LZTR1

Summary

LZTR1 (leucine zipper like post translational regulator 1, HGNC:6742) is a protein-coding gene on chromosome 22q11.21, encoding Leucine-zipper-like transcriptional regulator 1 (Q8N653). Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination of Ras (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS).

This gene encodes a member of the BTB-kelch superfamily. Initially described as a putative transcriptional regulator based on weak homology to members of the basic leucine zipper-like family, the encoded protein subsequently has been shown to localize exclusively to the Golgi network where it may help stabilize the Gogli complex. Deletion of this gene may be associated with DiGeorge syndrome.

Source: NCBI Gene 8216 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Noonan syndrome (Definitive, ClinGen) — +5 more curated relationships
• Clinical variants (ClinVar): 4,555 total — 473 pathogenic, 187 likely-pathogenic
• Phenotypes (HPO): 159
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 4 cancer types
• MANE Select transcript: NM_006767

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6742
Approved symbol	LZTR1
Name	leucine zipper like post translational regulator 1
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Aliases	LZTR-1, BTBD29
Ensembl gene	ENSG00000099949
Ensembl biotype	protein_coding
OMIM	600574
Entrez	8216

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 9 retained_intron, 9 protein_coding, 8 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000414985, ENST00000415354, ENST00000415817, ENST00000439171, ENST00000443265, ENST00000452988, ENST00000461510, ENST00000463909, ENST00000480895, ENST00000491432, ENST00000492480, ENST00000493460, ENST00000495142, ENST00000497716, ENST00000498649, ENST00000642151, ENST00000643578, ENST00000643710, ENST00000644435, ENST00000645935, ENST00000646124, ENST00000646506, ENST00000700578, ENST00000888029, ENST00000888030, ENST00000888031, ENST00000888032, ENST00000916176

RefSeq mRNA: 1 — MANE Select: NM_006767 NM_006767

CCDS: CCDS33606

Canonical transcript exons

ENST00000646124 — 21 exons

Exon	Start	End
ENSE00003459800	20993662	20993754
ENSE00003459928	20992794	20992904
ENSE00003470272	20988010	20988118
ENSE00003489826	20994104	20994269
ENSE00003502709	20994558	20994727
ENSE00003508485	20985841	20985897
ENSE00003532860	20990386	20990525
ENSE00003542765	20995746	20995872
ENSE00003569152	20988789	20988872
ENSE00003578472	20995963	20996112
ENSE00003599943	20994870	20995026
ENSE00003619328	20983027	20983089
ENSE00003623090	20993924	20994019
ENSE00003634607	20996886	20996966
ENSE00003636692	20996696	20996801
ENSE00003656947	20991628	20991829
ENSE00003660441	20992214	20992369
ENSE00003673759	20989625	20989682
ENSE00003677839	20987504	20987583
ENSE00003814803	20982297	20982571
ENSE00003980199	20997232	20999032

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 96.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.0158 / max 173.8431, expressed in 1804 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191179	16.8048	1803
191178	1.5282	899
191177	0.6828	299

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	96.14	gold quality
pituitary gland	UBERON:0000007	95.76	gold quality
adenohypophysis	UBERON:0002196	94.98	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.47	gold quality
stromal cell of endometrium	CL:0002255	94.44	gold quality
granulocyte	CL:0000094	94.16	gold quality
tibial nerve	UBERON:0001323	93.84	gold quality
metanephros cortex	UBERON:0010533	93.74	gold quality
body of uterus	UBERON:0009853	93.73	gold quality
right ovary	UBERON:0002118	93.72	gold quality
cerebellar hemisphere	UBERON:0002245	93.63	gold quality
cerebellum	UBERON:0002037	93.61	gold quality
cerebellar cortex	UBERON:0002129	93.60	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.60	gold quality
lower esophagus	UBERON:0013473	93.58	gold quality
myometrium	UBERON:0001296	93.43	gold quality
left ovary	UBERON:0002119	93.38	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.28	gold quality
endocervix	UBERON:0000458	93.02	gold quality
ovary	UBERON:0000992	93.02	gold quality
cortical plate	UBERON:0005343	93.00	gold quality
left uterine tube	UBERON:0001303	92.92	gold quality
left coronary artery	UBERON:0001626	92.84	gold quality
right lobe of thyroid gland	UBERON:0001119	92.83	gold quality
vermiform appendix	UBERON:0001154	92.78	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.77	gold quality
ascending aorta	UBERON:0001496	92.56	gold quality
thoracic aorta	UBERON:0001515	92.51	gold quality
gall bladder	UBERON:0002110	92.40	gold quality
left lobe of thyroid gland	UBERON:0001120	92.35	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.99
E-ENAD-20	no	2160.77
E-MTAB-6911	no	461.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

48 targeting LZTR1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-5190	99.15	67.76	1234
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-6804-5P	98.39	65.77	1084
HSA-MIR-4436B-3P	98.25	65.26	1494

Literature-anchored findings (GeneRIF, showing 32)

• LZTR-1 is the first BTB-kelch protein that exclusively localizes to the Golgi network (PMID:16356934)
• Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. (PMID:24362817)
• Data indicate that molecular analysis of leucine-zipper-like transcription regulator 1 (LZTR1) may contribute to the molecular characterization of schwannomatosis patients. (PMID:25335493)
• Data confirm the relationship between mutations in LZTR1 and schwannomatosis. They indicate that germline mutations in LZTR1 confer an increased risk of vestibular schwannoma. (PMID:25480913)
• We show for the first time that an inherited mutation in PBRM1 predisposes to RCC. (PMID:25795793)
• Nerve lesions and LZTR1 germline mutations in segmental schwannomatosis. (PMID:27472264)
• the malignancy risk in schwannomatosis is not well defined but may include an increased risk of malignant peripheral nerve sheath tumor in SMARCB1 Imaging protocols are also proposed for SMARCB1 and LZTR1 schwannomatosis and SMARCE1-related meningioma predisposition. (PMID:28620005)
• These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1. (PMID:29469822)
• LZTR1 mutation is associated with Noonan syndrome. (PMID:30368668)
• RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease. (PMID:30442762)
• LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. Because LZTR1 disease mutations failed to revert loss-of-function phenotypes, these findings provide a molecular rationale for LZTR1 involvement in a variety of inherited and acquired human disorders. (PMID:30442766)
• LZTR1 mutations are predicted to variably impair binding of these substrates to the multi-component ligase complex and their efficient ubiquitination and degradation, resulting in MAPK signaling upregulation. (PMID:30481304)
• Oligo-astrocytoma in LZTR1-related Noonan syndrome. (PMID:30664951)
• Pathogenic mutations affecting either RIT1 or LZTR1 resulted in incomplete degradation of RIT1. (PMID:30872527)
• Parallel sequencing of 22q11.2 region in patients with bladder exstrophy-epispadias complex (BEEC) without 22q11.2 microduplication identified a novel variant in LZTR1 p.Ser698Phe that displayed altered concentration and mobility in live cells, suggesting LZTR1 as a candidate gene underlying the urogenital malformation. (PMID:31044557)
• We report here two families in which segregate both multiple schwannomas and glioblastoma. In the first family, the proband received a diagnosis with of schwannomatosis after a surgery for a lumbar schwannoma at age 43, molecularly confirmed by identification of a germline heterozygous mutation in LZTR1. (PMID:31128261)
• LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases. (PMID:31337872)
• Providing more evidence on LZTR1 variants in Noonan syndrome patients. (PMID:31825158)
• LZTR1-Related Hypertrophic Cardiomyopathy Without Typical Noonan Syndrome Features. (PMID:32004086)
• Simultaneous Detection of NF1, SPRED1, LZTR1, and NF2 Gene Mutations by Targeted NGS in an Italian Cohort of Suspected NF1 Patients. (PMID:32575496)
• Sporadic vestibular schwannoma: a molecular testing summary. (PMID:32576656)
• A Chinese family with Noonan syndrome caused by a heterozygous variant in LZTR1: a case report and literature review. (PMID:33407364)
• Expanding the clinical phenotype of RASopathies in 38 Turkish patients, including the rare LZTR1, RAF1, RIT1 variants, and large deletion in NF1. (PMID:34184824)
• Pathogenic noncoding variants in the neurofibromatosis and schwannomatosis predisposition genes. (PMID:34273915)
• The GSK3 kinase and LZTR1 protein regulate the stability of Ras family proteins and the proliferation of pancreatic cancer cells. (PMID:35114566)
• LZTR1 molecular genetic overlap with clinical implications for Noonan syndrome and schwannomatosis. (PMID:35840934)
• LZTR1 Mutation Mediates Oncogenesis through Stabilization of EGFR and AXL. (PMID:36445254)
• Exome Survey and Candidate Gene Re-Sequencing Identifies Novel Exstrophy Candidate Genes and Implicates LZTR1 in Disease Formation. (PMID:37509153)
• Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk. (PMID:37592023)
• Prenatal diagnosis of autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants presented with thick nuchal translucency and cardiac abnormalities. (PMID:37936555)
• Oncogenic mutations of KRAS modulate its turnover by the CUL3/LZTR1 E3 ligase complex. (PMID:38453365)
• Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome. (PMID:39003740)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lztr1	ENSDARG00000015905
mus_musculus	Lztr1	ENSMUSG00000022761
rattus_norvegicus	Lztr1	ENSRNOG00000001870
drosophila_melanogaster	Lztr1	FBGN0040344

Paralogs (10): FBXO42 (ENSG00000037637), KLHDC4 (ENSG00000104731), HCFC2 (ENSG00000111727), KLHDC3 (ENSG00000124702), KLHDC10 (ENSG00000128607), RABEPK (ENSG00000136933), KLHDC9 (ENSG00000162755), KLHDC2 (ENSG00000165516), HCFC1 (ENSG00000172534), KLHDC1 (ENSG00000197776)

Protein

Protein identifiers

Leucine-zipper-like transcriptional regulator 1 — Q8N653 (reviewed: Q8N653)

All UniProt accessions (13): Q8N653, A0A2R8Y4K9, A0A2R8Y656, A0A2R8Y7K3, A0A2R8YCD2, A0A384NL67, A0A8V8TQF0, F8WB67, F8WCB6, F8WEQ8, H7BZQ9, H7C0X1, H7C305

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination of Ras (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS). Is a negative regulator of RAS-MAPK signaling that acts by controlling Ras levels and decreasing Ras association with membranes.

Subunit / interactions. Homodimer. Component of the BCR(LZTR1) E3 ubiquitin ligase complex, at least composed of CUL3, LZTR1 and RBX1. Interacts with Ras (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS). Interacts with RAF1. Interacts with SHOC2. Interacts with PPP1CB.

Subcellular location. Endomembrane system. Recycling endosome. Golgi apparatus.

Post-translational modifications. Phosphorylated on tyrosine upon induction of apoptosis, leading to its degradation by the proteasome.

Disease relevance. Glioma (GLM) [MIM:137800] Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. The protein represented in this entry may be involved in disease pathogenesis. Schwannomatosis 2 (SWN2) [MIM:615670] A form of schwannomatosis, a tumor predisposition syndrome characterized by the development of multiple benign nerve sheath tumors called schwannomas on cranial, spinal, and peripheral nerves, without involvement of the vestibular nerve. SWN2 affected individuals have multiple schwannomas in various areas of the body. SWN2 transmission pattern is consistent with autosomal dominant inheritance and incomplete penetrance. Disease susceptibility is associated with variants affecting the gene represented in this entry. Noonan syndrome 10 (NS10) [MIM:616564] A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. NS10 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Noonan syndrome 2 (NS2) [MIM:605275] A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. NS2 inheritance is autosomal recessive. The disease may be caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the LZTR1 family.

RefSeq proteins (1): NP_006758* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR006652	Kelch_1	Repeat
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR051568	LZTR1/Attractin	Family

Pfam: PF00651, PF01344, PF24681

UniProt features (72 total): sequence variant 57, repeat 6, mutagenesis site 3, domain 2, initiator methionine 1, chain 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9MEZ	X-RAY DIFFRACTION	2.8
9MEY	X-RAY DIFFRACTION	2.95
9MF0	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N653-F1	80.95	0.49

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 (1): 2

Mutagenesis-validated functional residues (3):

Position	Phenotype
91	increased ras-mapk signaling.
193	increased ras-mapk signaling.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 474 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOMF_GTPASE_BINDING, GOBP_NEGATIVE_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, BLALOCK_ALZHEIMERS_DISEASE_UP, GROSS_HYPOXIA_VIA_HIF1A_UP, GROSS_HYPOXIA_VIA_ELK3_AND_HIF1A_DN, GOBP_RAS_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, DANG_BOUND_BY_MYC, GOBP_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOCC_TRANSFERASE_COMPLEX, MODULE_192

GO Biological Process (2): protein ubiquitination (GO:0016567), negative regulation of Ras protein signal transduction (GO:0046580)

GO Molecular Function (2): small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (7): Golgi apparatus (GO:0005794), endomembrane system (GO:0012505), Cul3-RING ubiquitin ligase complex (GO:0031463), recycling endosome membrane (GO:0055038), endosome (GO:0005768), membrane (GO:0016020), recycling endosome (GO:0055037)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endomembrane system	2
cellular anatomical structure	2
protein modification by small protein conjugation	1
Ras protein signal transduction	1
regulation of Ras protein signal transduction	1
negative regulation of small GTPase mediated signal transduction	1
GTPase binding	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
vacuole	1
plasma membrane	1
cullin-RING ubiquitin ligase complex	1
endosome membrane	1
recycling endosome	1
cytoplasmic vesicle	1
endosome	1

Protein interactions and networks

STRING

1254 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LZTR1	CUL3	Q13618	953
LZTR1	SNAP29	O95721	754
LZTR1	SERPIND1	P05546	669
LZTR1	HDAC4	P56524	667
LZTR1	SHOC2	Q9UQ13	661
LZTR1	SMARCB1	Q12824	653
LZTR1	KRAS	P01116	652
LZTR1	NF2	P35240	647
LZTR1	NRAS	P01111	635
LZTR1	PI4KA	P42356	626
LZTR1	A2ML1	A8K2U0	621
LZTR1	SOS1	Q07889	612
LZTR1	SOS2	Q07890	611
LZTR1	RASA2	Q15283	607
LZTR1	THAP7	Q9BT49	583

IntAct

124 interactions, top by confidence:

A	B	Type	Score
EIF4A3	CASC3	psi-mi:“MI:0914”(association)	0.980
NCK2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.640
NUAK2	PPP1R12A	psi-mi:“MI:0914”(association)	0.640
TUBGCP4	LZTR1	psi-mi:“MI:0915”(physical association)	0.620
GABARAPL2	LZTR1	psi-mi:“MI:0915”(physical association)	0.560
KBTBD4	KPNA5	psi-mi:“MI:0914”(association)	0.530
PRPSAP2	CCNB1	psi-mi:“MI:0914”(association)	0.530
RIT1	MAD2L1BP	psi-mi:“MI:0914”(association)	0.530
CAPN2	MYO9A	psi-mi:“MI:0914”(association)	0.530
UBE2O	RPL23	psi-mi:“MI:0914”(association)	0.530
PTPN9	LZTR1	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
LZTR1	SMAD4	psi-mi:“MI:2364”(proximity)	0.470
SMAD4	LZTR1	psi-mi:“MI:2364”(proximity)	0.470
SMAD4	LZTR1	psi-mi:“MI:0915”(physical association)	0.470
RIT2	LZTR1	psi-mi:“MI:0915”(physical association)	0.400
LZTR1	MED16	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (184): LZTR1 (Two-hybrid), LZTR1 (Affinity Capture-MS), LZTR1 (Affinity Capture-MS), LZTR1 (Affinity Capture-MS), LZTR1 (Affinity Capture-MS), LZTR1 (Affinity Capture-MS), LZTR1 (Affinity Capture-MS), LZTR1 (Affinity Capture-MS), LZTR1 (Affinity Capture-MS), LZTR1 (Affinity Capture-MS), LZTR1 (Affinity Capture-MS), LZTR1 (Affinity Capture-MS), LZTR1 (Affinity Capture-MS), LZTR1 (Affinity Capture-MS), LZTR1 (Affinity Capture-MS)

ESM2 similar proteins: A4FUN7, A5D9H7, A5PKA5, A5WWB0, A6H8I0, A6NNY8, C0HB46, D0RB01, F1M625, O75317, O89050, P0C8Z3, P50876, P50904, P62068, P62069, Q09LZ8, Q3TIX9, Q3UHD6, Q52KZ6, Q53GS9, Q5DU02, Q5F415, Q5F450, Q5IFJ9, Q5IS37, Q5IS82, Q5M981, Q5R4Q7, Q5R573, Q5R761, Q5RB35, Q5RBQ4, Q5RDP3, Q5VU57, Q60969, Q6DCJ1, Q6GNI6, Q8CEG8, Q8K4V4

Diamond homologs: A0JMG1, A1YEX3, B0WWP2, B3DIV9, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, B7U179, D3Z8N4, D4A2K4, E0CZ16, E7F6F9, F1LZF0, F1MBP6, O14682, O22286, O35709, O43791, O81432, O95198, P0DMR5, P0DMR6, P24278, P28575, P34568, P58544, P58545, Q08DK3, Q08DS0, Q0D2A9, Q0IHH9, Q0VCW1, Q16RL8

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
TNF	“down-regulates quantity by destabilization”	LZTR1
LZTR1	“down-regulates activity”	KRAS	ubiquitination
LZTR1	“down-regulates quantity”	KRAS	ubiquitination
CUL3	“up-regulates activity”	LZTR1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 105 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
Downstream signal transduction	6	28.2×	4e-05
FLT3 Signaling	5	21.4×	2e-04
Signaling by FGFR2 in disease	5	16.4×	4e-04
Transcriptional regulation by RUNX2	5	15.7×	4e-04
Signaling by SCF-KIT	5	15.3×	5e-04
Mitotic G1 phase and G1/S transition	5	11.4×	1e-03
Signaling by BRAF and RAF1 fusions	5	10.5×	2e-03
Signaling by ALK fusions and activated point mutants	5	9.3×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of ubiquitin-dependent protein catabolic process	5	28.1×	3e-04
epidermal growth factor receptor signaling pathway	6	14.9×	8e-04
positive regulation of miRNA transcription	5	14.5×	4e-03
Ras protein signal transduction	6	12.3×	2e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 4 cancer types — GBM, HCC, PRAD, UCEC.

Clinical variants and AI predictions

ClinVar

4555 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	473
Likely pathogenic	187
Uncertain significance	2262
Likely benign	1117
Benign	68

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1021358	NM_006767.4(LZTR1):c.2352_2362del (p.Gln784fs)	Pathogenic
1068895	NM_006767.4(LZTR1):c.563G>A (p.Trp188Ter)	Pathogenic
1071200	NM_006767.4(LZTR1):c.180C>A (p.Cys60Ter)	Pathogenic
1071803	NM_006767.4(LZTR1):c.579T>G (p.Tyr193Ter)	Pathogenic
1072283	NM_006767.4(LZTR1):c.365C>A (p.Ser122Ter)	Pathogenic
1072827	NC_000022.10:g.(?21336661)(21351637_?)del	Pathogenic
1073027	NM_006767.4(LZTR1):c.876del (p.Phe292fs)	Pathogenic
1073051	NM_006767.4(LZTR1):c.877_889del (p.Asp293fs)	Pathogenic
1075272	NM_006767.4(LZTR1):c.1568del (p.Val523fs)	Pathogenic
1076017	NM_006767.4(LZTR1):c.138del (p.Phe48fs)	Pathogenic
1076480	NM_006767.4(LZTR1):c.2089del (p.Arg697fs)	Pathogenic
1319823	NM_006767.4(LZTR1):c.2277C>G (p.Tyr759Ter)	Pathogenic
1319831	NM_006767.4(LZTR1):c.1251dup (p.Arg418fs)	Pathogenic
1320159	NM_006767.4(LZTR1):c.2501_2502del (p.Ala834fs)	Pathogenic
1321013	NM_006767.4(LZTR1):c.485G>A (p.Trp162Ter)	Pathogenic
1324690	NM_006767.4(LZTR1):c.1258C>T (p.Gln420Ter)	Pathogenic
1343873	NM_006767.4(LZTR1):c.1974C>G (p.Tyr658Ter)	Pathogenic
1364132	NM_006767.4(LZTR1):c.382dup (p.Ser128fs)	Pathogenic
1371797	NM_006767.4(LZTR1):c.2017del (p.Asp674fs)	Pathogenic
1372950	NM_006767.4(LZTR1):c.1768C>T (p.Gln590Ter)	Pathogenic
1373015	NM_006767.4(LZTR1):c.2111_2118del (p.Gly704fs)	Pathogenic
1385438	NM_006767.4(LZTR1):c.1190C>A (p.Ser397Ter)	Pathogenic
1392630	NM_006767.4(LZTR1):c.1003del (p.Ala335fs)	Pathogenic
1412195	NM_006767.4(LZTR1):c.242_243insGGCCGGGCGCGGTGGCTCACGCCTGTCATCCCAGCACTTGGGGAGGCCGAGGCGGGCGGATCACGAGGNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAGATGCCATTTA (p.Tyr81Ter)	Pathogenic
1418152	NM_006767.4(LZTR1):c.646del (p.Glu216fs)	Pathogenic
1422315	NM_006767.4(LZTR1):c.992del (p.Glu331fs)	Pathogenic
1427658	NM_006767.4(LZTR1):c.1531del (p.Val511fs)	Pathogenic
1430266	NM_006767.4(LZTR1):c.1779_1780del (p.Gln593fs)	Pathogenic
1435846	NM_006767.4(LZTR1):c.1053del (p.Tyr352fs)	Pathogenic
1441289	NM_006767.4(LZTR1):c.644G>A (p.Trp215Ter)	Pathogenic

SpliceAI

3758 predictions. Top by Δscore:

Variant	Effect	Δscore
22:20982557:GTTC:G	donor_gain	1.0000
22:20988007:CA:C	acceptor_loss	1.0000
22:20988008:A:T	acceptor_loss	1.0000
22:20988008:AG:A	acceptor_gain	1.0000
22:20988008:AGG:A	acceptor_gain	1.0000
22:20988008:AGGG:A	acceptor_gain	1.0000
22:20988009:GG:G	acceptor_gain	1.0000
22:20988009:GGG:G	acceptor_gain	1.0000
22:20988009:GGGG:G	acceptor_gain	1.0000
22:20988114:GGACG:G	donor_gain	1.0000
22:20988115:GACGG:G	donor_gain	1.0000
22:20988869:CCAG:C	donor_loss	1.0000
22:20988870:CAGG:C	donor_loss	1.0000
22:20988871:AG:A	donor_loss	1.0000
22:20988872:GG:G	donor_loss	1.0000
22:20988873:GTG:G	donor_loss	1.0000
22:20988874:T:A	donor_loss	1.0000
22:20990380:CTGCA:C	acceptor_loss	1.0000
22:20990381:TGCA:T	acceptor_loss	1.0000
22:20990382:GCAG:G	acceptor_loss	1.0000
22:20990522:AGAC:A	donor_gain	1.0000
22:20990523:GAC:G	donor_gain	1.0000
22:20990523:GACG:G	donor_gain	1.0000
22:20990524:AC:A	donor_gain	1.0000
22:20990524:ACGT:A	donor_loss	1.0000
22:20990525:CGTG:C	donor_loss	1.0000
22:20990526:G:GG	donor_gain	1.0000
22:20990527:TGAG:T	donor_loss	1.0000
22:20990528:GAGTA:G	donor_loss	1.0000
22:20991620:A:AG	acceptor_gain	1.0000

AlphaMissense

5528 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:20982531:T:A	W54R	1.000
22:20982531:T:C	W54R	1.000
22:20982532:G:C	W54S	1.000
22:20982533:G:C	W54C	1.000
22:20982533:G:T	W54C	1.000
22:20982551:C:G	C60W	1.000
22:20982558:T:C	F63L	1.000
22:20982559:T:C	F63S	1.000
22:20982559:T:G	F63C	1.000
22:20982560:C:A	F63L	1.000
22:20982560:C:G	F63L	1.000
22:20982564:G:C	G65R	1.000
22:20983028:C:A	R68S	1.000
22:20983031:A:C	S69R	1.000
22:20983033:C:A	S69R	1.000
22:20983033:C:G	S69R	1.000
22:20983034:A:G	K70E	1.000
22:20983036:G:C	K70N	1.000
22:20983036:G:T	K70N	1.000
22:20983067:T:G	Y81D	1.000
22:20983071:T:A	V82E	1.000
22:20983073:T:C	F83L	1.000
22:20983075:T:A	F83L	1.000
22:20983075:T:G	F83L	1.000
22:20983076:G:C	G84R	1.000
22:20983077:G:A	G84D	1.000
22:20983077:G:T	G84V	1.000
22:20983079:G:A	G85R	1.000
22:20983079:G:C	G85R	1.000
22:20983080:G:A	G85E	1.000

dbSNP variants (sampled 300 via entrez): RS1000008615 (22:20981672 C>T), RS1000174684 (22:20988382 A>T), RS1000379425 (22:20997261 G>A,C), RS1000999408 (22:20992270 G>A,C), RS1001189100 (22:20997888 T>C), RS1001220331 (22:20997730 G>A,T), RS1001386557 (22:20993325 G>A), RS1001390438 (22:20980663 C>T), RS1001462523 (22:20988469 C>G), RS1001515477 (22:20991969 C>T), RS1001554388 (22:20988171 G>A), RS1001616645 (22:20991523 G>A,T), RS1001650625 (22:20996224 G>A), RS1001752520 (22:20993605 C>T), RS1001891526 (22:20989413 C>A)

Disease associations

OMIM: gene MIM:600574 | disease phenotypes: MIM:616564, MIM:605275, MIM:615670, MIM:162091, MIM:163950, MIM:192600, MIM:611867, MIM:310300, MIM:236750, MIM:142340

GenCC curated gene-disease

Disease	Classification	Inheritance
LZTR1-related schwannomatosis	Definitive	Autosomal dominant
Noonan syndrome 10	Definitive	Autosomal dominant
Noonan syndrome	Definitive	Autosomal dominant
schwannomatosis	Definitive	Autosomal dominant
Noonan syndrome 2	Strong	Autosomal recessive
breast cancer	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Noonan syndrome	Definitive	AD
Noonan syndrome	Definitive	AR

Mondo (24): Noonan syndrome 10 (MONDO:0014693), hereditary neoplastic syndrome (MONDO:0015356), Noonan syndrome 2 (MONDO:0011531), LZTR1-related schwannomatosis (MONDO:0014299), schwannomatosis (MONDO:0008075), diffuse midline glioma, H3 K27-altered (MONDO:1060171), Noonan syndrome and Noonan-related syndrome (MONDO:0020297), RASopathy (MONDO:0021060), Noonan syndrome (MONDO:0018997), cardiomyopathy (MONDO:0004994), dilated cardiomyopathy (MONDO:0005021), Noonan syndrome 1 (MONDO:0008104), hypertrophic cardiomyopathy 1 (MONDO:0008647), chromosome 22q11.2 deletion syndrome, distal (MONDO:0012740), Emery-Dreifuss muscular dystrophy (MONDO:0016830)

Orphanet (19): Inherited cancer-predisposing syndrome (Orphanet:140162), Noonan syndrome (Orphanet:648), Full schwannomatosis (Orphanet:93921), Noonan syndrome and Noonan-related syndrome (Orphanet:98733), RASopathy (Orphanet:536391), Rare cardiomyopathy (Orphanet:167848), Dilated cardiomyopathy (Orphanet:217604), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805), Cystic hygroma (Orphanet:79486), Distal 22q11.2 microdeletion syndrome (Orphanet:261330), Emery-Dreifuss muscular dystrophy (Orphanet:261), Non-immune hydrops fetalis (Orphanet:363999), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), Classic bladder exstrophy (Orphanet:93930), Congenital diaphragmatic hernia (Orphanet:2140)

HPO phenotypes

159 total (30 of 159 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000078	Abnormality of the genital system
HP:0000131	Uterine leiomyoma
HP:0000154	Wide mouth
HP:0000175	Cleft palate
HP:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000286	Epicanthus
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000360	Tinnitus
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000391	Thickened helices
HP:0000396	Overfolded helix
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000474	Thickened nuchal skin fold

GWAS associations

0 associations (top):

MeSH disease descriptors (13)

Descriptor	Name	Tree numbers
D001746	Bladder Exstrophy	C12.050.351.875.132; C12.050.351.968.829.132; C12.200.706.132; C12.200.777.829.132; C12.800.132; C12.950.829.132; C16.131.939.132
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D065630	Hernias, Diaphragmatic, Congenital	C16.131.433; C23.300.707.960.500.116
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D020389	Muscular Dystrophy, Emery-Dreifuss	C05.651.534.500.350; C10.668.491.175.500.350; C16.320.322.625; C16.320.577.350
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D009634	Noonan Syndrome	C05.660.207.690; C14.240.400.787; C14.280.400.787; C16.131.240.400.784; C16.131.621.207.690; C17.300.690
C567511	Chromosome 22q11.2 Deletion Syndrome, Distal (supp.)
C548081	Noonan Syndrome 2 (supp.)
C537846	Noonan like syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1411200130	LZTR1		0.00	0

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	2
aristolochic acid I	increases expression	1
geraniol	increases expression	1
beta-lapachone	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
CGP 52608	increases reaction, affects binding	1
ICG 001	increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	increases expression, affects cotreatment	1
Asbestos	affects expression	1
Cadmium	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Quercetin	increases expression	1
Smoke	decreases expression	1
Valproic Acid	increases methylation	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D9W5	Ubigene Hep 3B2.1-7 LZTR1 KO	Cancer cell line	Male
CVCL_E1CC	Ubigene SNU-398 LZTR1 KO	Cancer cell line	Male
CVCL_E3T7	CHZJUi001-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00014638	PHASE4	COMPLETED	Letrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
NCT00022386	PHASE4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00082277	PHASE4	COMPLETED	Anastrozole Biphosphonate Study in Postmenopausal Women With Hormone-Receptor-Positive Early Breast Cancer
NCT00087620	PHASE4	TERMINATED	A Study of Capecitabine In Combination With Docetaxel vs Capecitabine Followed by Docetaxel As First-Line Treatment For Metastatic Breast Cancer
NCT00121836	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) in Women With HER2-Negative Metastatic Breast Cancer
NCT00126360	PHASE4	UNKNOWN	STARS Breast Trial (Study of Anastrozole and Radiotherapy Sequencing Pilot)
NCT00127933	PHASE4	COMPLETED	XeNA Study - A Study of Xeloda (Capecitabine) in Patients With Invasive Breast Cancer
NCT00128297	PHASE4	COMPLETED	Pamidronate Administration in Breast Cancer Patients With Bone Metastases
NCT00129597	PHASE4	UNKNOWN	Effect of Ketalar to Prevent Postoperative Chronic Pain After Mastectomy
NCT00131170	PHASE4	COMPLETED	Paravertebral Block for Breast Surgery
NCT00156039	PHASE4	COMPLETED	Randomized Trial of Follow-up Strategies in Breast Cancer
NCT00160901	PHASE4	COMPLETED	Complementary Therapies for the Reduction of Side Effects During Chemotherapy for Breast Cancer
NCT00171847	PHASE4	TERMINATED	Study of the Efficacy and Safety of Letrozole Combined With Trastuzumab in Patients With Metastatic Breast Cancer
NCT00176046	PHASE4	COMPLETED	Mistletoe Extract in Early or Advanced Breast Cancer, A Feasibility Study
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00234195	PHASE4	COMPLETED	Wellbutrin XL, Major Depressive Disorder and Breast Cancer
NCT00237133	PHASE4	COMPLETED	Treatment of Locally Advanced Breast Cancer With Letrozole in Postmenopausal Women
NCT00237224	PHASE4	COMPLETED	Open Label Study of Postmenopausal Women With ER and /or PgR Positive Breast Cancer Treated With Letrozole
NCT00241046	PHASE4	TERMINATED	Letrozole in the Treatment of 1st and 2nd Line Hormone Receptor Positive Breast Cancer: Pre-therapeutic Risk Assessment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00323479	PHASE4	COMPLETED	Arthralgia During Anastrozole Therapy for Breast Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00356148	PHASE4	COMPLETED	The Efficacy of Prophylactic Antibiotic Administration During Breast Cancer Surgery in Overweight Patients.
NCT00372476	PHASE4	COMPLETED	Efficacy and Safety of Imatinib and Vinorelbine in Patients With Advanced Breast Cancer
NCT00413491	PHASE4	UNKNOWN	National Screening in Denmark With MR Versus Mammography and Ultrasound of Women With BRCA1 or BRCA2 Mutations
NCT00484614	PHASE4	UNKNOWN	Study the Role of Positron Emission Mammography in Pre-surgical Planning for Breast Cancer
NCT00485953	PHASE4	COMPLETED	Effect of Bisphosphonate on Bone Loss in Postmenopausal Women With Breast Cancer Initiating Aromatase Inhibitor Therapy
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00531973	PHASE4	UNKNOWN	A Study of Liposomal Doxorubicin in Women With Breast Cancer Exploiting Tissue Doppler Imaging
NCT00537771	PHASE4	COMPLETED	Liver Safety Under Upfront Arimidex vs Tamoxifen
NCT00544986	PHASE4	COMPLETED	A Prospective,Open-label Study of Anastrozole in Post-menopausal Women With Hormone Sensitive Advanced Breast Cancer
NCT00613275	PHASE4	COMPLETED	Patient Navigation in the Safety Net:CONNECTeDD
NCT00638599	PHASE4	COMPLETED	Comparison of Laryngeal Mask Airway (LMA®) and Tracheal Tube in Modified Radical Mastectomy on Breast Cancer
NCT00647075	PHASE4	UNKNOWN	Yunzhi as Dietary Supplement in Breast Cancer
NCT00688909	PHASE4	COMPLETED	Rheumatological Evaluation of Anastrozole and Letrozole as Adjuvant Treatment in Post-menopausal Women With Breast Cancer
NCT00699101	PHASE4	TERMINATED	Using the Conture® Multi-Lumen Balloon to Deliver Accelerated Partial Breast Brachytherapy
NCT00742222	PHASE4	COMPLETED	Electronic Xoft Intersociety Brachytherapy Trial: Electronic Brachytherapy (EBT) For Treatment of Early Stage Breast Cancer
NCT00754767	PHASE4	TERMINATED	L-Carnitine L-Tartrate in Preventing Peripheral Neuropathy Caused By Chemotherapy in Women With Metastatic Breast Cancer