space. Extracellular matrix. Basement membrane.

Tissue specificity. The large variant is expressed only in specific epithelial cells of embryonic and neonatal tissues. In 17-week old embryo the small variant is found in cerebral cortex, lung, and distal tubes of kidney, but not in epithelia except for distal tubuli.

Post-translational modifications. O-glycosylated; contains chondroitin sulfate (CS). CS attachment is on either Ser-803 or Ser-805.

Disease relevance. Epidermolysis bullosa, junctional 3A, intermediate (JEB3A) [MIM:619785] A form of epidermolysis bullosa, a genodermatosis characterized by recurrent blistering, fragility of the skin and mucosal epithelia, and erosions caused by minor mechanical trauma. JEB3A is an autosomal recessive, intermediate form in which blistering lesions occur between the epidermis and the dermis at the lamina lucida level of the basement membrane zone. In intermediate forms of junctional epidermolysis bullosa, blistering does not lead to the formation of chronic granulation tissue and does not affect the lifespan of affected individuals. Nail dystrophy and dental enamel defects are present. Scarring or non-scarring alopecia and diffuse hair loss may occur. The disease is caused by variants affecting the gene represented in this entry. Epidermolysis bullosa, junctional 3B, severe (JEB3B) [MIM:619786] A form of epidermolysis bullosa, a genodermatosis characterized by recurrent blistering, fragility of the skin and mucosal epithelia, and erosions caused by minor mechanical trauma. JEB3B is an autosomal recessive form in which blistering lesions occur between the epidermis and the dermis at the lamina lucida level of the basement membrane zone. It belongs to the severe spectrum of junctional epidermolysis bullosa (previously known as generalized severe or Herlitz type), characterized by onset of blistering over large regions of the body at birth or in early infancy. Blistering also affects the mucous membranes, such as the moist lining of the mouth and digestive tract, which can make it difficult to eat and digest food. The extensive blistering leads to scarring and the formation of red, bumpy patches called granulation tissue. Other complications can include fusion of the fingers and toes, abnormalities of the fingernails and toenails, joint deformities, dental enamel defects, and alopecia. Severe, junctional forms are associated with death in the first 6 to 24 months of life. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The alpha-helical domains I and II are thought to interact with other laminin chains to form a coiled coil structure. Domain IV is globular.

Miscellaneous. Binds heparin.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13753-1	Long	yes
Q13753-2	Short

RefSeq proteins (2): NP_005553, NP_061486 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000034	Laminin_IV	Domain
IPR000742	EGF	Domain
IPR002049	LE_dom	Domain
IPR050440	Laminin/Netrin_ECM	Family

Pfam: PF00052, PF00053

UniProt features (61 total): disulfide bond 26, domain 10, sequence variant 7, glycosylation site 6, sequence conflict 5, coiled-coil region 3, signal peptide 1, chain 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13753-F1	72.89	0.20

Functional residue map

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

Disulfide bonds (26): 28–37, 30–53, 56–65, 68–81, 84–96, 86–102, 104–113, 116–128, 139–150, 141–155, 157–166, 169–184, 462–470, 464–481, 484–493, 496–514, 517–531, 519–538, 541–550, 553–570 …

Glycosylation sites (6): 342, 362, 803, 805, 942, 1033

Function

Pathways and Gene Ontology

Reactome pathways

18 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-2022090	Assembly of collagen fibrils and other multimeric structures
R-HSA-2214320	Anchoring fibril formation
R-HSA-3000157	Laminin interactions
R-HSA-3000171	Non-integrin membrane-ECM interactions
R-HSA-446107	Type I hemidesmosome assembly
R-HSA-8874081	MET activates PTK2 signaling
R-HSA-9638630	Attachment of bacteria to epithelial cells
R-HSA-9913351	Formation of the dystrophin-glycoprotein complex (DGC)
R-HSA-9925563	Developmental Lineage of Pancreatic Ductal Cells
R-HSA-1474244	Extracellular matrix organization
R-HSA-1474290	Collagen formation
R-HSA-1500931	Cell-Cell communication
R-HSA-162582	Signal Transduction
R-HSA-446728	Cell junction organization
R-HSA-6806834	Signaling by MET
R-HSA-8875878	MET promotes cell motility
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 439 (showing top): BROWNE_HCMV_INFECTION_6HR_DN, JAEGER_METASTASIS_DN, LI_PROSTATE_CANCER_EPIGENETIC, AREB6_03, AREB6_01, KANNAN_TP53_TARGETS_DN, NAGASHIMA_NRG1_SIGNALING_UP, PUJANA_CHEK2_PCC_NETWORK, KANG_FLUOROURACIL_RESISTANCE_DN, BROWNE_HCMV_INFECTION_48HR_DN, AP1_Q4_01, MYOD_01, KIM_RESPONSE_TO_TSA_AND_DECITABINE_UP, KOYAMA_SEMA3B_TARGETS_UP, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM5

GO Biological Process (4): cell adhesion (GO:0007155), positive regulation of cell population proliferation (GO:0008284), epidermis development (GO:0008544), positive regulation of cell migration (GO:0030335)

GO Molecular Function (2): heparin binding (GO:0008201), extracellular matrix structural constituent (GO:0005201)

GO Cellular Component (7): extracellular region (GO:0005576), laminin-211 trimer (GO:0005607), obsolete extracellular space (GO:0005615), cell cortex (GO:0005938), extracellular matrix (GO:0031012), perinuclear region of cytoplasm (GO:0048471), basement membrane (GO:0005604)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Extracellular matrix organization	4
Collagen formation	1
Assembly of collagen fibrils and other multimeric structures	1
Cell junction organization	1
MET promotes cell motility	1
Biofilm formation	1
Non-integrin membrane-ECM interactions	1
Developmental Cell Lineages of the Exocrine Pancreas	1
Cell-Cell communication	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by MET	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
extracellular matrix	2
cellular anatomical structure	2
cytoplasm	2
cellular process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
tissue development	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
glycosaminoglycan binding	1
sulfur compound binding	1
structural molecule activity	1
laminin trimer	1
cell periphery	1
external encapsulating structure	1

Protein interactions and networks

STRING

1988 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LAMC2	LAMB3	Q13751	988
LAMC2	LAMA4	Q16363	982
LAMC2	LAMA3	Q16787	982
LAMC2	ITGB4	P16144	881
LAMC2	COL17A1	Q9UMD9	863
LAMC2	COL7A1	Q02388	788
LAMC2	NMNAT2	Q9BZQ4	762
LAMC2	COL4A1	P02462	712
LAMC2	ITGA6	P23229	701
LAMC2	EGFR	P00533	689
LAMC2	SMG7	Q92540	680
LAMC2	ITGA5	P08648	612
LAMC2	ITGA2	P17301	598
LAMC2	LAMB2	P55268	591
LAMC2	TLL2	Q9Y6L7	589

IntAct

30 interactions, top by confidence:

A	B	Type	Score
FGL1	LCMT2	psi-mi:“MI:0914”(association)	0.640
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
CLEC11A	VWA8	psi-mi:“MI:0914”(association)	0.530
NOTCH2	ZNF316	psi-mi:“MI:0914”(association)	0.530
PIGT	ZNF609	psi-mi:“MI:0914”(association)	0.530
PNMA2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
PDIA3	LAMC2	psi-mi:“MI:0408”(disulfide bond)	0.440
CFTR	POTEF	psi-mi:“MI:0914”(association)	0.350
N	MRPL45	psi-mi:“MI:0914”(association)	0.350
ESR1	ARPC1B	psi-mi:“MI:0914”(association)	0.350
HRAS	MET	psi-mi:“MI:0914”(association)	0.350
DTNBP1	AP3B1	psi-mi:“MI:0914”(association)	0.350
PTCH1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
PRG2	QSOX1	psi-mi:“MI:0914”(association)	0.350
ERP27	DDX3Y	psi-mi:“MI:0914”(association)	0.350
IKBIP	LAMB1	psi-mi:“MI:0914”(association)	0.350
ANTXR1	CLGN	psi-mi:“MI:0914”(association)	0.350
ASGR2	SCAMP2	psi-mi:“MI:0914”(association)	0.350
CLGN	TMEM131L	psi-mi:“MI:0914”(association)	0.350
DEFA5	PDE2A	psi-mi:“MI:0914”(association)	0.350
FBXO6	TMEM131L	psi-mi:“MI:0914”(association)	0.350
IKBIP	RRP1	psi-mi:“MI:0914”(association)	0.350
KLK1	PPOX	psi-mi:“MI:0914”(association)	0.350
LYPD1	ADAM10	psi-mi:“MI:0914”(association)	0.350
OLFM2	CLGN	psi-mi:“MI:0914”(association)	0.350
PRG3	IGLL5	psi-mi:“MI:0914”(association)	0.350

BioGRID (43): LAMC2 (Affinity Capture-MS), LAMC2 (Affinity Capture-MS), LAMC2 (Affinity Capture-MS), CSF1R (Protein-peptide), LAMC2 (Affinity Capture-MS), LAMC2 (Affinity Capture-MS), LAMC2 (Proximity Label-MS), LAMC2 (Affinity Capture-MS), LAMC2 (Reconstituted Complex), LAMC2 (Affinity Capture-MS), LAMC2 (Affinity Capture-MS), LAMC2 (Affinity Capture-MS), LAMC2 (Affinity Capture-MS), LAMC2 (Affinity Capture-MS), LAMC2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IKU3, A0A8M9PFP2, A1A5Y0, A2A863, A2VCU8, A5A6L1, B0S5G3, L7VG99, O00622, O08841, O35118, O42493, O93512, P08163, P08833, P16042, P16144, P17668, P18406, Q07663, Q0VCN6, Q13753, Q501P1, Q53RD9, Q5R9Q9, Q61220, Q61592, Q64632, Q6DDW2, Q7T3Q2, Q7ZV46, Q7ZXL5, Q8R4Y4, Q8R553, Q8VDA1, Q91166, Q91167, Q91713, Q99JH7, Q9BQT9

Diamond homologs: A0JP86, A2ASQ1, G5ECE3, O00468, O00634, O09118, O15230, O75445, O75882, O95631, P02468, P11047, P15215, P19137, P24043, P25304, P25391, P31696, P34710, P97927, Q00174, Q01635, Q13751, Q13753, Q16363, Q16787, Q18823, Q19981, Q1LVF0, Q24567, Q24568, Q27262, Q2HXW4, Q2QI47, Q5RB89, Q5VV63, Q60675, Q61001, Q61087, Q61092

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
LAMC2	“form complex”	Laminin-5	binding
MMP2	“up-regulates activity”	LAMC2	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

1316 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	98
Likely pathogenic	121
Uncertain significance	255
Likely benign	676
Benign	81

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028397	NM_005562.3(LAMC2):c.343C>T (p.Arg115Ter)	Pathogenic
1047956	NM_005562.3(LAMC2):c.3343_3344del (p.Val1115fs)	Pathogenic
1048069	NM_005562.3(LAMC2):c.379G>T (p.Gly127Trp)	Pathogenic
1048070	NM_005562.3(LAMC2):c.404+3_404+6del	Pathogenic
1048071	NM_005562.3(LAMC2):c.2015-2A>G	Pathogenic
1069137	NM_005562.3(LAMC2):c.2511_2572del (p.Glu838fs)	Pathogenic
1071150	NM_005562.3(LAMC2):c.2857A>T (p.Lys953Ter)	Pathogenic
1071582	NM_005562.3(LAMC2):c.1009C>T (p.Arg337Ter)	Pathogenic
1071949	NM_005562.3(LAMC2):c.1849A>T (p.Lys617Ter)	Pathogenic
1073365	NM_005562.3(LAMC2):c.945C>G (p.Tyr315Ter)	Pathogenic
1074699	NM_005562.3(LAMC2):c.136C>T (p.Gln46Ter)	Pathogenic
1074740	NM_005562.3(LAMC2):c.1432del (p.Glu478fs)	Pathogenic
1075862	NM_005562.3(LAMC2):c.2420del (p.Ser807fs)	Pathogenic
1177256	NM_005562.3(LAMC2):c.1045C>T (p.Arg349Ter)	Pathogenic
1332785	NM_005562.3(LAMC2):c.3451C>T (p.Gln1151Ter)	Pathogenic
1333523	NM_005562.3(LAMC2):c.1043del (p.Ile348fs)	Pathogenic
1357680	NM_005562.3(LAMC2):c.1285G>T (p.Gly429Ter)	Pathogenic
1360353	NM_005562.3(LAMC2):c.539del (p.Asn180fs)	Pathogenic
1365433	NM_005562.3(LAMC2):c.258dup (p.Asn87Ter)	Pathogenic
1374561	NM_005562.3(LAMC2):c.725C>G (p.Ser242Ter)	Pathogenic
1391831	NM_005562.3(LAMC2):c.787del (p.Gln262_Val263insTer)	Pathogenic
1394167	NM_005562.3(LAMC2):c.3296_3297del (p.Leu1099fs)	Pathogenic
1396083	NM_005562.3(LAMC2):c.1515del (p.Phe505fs)	Pathogenic
1398344	NM_005562.3(LAMC2):c.1002del (p.Phe334fs)	Pathogenic
1410517	NM_005562.3(LAMC2):c.2565del (p.Ser856fs)	Pathogenic
1439758	NM_005562.3(LAMC2):c.745_748del (p.Val249fs)	Pathogenic
1440397	NM_005562.3(LAMC2):c.2423del (p.Pro808fs)	Pathogenic
1451372	NM_005562.3(LAMC2):c.664C>T (p.Gln222Ter)	Pathogenic
1451602	NM_005562.3(LAMC2):c.1597del (p.Arg533fs)	Pathogenic
1451947	NM_005562.3(LAMC2):c.2023A>T (p.Arg675Ter)	Pathogenic

SpliceAI

2541 predictions. Top by Δscore:

Variant	Effect	Δscore
1:183207879:A:AG	acceptor_gain	1.0000
1:183207880:G:GG	acceptor_gain	1.0000
1:183215437:ACCTT:A	acceptor_gain	1.0000
1:183215444:G:A	acceptor_gain	1.0000
1:183215451:A:AG	acceptor_gain	1.0000
1:183215451:AG:A	acceptor_gain	1.0000
1:183215452:G:GA	acceptor_loss	1.0000
1:183215452:G:GG	acceptor_gain	1.0000
1:183215452:GG:G	acceptor_gain	1.0000
1:183215584:CTGCT:C	donor_gain	1.0000
1:183215586:GCT:G	donor_gain	1.0000
1:183215589:G:GG	donor_gain	1.0000
1:183215589:GTGA:G	donor_loss	1.0000
1:183215590:T:A	donor_loss	1.0000
1:183218388:A:AG	acceptor_gain	1.0000
1:183218389:G:GA	acceptor_gain	1.0000
1:183218389:GA:G	acceptor_gain	1.0000
1:183225603:T:TA	acceptor_gain	1.0000
1:183225603:TGCA:T	acceptor_loss	1.0000
1:183225604:GCAG:G	acceptor_loss	1.0000
1:183225605:CAGGT:C	acceptor_loss	1.0000
1:183225606:A:AG	acceptor_gain	1.0000
1:183225606:A:AT	acceptor_loss	1.0000
1:183225607:G:GG	acceptor_gain	1.0000
1:183225607:GGTT:G	acceptor_gain	1.0000
1:183225716:ATACA:A	donor_gain	1.0000
1:183225717:TACA:T	donor_gain	1.0000
1:183225719:CA:C	donor_gain	1.0000
1:183225720:AGTAA:A	donor_loss	1.0000
1:183225721:G:GG	donor_gain	1.0000

AlphaMissense

7866 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:183222100:T:A	W218R	0.997
1:183222100:T:C	W218R	0.997
1:183222102:G:C	W218C	0.996
1:183222102:G:T	W218C	0.996
1:183223161:A:C	S264R	0.995
1:183223163:C:A	S264R	0.995
1:183223163:C:G	S264R	0.995
1:183226765:G:C	W378C	0.995
1:183226765:G:T	W378C	0.995
1:183239399:G:C	A969P	0.995
1:183207994:T:A	C65S	0.994
1:183207995:G:C	C65S	0.994
1:183226808:T:A	C393S	0.994
1:183226809:G:C	C393S	0.994
1:183238416:T:C	L955P	0.994
1:183226725:T:C	L365P	0.993
1:183226808:T:C	C393R	0.993
1:183226810:C:G	C393W	0.993
1:183227520:T:A	C431S	0.993
1:183227521:G:C	C431S	0.993
1:183228517:T:A	C538S	0.993
1:183228518:G:C	C538S	0.993
1:183228562:T:A	C553S	0.993
1:183228563:G:C	C553S	0.993
1:183228613:T:A	C570S	0.993
1:183228614:G:C	C570S	0.993
1:183207958:T:A	C53S	0.992
1:183207959:G:C	C53S	0.992
1:183220888:C:G	C189W	0.992
1:183226775:T:A	C382S	0.992

dbSNP variants (sampled 300 via entrez): RS1000017772 (1:183200255 T>G), RS1000124753 (1:183208587 CTT>C), RS1000157554 (1:183185273 T>C), RS1000180787 (1:183256199 C>A,T), RS1000202422 (1:183253502 A>T), RS1000297974 (1:183236172 T>A), RS1000355030 (1:183221866 A>G), RS1000355533 (1:183249663 T>G), RS1000598885 (1:183243014 A>G,T), RS1000609902 (1:183229022 G>A), RS1000675615 (1:183191652 G>T), RS1000685178 (1:183203438 A>C), RS1000730283 (1:183198176 T>C), RS1000778803 (1:183197454 C>T), RS1000825797 (1:183189895 A>C)

Disease associations

OMIM: gene MIM:150292 | disease phenotypes: MIM:226700, MIM:226650, MIM:619785, MIM:619786

GenCC curated gene-disease

Disease	Classification	Inheritance
junctional epidermolysis bullosa	Definitive	Autosomal recessive
junctional epidermolysis bullosa, non-Herlitz type	Strong	Autosomal recessive
junctional epidermolysis bullosa Herlitz type	Strong	Autosomal recessive
epidermolysis bullosa, junctional 3A, intermediate	Strong	Autosomal recessive
epidermolysis bullosa, junctional 3B, severe	Strong	Autosomal recessive
generalized junctional epidermolysis bullosa non-Herlitz type	Supportive	Autosomal recessive

Mondo (7): junctional epidermolysis bullosa Herlitz type (MONDO:0009182), junctional epidermolysis bullosa (MONDO:0017612), epidermolysis bullosa, junctional 3A, intermediate (MONDO:0030748), epidermolysis bullosa, junctional 3B, severe (MONDO:0030749), junctional epidermolysis bullosa, non-Herlitz type (MONDO:0009180), amelogenesis imperfecta type 1 (MONDO:0015047), generalized junctional epidermolysis bullosa non-Herlitz type (MONDO:0019307)

Orphanet (7): Severe generalized junctional epidermolysis bullosa (Orphanet:79404), Junctional epidermolysis bullosa (Orphanet:305), Localized junctional epidermolysis bullosa (Orphanet:251393), Intermediate generalized junctional epidermolysis bullosa (Orphanet:79402), Junctional epidermolysis bullosa inversa (Orphanet:79405), OBSOLETE: Junctional epidermolysis bullosa, non-Herlitz type (Orphanet:89840), Hypoplastic amelogenesis imperfecta (Orphanet:100031)

HPO phenotypes

78 total (30 of 78 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000014	Abnormality of the bladder
HP:0000016	Urinary retention
HP:0000070	Ureterocele
HP:0000072	Hydroureter
HP:0000081	Duplicated collecting system
HP:0000107	Renal cyst
HP:0000126	Hydronephrosis
HP:0000481	Abnormal cornea morphology
HP:0000670	Carious teeth
HP:0000939	Osteoporosis
HP:0000969	Edema
HP:0000982	Palmoplantar keratoderma
HP:0000999	Pyoderma
HP:0001000	Abnormality of skin pigmentation
HP:0001030	Fragile skin
HP:0001056	Milia
HP:0001057	Aplasia cutis congenita
HP:0001075	Atrophic scars
HP:0001159	Syndactyly
HP:0001211	Abnormal fingertip morphology
HP:0001250	Seizure
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001522	Death in infancy
HP:0001581	Recurrent skin infections
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000974_1	HDL cholesterol	4.000000e-06
GCST000996_9	Systemic lupus erythematosus	6.000000e-07
GCST002595_11	Clozapine-induced agranulocytosis	1.000000e-06
GCST006585_1913	Blood protein levels	2.000000e-81
GCST007234_1	Acne (severe)	4.000000e-12
GCST007565_107	Morning person	1.000000e-19
GCST010204_57	Low density lipoprotein cholesterol levels	8.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0008328	chronotype measurement
EFO:0004611	low density lipoprotein cholesterol measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016109	Epidermolysis Bullosa, Junctional	C16.131.831.493.170; C16.320.850.275.170; C17.800.804.493.170; C17.800.827.275.170; C17.800.865.410.170

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2364187 (PROTEIN COMPLEX GROUP)

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

CTD chemical–gene interactions

102 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, decreases expression, decreases methylation, affects cotreatment	5
bisphenol A	affects cotreatment, decreases methylation, decreases expression, increases expression	4
Estradiol	affects cotreatment, decreases expression, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
Mustard Gas	decreases reaction, increases degradation, decreases expression, affects binding	3
Tobacco Smoke Pollution	affects expression, increases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
sodium arsenite	increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
perfluorooctane sulfonic acid	decreases expression, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Air Pollutants	increases expression, increases abundance	2
Benzo(a)pyrene	increases expression, decreases methylation	2
Copper	affects binding, increases expression	2
Mechlorethamine	decreases expression, increases degradation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	increases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, affects expression, increases expression	2
Aflatoxin B1	increases expression	2
Particulate Matter	affects cotreatment, increases abundance, increases expression	2
bisphenol F	decreases methylation	1
sotorasib	affects cotreatment, decreases expression	1
4-toluenesulfonyl fluoride	decreases reaction, increases degradation	1
propionaldehyde	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
pyrazolo(3,4-d)pyrimidine	affects expression	1
beta-lapachone	increases expression	1
methylparaben	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1

Cellosaurus cell lines

2 cell lines: 1 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8P2	Ubigene HCT 116 LAMC2 KO	Cancer cell line	Male
CVCL_E3C4	LSV5	Transformed cell line	Sex unspecified

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00587223	PHASE3	TERMINATED	Safety and Efficacy of Apligraf in Nonhealing Wounds of Subjects With Junctional or Dystrophic Epidermolysis Bullosa (EB)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT03578029	PHASE2	TERMINATED	Evaluation of the Safety and Efficacy Study of RGN-137 Topical Gel for Junctional and Dystrophic Epidermolysis Bullosa
NCT04908215	PHASE2	COMPLETED	INM-755 (Cannabinol) Cream for Treatment of Epidermolysis Bullosa
NCT06594393	PHASE2	RECRUITING	A Phase 2 Study of TCP-25 Gel in Patients With Epidermolysis Bullosa, STEP-study
NCT03472287	PHASE1	COMPLETED	To Evaluate the Pharmacokinetic of Diacerein and Rhein After Maximum Use in Patients With Epidermolysis Bullosa (EB)
NCT06713434	PHASE1	ACTIVE_NOT_RECRUITING	Pilot Study of ELK-003 Eye Drops for Treating Ocular Manifestations of Epidermolysis Bullosa
NCT03490331	PHASE1/PHASE2	TERMINATED	Clinical Trial to Assess Safety and Efficacy of Autologous Cultured Epidermal Grafts Containing Epidermal Stem Cells Genetically Modified in Patients With JEB (HOLOGENE17)
NCT03526159	PHASE1/PHASE2	RECRUITING	Gentamicin for Junctional Epidermolysis Bullosa
NCT04140786	PHASE1/PHASE2	UNKNOWN	Optimizing IV Gentamicin in JEB
NCT03269474	Not specified	UNKNOWN	Computational Drug Repurposing for All EBS Cases
NCT04727268	Not specified	UNKNOWN	Genotype-phenotype Correlation in Junctional Epidermolysis Bullosa
NCT05033574	Not specified	UNKNOWN	The State of Sexual Development in Children With Inherited Epidermolysis Bullosa
NCT06007235	Not specified	UNKNOWN	CACIPLIQ20 in Wound Healing in Subjects With Epidermolysis Bullosa
NCT06423573	Not specified	RECRUITING	A Study to Assess the Incidence of Skin Cancers in Patients With Epidermolysis Bullosa Receiving Filsuvez