LIPN

Summary

LIPN (lipase family member N, HGNC:23452) is a protein-coding gene on chromosome 10q23.31, encoding Lipase member N (Q5VXI9). Plays a highly specific role in the last step of keratinocyte differentiation.

The gene encodes a lipase that is highly expressed in granular keratinocytes in the epidermis, and plays a role in the differentiation of keratinocytes. Mutations in this gene are associated with lamellar ichthyosis type 4.

Source: NCBI Gene 643418 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive congenital ichthyosis 8 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 138 total — 1 pathogenic
• Phenotypes (HPO): 27
• MANE Select transcript: NM_001102469

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23452
Approved symbol	LIPN
Name	lipase family member N
Location	10q23.31
Locus type	gene with protein product
Status	Approved
Aliases	bA186O14.3
Ensembl gene	ENSG00000204020
Ensembl biotype	protein_coding
OMIM	613924
Entrez	643418

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 retained_intron

ENST00000404459, ENST00000674982

RefSeq mRNA: 1 — MANE Select: NM_001102469 NM_001102469

CCDS: CCDS44456

Canonical transcript exons

ENST00000404459 — 10 exons

Exon	Start	End
ENSE00001456469	88778009	88779626
ENSE00001456475	88764410	88764608
ENSE00001552208	88761398	88761513
ENSE00003232003	88762188	88762305
ENSE00003235255	88768792	88768928
ENSE00003242028	88770845	88770991
ENSE00003339325	88766269	88766378
ENSE00003359781	88774473	88774544
ENSE00003415446	88775092	88775163
ENSE00003901510	88760020	88760106

Expression profiles

Bgee: expression breadth broad, 88 present calls, max score 82.98.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 4.9028 / max 655.1544, expressed in 165 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106064	3.3328	119
106063	1.3250	124
106065	0.2450	56

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	82.98	gold quality
leukocyte	CL:0000738	82.92	gold quality
skin of abdomen	UBERON:0001416	81.64	gold quality
blood	UBERON:0000178	81.52	gold quality
zone of skin	UBERON:0000014	80.01	gold quality
skin of leg	UBERON:0001511	78.55	gold quality
granulocyte	CL:0000094	78.05	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.01	gold quality
bone marrow	UBERON:0002371	68.83	gold quality
vermiform appendix	UBERON:0001154	67.00	gold quality
right lung	UBERON:0002167	66.32	gold quality
bone marrow cell	CL:0002092	65.51	silver quality
spleen	UBERON:0002106	63.27	gold quality
upper lobe of left lung	UBERON:0008952	56.31	gold quality
smooth muscle tissue	UBERON:0001135	53.73	gold quality
lung	UBERON:0002048	53.14	gold quality
gall bladder	UBERON:0002110	53.04	gold quality
omental fat pad	UBERON:0010414	50.59	gold quality
vagina	UBERON:0000996	48.94	gold quality
colonic epithelium	UBERON:0000397	48.11	silver quality
placenta	UBERON:0001987	47.80	gold quality
lymph node	UBERON:0000029	47.24	silver quality
muscle tissue	UBERON:0002385	46.09	gold quality
left uterine tube	UBERON:0001303	46.08	gold quality
adipose tissue	UBERON:0001013	45.96	gold quality
liver	UBERON:0002107	43.94	gold quality
left adrenal gland	UBERON:0001234	43.82	gold quality
right adrenal gland	UBERON:0001233	43.64	gold quality
skeletal muscle tissue	UBERON:0001134	43.44	silver quality
descending thoracic aorta	UBERON:0002345	43.17	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.21

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• describe a late-onset form of recessive ichthyosis in a large consanguineous pedigree with a 2 bp deletion in LIPN that segregated with the disease phenotype throughout the family (PMID:21439540)

Cross-species orthologs

30 orthologs

Organism	Symbol	Gene ID
mus_musculus	Lipn	ENSMUSG00000024770
rattus_norvegicus	Lipn	ENSRNOG00000057173
drosophila_melanogaster	Lip3	FBGN0023495
drosophila_melanogaster	Lip1	FBGN0023496
drosophila_melanogaster	Lip2	FBGN0024740
drosophila_melanogaster	CG2772	FBGN0031533
drosophila_melanogaster	Lip4	FBGN0032264
drosophila_melanogaster	CG18301	FBGN0032265
drosophila_melanogaster	CG18302	FBGN0032266
drosophila_melanogaster	CG7329	FBGN0032271
drosophila_melanogaster	CG3635	FBGN0032981
drosophila_melanogaster	CG8093	FBGN0033999
drosophila_melanogaster	CG11406	FBGN0034990
drosophila_melanogaster	mag	FBGN0036996
drosophila_melanogaster	CG11598	FBGN0038067
drosophila_melanogaster	CG11600	FBGN0038068
drosophila_melanogaster	CG11608	FBGN0038069
drosophila_melanogaster	CG6753	FBGN0038070
drosophila_melanogaster	CG18530	FBGN0042207
drosophila_melanogaster	CG18284	FBGN0043825
drosophila_melanogaster	CG31089	FBGN0051089
drosophila_melanogaster	CG31091	FBGN0051091
drosophila_melanogaster	CG31871	FBGN0051871
drosophila_melanogaster	CG31872	FBGN0051872
drosophila_melanogaster	CG17097	FBGN0265264
caenorhabditis_elegans		WBGENE00009773
caenorhabditis_elegans		WBGENE00010062
caenorhabditis_elegans		WBGENE00020016
caenorhabditis_elegans		WBGENE00021963
caenorhabditis_elegans		WBGENE00022642

Paralogs (5): LIPA (ENSG00000107798), LIPM (ENSG00000173239), LIPF (ENSG00000182333), LIPK (ENSG00000204021), LIPJ (ENSG00000204022)

Protein

Protein identifiers

Lipase member N — Q5VXI9 (reviewed: Q5VXI9)

Alternative names: Lipase-like abhydrolase domain-containing protein 4

All UniProt accessions (1): Q5VXI9

UniProt curated annotations — full annotation on UniProt →

Function. Plays a highly specific role in the last step of keratinocyte differentiation. Contains two distinct domains: the alpha/beta hydrolase fold and the abhydrolase-associated lipase region, also features the consensus sequence of the active site of a genuine lipase. May have an essential function in lipid metabolism of the most differentiated epidermal layers.

Subcellular location. Secreted.

Tissue specificity. Highly expressed in the epidermis in the granular keratinocytes. Also detected in other tissues, although at much lower levels, including lung and spleen.

Disease relevance. Ichthyosis, congenital, autosomal recessive 8 (ARCI8) [MIM:613943] A form of autosomal recessive congenital ichthyosis, a disorder of keratinization with abnormal differentiation and desquamation of the epidermis, resulting in abnormal skin scaling over the whole body. The main skin phenotypes are lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur. Lamellar ichthyosis is a condition often associated with an embedment in a collodion-like membrane at birth; skin scales later develop, covering the entire body surface. Non-bullous congenital ichthyosiform erythroderma characterized by fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the AB hydrolase superfamily. Lipase family.

RefSeq proteins (1): NP_001095939* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000073	AB_hydrolase_1	Domain
IPR025483	Lipase_euk	Family
IPR029058	AB_hydrolase_fold	Homologous_superfamily

Pfam: PF00561

Catalyzed reactions (Rhea), 4 shown:

• a sterol ester + H2O = a sterol + a fatty acid + H(+) (RHEA:10100)
• a triacylglycerol + H2O = a diacylglycerol + a fatty acid + H(+) (RHEA:12044)
• a triacylglycerol + H2O = a 1,2-diacylglycerol + a fatty acid + H(+) (RHEA:35667)
• a cholesterol ester + H2O = cholesterol + a fatty acid + H(+) (RHEA:36403)

UniProt features (9 total): active site 3, signal peptide 1, chain 1, domain 1, glycosylation site 1, disulfide bond 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5VXI9-F1	92.14	0.81

Functional residue map

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

Catalytic / active sites (3): 173 (nucleophile); 344 (charge relay system); 373 (charge relay system)

Disulfide bonds (1): 247–256

Glycosylation sites (1): 272

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6809371	Formation of the cornified envelope
R-HSA-1266738	Developmental Biology
R-HSA-6805567	Keratinization

MSigDB gene sets: 87 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GOBP_EPIDERMIS_DEVELOPMENT, GOBP_LIPID_METABOLIC_PROCESS, GOBP_KERATINIZATION, GOBP_LIPID_CATABOLIC_PROCESS, GOBP_SKIN_DEVELOPMENT, GOMF_TRIACYLGLYCEROL_LIPASE_ACTIVITY, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ESTER_BONDS, GOMF_CARBOXYLIC_ESTER_HYDROLASE_ACTIVITY, GOMF_LIPASE_ACTIVITY, chr10q23, GOBP_CORNIFICATION, GOMF_STEROL_ESTER_ESTERASE_ACTIVITY, REACTOME_KERATINIZATION

GO Biological Process (3): lipid metabolic process (GO:0006629), lipid catabolic process (GO:0016042), cornification (GO:0070268)

GO Molecular Function (7): lipoprotein lipase activity (GO:0004465), sterol ester esterase activity (GO:0004771), lipase activity (GO:0016298), triacylglycerol lipase activity (GO:0004806), hydrolase activity (GO:0016787), hydrolase activity, acting on ester bonds (GO:0016788), carboxylic ester hydrolase activity (GO:0052689)

GO Cellular Component (1): extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Keratinization	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipase activity	2
carboxylic ester hydrolase activity	2
hydrolase activity, acting on ester bonds	2
primary metabolic process	1
lipid metabolic process	1
catabolic process	1
programmed cell death	1
keratinization	1
cornified envelope assembly	1
triacylglycerol lipase activity	1
catalytic activity	1
hydrolase activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1288 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LIPN	PCSK5	Q92824	891
LIPN	SP6	Q3SY56	879
LIPN	LRP5	O75197	872
LIPN	CYP4F22	Q6NT55	863
LIPN	ABCA12	Q86UK0	829
LIPN	ACRV1	P26436	793
LIPN	MARVELD1	Q9BSK0	793
LIPN	SP9	P0CG40	792
LIPN	MTRNR2L5	P0CJ72	786
LIPN	PNPLA1	Q8N8W4	775
LIPN	NIPAL4	Q0D2K0	763
LIPN	ALOXE3	Q9BYJ1	680
LIPN	ALOX12B	O75342	659
LIPN	CERS3	Q8IU89	655
LIPN	TGM1	P22735	625

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A5D6U8, A6H730, J3SDX8, O16956, O35409, O61866, O75795, P04068, P04634, P07098, P07099, P07687, P08430, P0DTE5, P11515, P19224, P21529, P36510, P37891, P38571, P49614, P70627, P70691, P79381, P80035, Q28611, Q29458, Q38924, Q3U4B4, Q3YBN2, Q41005, Q4R4S5, Q5VXI9, Q5VXJ0, Q5VYY2, Q5W064, Q64194, Q64435, Q64550, Q67ZU1

Diamond homologs: J3SDX8, O16956, O46107, O46108, O61866, O74430, P04634, P07098, P34163, P38571, P78898, P80035, Q29458, Q3U4B4, Q3YBN2, Q4R4S5, Q5VXI9, Q5VXJ0, Q5VYY2, Q5W064, Q64194, Q67ZU1, Q8BM14, Q8K2A6, Q93789, Q94252, Q9CPP7, Q9Z0M5, Q07950, Q71DJ5, O60095, Q07804

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	79
Likely benign	13
Benign	40

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
831557	NC_000010.11:g.(?87863161)(88948936_?)del	Pathogenic

SpliceAI

1468 predictions. Top by Δscore:

Variant	Effect	Δscore
10:88762246:A:G	donor_gain	1.0000
10:88762313:A:G	donor_gain	1.0000
10:88762360:G:GT	donor_gain	1.0000
10:88764587:A:G	donor_gain	1.0000
10:88761514:G:GG	donor_gain	0.9900
10:88762181:T:A	acceptor_gain	0.9900
10:88762187:GA:G	acceptor_gain	0.9900
10:88762363:G:GT	donor_gain	0.9900
10:88764406:CCA:C	acceptor_loss	0.9900
10:88764407:CA:C	acceptor_loss	0.9900
10:88764408:AGGT:A	acceptor_loss	0.9900
10:88764485:G:GT	donor_gain	0.9900
10:88764601:GCCTT:G	donor_gain	0.9900
10:88766267:A:AG	acceptor_gain	0.9900
10:88766268:G:GA	acceptor_gain	0.9900
10:88766268:GTTTT:G	acceptor_gain	0.9900
10:88778008:GA:G	acceptor_gain	0.9900
10:88761512:CT:C	donor_gain	0.9800
10:88761554:GAC:G	donor_gain	0.9800
10:88762182:G:A	acceptor_gain	0.9800
10:88762186:A:AG	acceptor_gain	0.9800
10:88762187:G:GG	acceptor_gain	0.9800
10:88762245:GATGG:G	donor_gain	0.9800
10:88764408:A:AG	acceptor_gain	0.9800
10:88764409:G:GC	acceptor_gain	0.9800
10:88764409:GGTC:G	acceptor_gain	0.9800
10:88764556:TCAAG:T	donor_gain	0.9800
10:88764604:TTTAG:T	donor_loss	0.9800
10:88764605:TTAGG:T	donor_loss	0.9800
10:88764606:TAGGT:T	donor_loss	0.9800

AlphaMissense

2661 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:88764604:T:C	F141L	0.994
10:88764606:T:A	F141L	0.994
10:88764606:T:G	F141L	0.994
10:88764526:T:A	W115R	0.992
10:88764526:T:C	W115R	0.992
10:88764595:T:C	F138L	0.987
10:88764597:C:A	F138L	0.987
10:88764597:C:G	F138L	0.987
10:88766360:T:C	S173P	0.987
10:88774477:G:C	R275P	0.984
10:88778060:T:A	W339R	0.984
10:88778060:T:C	W339R	0.984
10:88762271:A:C	R64S	0.982
10:88762271:A:T	R64S	0.982
10:88764487:A:C	S102R	0.978
10:88764489:C:A	S102R	0.978
10:88764489:C:G	S102R	0.978
10:88778054:G:C	A337P	0.978
10:88762270:G:C	R64T	0.977
10:88764537:C:A	N118K	0.977
10:88764537:C:G	N118K	0.977
10:88764463:T:A	W94R	0.975
10:88764463:T:C	W94R	0.975
10:88764528:G:C	W115C	0.975
10:88764528:G:T	W115C	0.975
10:88764542:G:C	R120P	0.975
10:88764425:T:A	V81E	0.974
10:88764496:T:C	F105L	0.973
10:88764498:C:A	F105L	0.973
10:88764498:C:G	F105L	0.973

dbSNP variants (sampled 300 via entrez): RS1000061844 (10:88758889 C>A), RS1000071185 (10:88770540 G>T), RS1000123413 (10:88770318 T>C), RS1000266419 (10:88775938 C>G,T), RS1000363455 (10:88775281 T>C), RS1000409913 (10:88769389 A>G), RS1000564872 (10:88763897 T>C), RS1000664517 (10:88757380 G>A,T), RS1001116140 (10:88758431 G>C), RS1001182772 (10:88757053 A>G), RS1001238902 (10:88758206 T>C), RS1001727559 (10:88760776 A>C,G,T), RS1001852895 (10:88768764 A>T), RS1001923711 (10:88774876 C>A,G,T), RS1001998053 (10:88766433 G>A)

Disease associations

OMIM: gene MIM:613924 | disease phenotypes: MIM:613943

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive congenital ichthyosis 8	Strong	Autosomal recessive
lamellar ichthyosis	Supportive	Autosomal recessive

Mondo (3): autosomal recessive congenital ichthyosis 8 (MONDO:0013495), PTEN hamartoma tumor syndrome (MONDO:0017623), lamellar ichthyosis (MONDO:0017778)

Orphanet (2): Lamellar ichthyosis (Orphanet:313), PTEN hamartoma tumor syndrome (Orphanet:306498)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000164	Abnormality of the dentition
HP:0000232	Everted lower lip vermilion
HP:0000389	Chronic otitis media
HP:0000656	Ectropion
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000989	Pruritus
HP:0001019	Erythroderma
HP:0001597	Abnormal nail morphology
HP:0001944	Dehydration
HP:0002205	Recurrent respiratory infections
HP:0004322	Short stature
HP:0008064	Ichthyosis
HP:0008070	Sparse hair
HP:0010783	Erythema
HP:0011039	Abnormal helix morphology
HP:0011463	Childhood onset
HP:0025092	Epidermal acanthosis
HP:0025114	Hypergranulosis
HP:0040162	Orthokeratosis
HP:0100543	Cognitive impairment
HP:0100679	Lack of skin elasticity
HP:0100758	Gangrene
HP:0100806	Sepsis
HP:0100840	Aplasia/Hypoplasia of the eyebrow

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_1485	Blood protein levels	7.000000e-104

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
sodium arsenate	increases abundance, decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	increases expression	1
Tretinoin	increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01222000	PHASE3	UNKNOWN	Treatment of the Recessive Nonbullous Congenital Ichthyosis by the Epigallocatechine Cutaneous
NCT03041038	PHASE2	COMPLETED	The Efficacy and Safety of Secukinumab in Patients With Ichthyoses
NCT03738800	PHASE2	TERMINATED	A Safety, Efficacy and Systemic Exposure Study of CD5789 Cream in Adults and Adolescents With Lamellar Ichthyosis
NCT04094675	PHASE2	COMPLETED	Sirolimus for Cowden Syndrome With Colon Polyposis
NCT00001292	Not specified	COMPLETED	Study of Scaling Disorders and Other Inherited Skin Diseases
NCT07218575	PHASE2/PHASE3	NOT_YET_RECRUITING	Double-Blind Trial of Everolimus for Improving Social Abilities in PTEN Germline Mutations
NCT02991807	PHASE1/PHASE2	COMPLETED	RAD001 and Neurocognition in PTEN Hamartoma Tumor Syndrome
NCT06080165	PHASE1/PHASE2	WITHDRAWN	Sirolimus for Improving Social Abilities in People With PTEN Germline Mutations
NCT02461446	Not specified	RECRUITING	Natural History Study of Individuals With Autism and Germline Heterozygous PTEN Mutations
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03630523	Not specified	UNKNOWN	Response of Immune System to Flu Vaccination in PHTS
NCT05671107	Not specified	COMPLETED	Development and Validation of an Online Neurobehavioral Evaluation Tool for PTEN Patients
NCT06462430	Not specified	RECRUITING	PTEN Hamartoma Tumor Syndrome Pediatric Patient Registry