LRRK1

Summary

LRRK1 (leucine rich repeat kinase 1, HGNC:18608) is a protein-coding gene on chromosome 15q26.3, encoding Leucine-rich repeat serine/threonine-protein kinase 1 (Q38SD2). Serine/threonine-protein kinase which phosphorylates RAB proteins involved in intracellular trafficking.

This gene encodes a multi-domain protein that is a leucine-rich repeat kinase and a GDP/GTP binding protein. The encoded protein is thought to play a role in the regulation of bone mass. Mice lacking a similar gene showed severe osteopetrosis, increased bone mineralization and decreased bone resorption.

Source: NCBI Gene 79705 — RefSeq curated summary.

At a glance

• Gene–disease (curated): osteosclerotic metaphyseal dysplasia (Strong, GenCC)
• GWAS associations: 9
• Clinical variants (ClinVar): 1,018 total — 17 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 14
• MANE Select transcript: NM_024652

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18608
Approved symbol	LRRK1
Name	leucine rich repeat kinase 1
Location	15q26.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ23119, KIAA1790, ROCO1, RIPK6
Ensembl gene	ENSG00000154237
Ensembl biotype	protein_coding
OMIM	610986
Entrez	79705

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 3 protein_coding, 3 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000388948, ENST00000525284, ENST00000525395, ENST00000525617, ENST00000526457, ENST00000527698, ENST00000531270, ENST00000532029, ENST00000532145, ENST00000534045, ENST00000538064

RefSeq mRNA: 1 — MANE Select: NM_024652 NM_024652

CCDS: CCDS42086

Canonical transcript exons

ENST00000388948 — 34 exons

Exon	Start	End
ENSE00002157472	100919357	100919451
ENSE00002163761	101068671	101078257
ENSE00002441117	101021845	101021957
ENSE00002454177	101021053	101021182
ENSE00002455776	101010674	101010837
ENSE00002468196	101010450	101010577
ENSE00002478782	100988634	100988813
ENSE00002485892	100983528	100983699
ENSE00002493535	101014316	101014428
ENSE00002506449	100989250	100989398
ENSE00002512960	101015326	101015402
ENSE00002516955	101008837	101009063
ENSE00002517530	101012008	101012145
ENSE00002536282	100973804	100973967
ENSE00003459516	101048494	101048657
ENSE00003493119	101051711	101051960
ENSE00003493351	101045981	101046152
ENSE00003495684	101065352	101066205
ENSE00003523501	101061171	101061288
ENSE00003527920	101066640	101066741
ENSE00003533026	101057990	101058141
ENSE00003542104	101024803	101024967
ENSE00003550524	101056856	101057050
ENSE00003556654	101027261	101027381
ENSE00003582832	101028956	101029232
ENSE00003595426	101052922	101053088
ENSE00003617419	101054946	101055223
ENSE00003619410	101053223	101053420
ENSE00003619853	101022383	101022597
ENSE00003621269	101027638	101027797
ENSE00003638133	101049644	101049783
ENSE00003687490	101062574	101062690
ENSE00003694723	101025965	101026137
ENSE00003794413	100924511	100924729

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 88.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.1986 / max 87.5970, expressed in 1220 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
148947	2.1167	1049
148943	0.4342	148
148948	0.3046	158
148946	0.2358	111
148944	0.0491	12
148952	0.0328	4
148945	0.0255	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lymph node	UBERON:0000029	88.49	gold quality
vermiform appendix	UBERON:0001154	85.36	gold quality
transverse colon	UBERON:0001157	85.18	gold quality
spleen	UBERON:0002106	84.64	gold quality
caecum	UBERON:0001153	83.90	gold quality
monocyte	CL:0000576	83.86	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.81	gold quality
cervix squamous epithelium	UBERON:0006922	83.75	gold quality
mononuclear cell	CL:0000842	83.55	gold quality
mucosa of transverse colon	UBERON:0004991	83.50	gold quality
leukocyte	CL:0000738	83.04	gold quality
minor salivary gland	UBERON:0001830	83.03	gold quality
skin of leg	UBERON:0001511	82.92	gold quality
stromal cell of endometrium	CL:0002255	82.79	gold quality
rectum	UBERON:0001052	82.79	gold quality
saliva-secreting gland	UBERON:0001044	82.22	gold quality
small intestine	UBERON:0002108	82.10	gold quality
sural nerve	UBERON:0015488	82.06	gold quality
ectocervix	UBERON:0012249	81.89	gold quality
tonsil	UBERON:0002372	81.68	gold quality
colon	UBERON:0001155	81.60	gold quality
body of uterus	UBERON:0009853	81.60	gold quality
vagina	UBERON:0000996	81.52	gold quality
bone marrow cell	CL:0002092	81.47	gold quality
left uterine tube	UBERON:0001303	81.35	gold quality
endocervix	UBERON:0000458	81.30	gold quality
skin of abdomen	UBERON:0001416	81.21	gold quality
mouth mucosa	UBERON:0003729	81.17	gold quality
large intestine	UBERON:0000059	81.13	gold quality
intestine	UBERON:0000160	80.99	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-111727	yes	2858.35
E-MTAB-9388	yes	415.80
E-MTAB-10018	yes	339.04
E-ANND-3	yes	14.32
E-MTAB-6386	no	547.19
E-ENAD-20	no	347.54

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

60 targeting LRRK1, 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-3163	100.00	77.23	8605
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-4524A-5P	99.57	71.73	1193
HSA-MIR-4524B-5P	99.57	71.68	1195
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-6740-3P	99.48	68.49	1392

Literature-anchored findings (GeneRIF, showing 21)

• LRRK1 binds GTP and GDP via its Roc domain and autophosphorylation activity is selectively triggered by GTP. Kinase activity was decreased following introduction of mutations homologous to those of LRRK2 that have been associated with Parkinson’s disease. (PMID:16243488)
• We report the molecular characterization of human LRRK1 and show for the first time that LRRK1 is a functional protein kinase and a GDP/GTP-binding protein. We propose a model in which LRRK1 cycles between a GTP-bound active and a GDP-bound inactive state (PMID:16243488)
• Comparison of evolutionary interspecies sequences of LRRK1 and LRRK2 suggests they diverged from a common founder gene implicated in Parkinson disease. (PMID:17225181)
• Two rare coding variants ss65713826 and ss65713830 were more frequent in patients than controls in norwegain Parkinson’s disease. (PMID:17324517)
• mutations in LRRK2 are more prone to form inclusion bodies in transfected cells and are more toxic than equivalent mutations in LRRK1 (PMID:17394548)
• LRRK1 genes encode low levels of expressed mRNA corresponding to low levels of protein during development. (PMID:18045479)
• LRRK1 are active in the adult human cortex cerebri, hippocampus and also seen in the young human thymus. (PMID:18272292)
• feedback down-regulation of LRRK1 kinase activity by EGFR plays an important role in the appropriate endosomal trafficking of EGFR (PMID:22337768)
• purified and active LRRK1 and LRRK2 can form dimers in their full-length conformation (PMID:22952686)
• The function of LRRK1 and both the physiological and the pathological roles of LRRK2 are only beginning to unfold. (PMID:22988872)
• LRRK1 mutations may have a role in Parkinson’s disease (PMID:24241507)
• LRRK1 carries out distinct functions from LRRK2 by interacting with different cellular proteins. (PMID:24947832)
• We find that LRRK1-mediated phosphorylation of CLIP-170 causes the accumulation of p150(Glued) (also known as DCTN1) a subunit of dynactin, at microtubule plus ends, thereby facilitating the migration of EGFR-containing endosomes. (PMID:25413345)
• LRRK1 regulates mitotic spindle orientation downstream of PLK1 through CDK5RAP2-dependent centrosome maturation. (PMID:26192437)
• LRRK1 plays a critical role in the regulation of bone mass in humans. (PMID:27055475)
• A novel LRRK1 mutation has been identified in two siblings in an Indian family with osteosclerotic metaphyseal dysplasia. (PMID:27829680)
• data suggest that LRRK1 variant (rs2924835) and LRRK2 variants (rs34594498, rs34410987, and rs33949390) are not associated with essential tremor in this Han Chinese population (PMID:29812962)
• Deciphering the LRRK code: LRRK1 and LRRK2 phosphorylate distinct Rab proteins and are regulated by diverse mechanisms. (PMID:33459343)
• Broadening the phenotype of LRRK1 mutations - Features of malignant osteopetrosis and optic nerve atrophy with intrafamilial variable expressivity. (PMID:34798323)
• PKC isoforms activate LRRK1 kinase by phosphorylating conserved residues (Ser1064, Ser1074 and Thr1075) within the CORB GTPase domain. (PMID:36040231)
• Structure and regulation of full-length human leucine-rich repeat kinase 1. (PMID:37558661)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrrk1	ENSDARG00000007398
mus_musculus	Lrrk1	ENSMUSG00000015133
rattus_norvegicus	Lrrk1	ENSRNOG00000012730

Paralogs (31): LRRC7 (ENSG00000033122), PHLPP2 (ENSG00000040199), LRRC40 (ENSG00000066557), LRCH4 (ENSG00000077454), PHLPP1 (ENSG00000081913), SHOC2 (ENSG00000108061), ERBIN (ENSG00000112851), LRRC39 (ENSG00000122477), LRCH2 (ENSG00000130224), LRCH1 (ENSG00000136141), LRRC8A (ENSG00000136802), LRRC1 (ENSG00000137269), MFHAS1 (ENSG00000147324), LRRC27 (ENSG00000148814), LRRC58 (ENSG00000163428), LRRC2 (ENSG00000163827), LRRC18 (ENSG00000165383), LRRC28 (ENSG00000168904), LRRC8E (ENSG00000171017), LRRC8C (ENSG00000171488), LRRC8D (ENSG00000171492), PIDD1 (ENSG00000177595), SCRIB (ENSG00000180900), LRCH3 (ENSG00000186001), LRRIQ4 (ENSG00000188306), LRRC8B (ENSG00000197147), LRRC10 (ENSG00000198812), LRRC10B (ENSG00000204950), LRRC30 (ENSG00000206422), LRRC69 (ENSG00000214954), LRRD1 (ENSG00000240720)

Protein

Protein identifiers

Leucine-rich repeat serine/threonine-protein kinase 1 — Q38SD2 (reviewed: Q38SD2)

All UniProt accessions (5): Q38SD2, E9PK39, E9PLF8, E9PMK9, H0YEW1

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase which phosphorylates RAB proteins involved in intracellular trafficking. Phosphorylates RAB7A; this activity is dependent on protein kinase C (PKC) activation. Plays a role in the negative regulation of bone mass, acting through the maturation of osteoclasts.

Subunit / interactions. Homodimer. The homodimer is autoinhibited and stabilized by its N-terminal residues and ANK repeats. Interacts with CSK.

Subcellular location. Cytoplasm. Cell membrane.

Post-translational modifications. Autophosphorylated. Autophosphorylation is inhibited in its dimeric state. Phosphorylated by protein kinase C isozymes PRKCA, PRKCB, PRKCG, PRKCE, PRKCZ and PRKCT at Thr-1061, Ser-1064, Ser-1074 and Thr-1075. Phosphorylation at these Ser-1064, Ser-1074 and Thr-1075 activates the kinase activity of LRRK1 to phosphorylate RAB7A.

Disease relevance. Osteosclerotic metaphyseal dysplasia (OSMD) [MIM:615198] An autosomal recessive skeletal dysplasia characterized by osteosclerosis at multiple skeletal sites, predominantly at the metaphyses of the long bones and vertebral bodies. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by phosphorylation by PKC. Binds both GTP and GDP; binding of GTP stimulates kinase activity. Sterically autoinhibited in its dimeric state.

Similarity. Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. ROCO subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q38SD2-1	1	yes
Q38SD2-2	2

RefSeq proteins (1): NP_078928* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR002110	Ankyrin_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR020859	ROC	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR032171	COR-A	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR050647	Plant_LRR-RLKs	Family
IPR057263	COR-B	Domain

Pfam: PF00069, PF00560, PF08477, PF16095, PF25497

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (84 total): repeat 25, mutagenesis site 22, binding site 14, sequence variant 5, region of interest 4, modified residue 4, domain 3, splice variant 2, sequence conflict 2, chain 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8E04	ELECTRON MICROSCOPY	3.8
8FAC	ELECTRON MICROSCOPY	3.92
8E06	ELECTRON MICROSCOPY	4.3
8E05	ELECTRON MICROSCOPY	4.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q38SD2-F1	78.14	0.30

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 (1): 1386 (proton acceptor)

Ligand- & substrate-binding residues (14): 647; 648; 650; 651; 652; 653; 669; 670; 758; 760; 806; 807 …

Post-translational modifications (4): 1061, 1064, 1074, 1075

Mutagenesis-validated functional residues (22):

Position	Phenotype
1–48	enhances phosphorylation of rab7a, likely by destabilizing the dimer.
1–25	enhances phosphorylation of rab7a, likely by destabilizing the dimer.
651	loss of gtp/gdp-binding.
746	no effect on gtp-binding. increases phosphorylation of rab7a.
971	increases rab7a phosphorylation, likely by blocking egf-mediated inactivation.
1022	no effect on gtp-binding but loss of subsequent stimulation of kinase activity.
1034	abolishes phosphorylation of rab7a.
1061	slightly increases phosphorylation of rab7a.
1064	inhibits phosphorylation activity and blocks activation by phorbol ester; when associated with a-1074 and a-1075.
1064	phosphomimetic mutant which increases phosphorylation of rab7a by 2-6 fold; when associated with e-1074 and e-1075.
1074	inhibits phosphorylation activity and blocks activation by phorbol ester; when associated with a-1064 and a-1075.
1074	phosphomimetic mutant which increases phosphorylation of rab7a by 2 fold when activated by phorbol ester. phosphomimetic
1075	inhibits phosphorylation activity and blocks activation by phorbol ester. inhibits phosphorylation activity and blocks a
1075	phosphomimetic mutant which abolishes phosphorylation of rab7a and blocks activation by phorbol ester. increases phospho
1144	abolishes phosphorylation of rab7a.
1270	abolishes phosphorylation of rab7a.
1270	loss of autophosphorylation.
1298	enhances phosphorylation of rab7a.
1305	abolishes phosphorylation of rab7a.
1409	abolishes phosphorylation of rab7a.
1412	no effect on gtp-binding but reduction in subsequent stimulation of kinase activity.
1798–1885	increases phosphorylation of rab7a; the truncated wd40 loop likely destabilizes the dimer.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 207 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_BONE_CELL_DEVELOPMENT, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, CAGCTG_AP4_Q5, GOBP_BONE_DEVELOPMENT, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, TGCTGAY_UNKNOWN, MCBRYAN_PUBERTAL_BREAST_3_4WK_UP, RUTELLA_RESPONSE_TO_HGF_VS_CSF2RB_AND_IL4_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_12HR_UP, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP

GO Biological Process (7): intracellular signal transduction (GO:0035556), osteoclast development (GO:0036035), bone resorption (GO:0045453), positive regulation of canonical Wnt signaling pathway (GO:0090263), positive regulation of intracellular signal transduction (GO:1902533), protein phosphorylation (GO:0006468), positive regulation of signal transduction (GO:0009967)

GO Molecular Function (11): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), GTP binding (GO:0005525), identical protein binding (GO:0042802), metal ion binding (GO:0046872), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (5): mitochondrion (GO:0005739), cytosol (GO:0005829), plasma membrane (GO:0005886), cytoplasm (GO:0005737), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular anatomical structure	2
signal transduction	2
protein kinase activity	2
purine ribonucleoside triphosphate binding	2
cytoplasm	2
osteoclast differentiation	1
myeloid cell development	1
bone cell development	1
tissue homeostasis	1
bone remodeling	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
positive regulation of signal transduction	1
intracellular signal transduction	1
regulation of intracellular signal transduction	1
phosphorylation	1
protein modification process	1
regulation of signal transduction	1
positive regulation of cell communication	1
positive regulation of signaling	1
positive regulation of response to stimulus	1
adenyl ribonucleotide binding	1
guanyl ribonucleotide binding	1
protein binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1162 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRRK1	GTPBP4	Q9BZE4	689
LRRK1	ANK1	P16157	667
LRRK1	ANK2	Q01484	651
LRRK1	ANK3	Q12955	650
LRRK1	GRB2	P29354	589
LRRK1	LHFPL1	Q86WI0	516
LRRK1	TBC1D2	Q9BYX2	508
LRRK1	HIF1AN	Q9NWT6	484
LRRK1	GAREM1	Q9H706	476
LRRK1	RAB29	O14966	471
LRRK1	BAG5	Q9UL15	462
LRRK1	ARHGEF5	Q12774	448
LRRK1	UBE4B	O95155	448
LRRK1	IBTK	Q9P2D0	447
LRRK1	RBP7	Q96R05	434

IntAct

78 interactions, top by confidence:

A	B	Type	Score
LRRK1	LRRK1	psi-mi:“MI:0915”(physical association)	0.640
BAG5	LRRK1	psi-mi:“MI:0407”(direct interaction)	0.640
LRRK1	ABL1	psi-mi:“MI:0914”(association)	0.590
LRRK1	LRRK2	psi-mi:“MI:0915”(physical association)	0.590
LRRK2	LRRK1	psi-mi:“MI:0915”(physical association)	0.590
LRRK1	ABL1	psi-mi:“MI:0407”(direct interaction)	0.590
EGFR	LRRK1	psi-mi:“MI:0915”(physical association)	0.540
LRRK1	EGFR	psi-mi:“MI:0407”(direct interaction)	0.540
GRB2	ARHGEF35	psi-mi:“MI:0914”(association)	0.530
LRRK1	HSPA8	psi-mi:“MI:0914”(association)	0.530
LRRK1	CCL21	psi-mi:“MI:0407”(direct interaction)	0.440
GAK	LRRK1	psi-mi:“MI:0407”(direct interaction)	0.440
LRRK1	CIMIP4	psi-mi:“MI:0407”(direct interaction)	0.440
SCEL	LRRK1	psi-mi:“MI:0407”(direct interaction)	0.440
CD2BP2	LRRK1	psi-mi:“MI:0407”(direct interaction)	0.440
BAG2	LRRK1	psi-mi:“MI:0407”(direct interaction)	0.440
BAG3	LRRK1	psi-mi:“MI:0407”(direct interaction)	0.440
CHGB	LRRK1	psi-mi:“MI:0407”(direct interaction)	0.440
RET	LRRK1	psi-mi:“MI:0407”(direct interaction)	0.440
POLR2M	LRRK1	psi-mi:“MI:0407”(direct interaction)	0.440
LRRK1	GNAZ	psi-mi:“MI:0407”(direct interaction)	0.440
LRRK1	FGFR2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA8	LRRK1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (126): LRRK1 (Affinity Capture-Western), LRRK2 (Affinity Capture-Western), LRRK1 (Co-fractionation), LRRK1 (Affinity Capture-MS), LRRK1 (Affinity Capture-MS), PAK4 (Affinity Capture-MS), S100A8 (Affinity Capture-MS), RIMS1 (Affinity Capture-MS), C9orf163 (Affinity Capture-MS), LYZ (Affinity Capture-MS), HSPA8 (Affinity Capture-Western), BAG5 (Affinity Capture-Western), ECHS1 (Reconstituted Complex), C11orf52 (Reconstituted Complex), BAG3 (Reconstituted Complex)

ESM2 similar proteins: A0A1I1P2K9, A8D888, A8DYH2, A8Q8M5, A8XEZ1, B0WK43, B3DL37, B4GBR1, B4JVK9, B4KSR4, B4LP65, B5E0K3, B5LVL2, C1BJ98, P34661, P61960, P61961, P84193, Q00457, Q05921, Q09219, Q09JK2, Q176V0, Q2KJG2, Q2M3Z7, Q2M3Z8, Q38SD2, Q4N927, Q4PMC9, Q4R4I2, Q580P9, Q5BJP3, Q5PU89, Q5R4N5, Q5RJW4, Q5ZMK7, Q61E22, Q6DDB9, Q6VBQ6, Q6VEU3

Diamond homologs: A3LUB9, B0XPE4, C0LGF4, C0LGL9, D2HHP1, G0RBE3, O64784, O65530, O94537, P32361, P39073, P45983, P45984, P49185, P49186, P49187, P49336, P53779, P79996, P92208, Q09499, Q17IE8, Q1EBK0, Q1XHL7, Q336M2, Q38SD2, Q3UHC2, Q4P9T2, Q4WJJ0, Q4WKP8, Q54IE8, Q557G1, Q559A2, Q55DJ8, Q55GJ2, Q61831, Q66KH9, Q6CCB0, Q6P3N6, Q751F5

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
PLK1	“up-regulates activity”	LRRK1	phosphorylation
LRRK1	“up-regulates activity”	CDK5RAP2	phosphorylation
LRRK1	“up-regulates activity”	RAB7A	phosphorylation
LRRK1	“up-regulates activity”	RAC1	phosphorylation
EGFR	“down-regulates activity”	LRRK1	phosphorylation
LRRK1	“up-regulates activity”	CLIP1	phosphorylation
PRKCA	“up-regulates activity”	LRRK1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 64 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
Regulation of HSF1-mediated heat shock response	5	13.9×	1e-03
Clathrin-mediated endocytosis	5	8.5×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein folding	7	12.7×	5e-04
positive regulation of MAPK cascade	7	9.9×	1e-03
protein stabilization	8	9.4×	5e-04
positive regulation of ERK1 and ERK2 cascade	6	9.0×	5e-03
intracellular signal transduction	8	5.3×	7e-03
negative regulation of apoptotic process	8	4.9×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1018 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	6
Uncertain significance	421
Likely benign	447
Benign	60

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1327992	NM_024652.6(LRRK1):c.5971dup (p.Ala1991fs)	Pathogenic
1327994	NM_024652.6(LRRK1):c.261G>A (p.Lys87=)	Pathogenic
1436817	NM_024652.6(LRRK1):c.1150G>T (p.Glu384Ter)	Pathogenic
1455841	NM_024652.6(LRRK1):c.3618_3631dup (p.Leu1211fs)	Pathogenic
1679875	NM_024652.6(LRRK1):c.4480C>T (p.Arg1494Ter)	Pathogenic
2028154	NM_024652.6(LRRK1):c.3515G>A (p.Trp1172Ter)	Pathogenic
2031900	NM_024652.6(LRRK1):c.73G>T (p.Glu25Ter)	Pathogenic
254688	NM_024652.6(LRRK1):c.5939_5945del (p.Glu1980fs)	Pathogenic
2698171	NM_024652.6(LRRK1):c.4290C>A (p.Tyr1430Ter)	Pathogenic
2698615	NM_024652.6(LRRK1):c.3178dup (p.Val1060fs)	Pathogenic
2727686	NM_024652.6(LRRK1):c.4962_4963del (p.Phe1655fs)	Pathogenic
2759016	NM_024652.6(LRRK1):c.801G>A (p.Trp267Ter)	Pathogenic
2807781	NM_024652.6(LRRK1):c.3435del (p.Ala1147fs)	Pathogenic
2855621	NM_024652.6(LRRK1):c.2371del (p.Thr791fs)	Pathogenic
3727699	NM_024652.6(LRRK1):c.4365C>A (p.Tyr1455Ter)	Pathogenic
4721387	NM_024652.6(LRRK1):c.5870+1G>A	Pathogenic
522616	NM_024652.6(LRRK1):c.2785G>T (p.Glu929Ter)	Pathogenic
1523081	NM_024652.6(LRRK1):c.2233-1G>A	Likely pathogenic
2118954	NM_024652.6(LRRK1):c.3439+1G>C	Likely pathogenic
3383996	NM_024652.6(LRRK1):c.2404_2405+1del	Likely pathogenic
3726651	NM_024652.6(LRRK1):c.261+2T>G	Likely pathogenic
4400815	NM_024652.6(LRRK1):c.1532+1G>A	Likely pathogenic
4723729	NM_024652.6(LRRK1):c.98-1G>A	Likely pathogenic

SpliceAI

5542 predictions. Top by Δscore:

Variant	Effect	Δscore
15:100983678:G:GT	donor_gain	1.0000
15:100988758:G:GT	donor_gain	1.0000
15:100988809:GTCAG:G	donor_gain	1.0000
15:100988811:CAG:C	donor_loss	1.0000
15:100988813:GG:G	donor_loss	1.0000
15:100988814:G:GA	donor_loss	1.0000
15:100989248:A:AG	acceptor_gain	1.0000
15:100989248:AG:A	acceptor_gain	1.0000
15:100989249:G:GG	acceptor_gain	1.0000
15:100989249:GG:G	acceptor_gain	1.0000
15:100989395:AACA:A	donor_gain	1.0000
15:100989399:G:GG	donor_gain	1.0000
15:101008989:G:GT	donor_gain	1.0000
15:101010419:T:TA	acceptor_gain	1.0000
15:101010443:A:AG	acceptor_gain	1.0000
15:101010446:GCAGG:G	acceptor_loss	1.0000
15:101010447:CAGGC:C	acceptor_loss	1.0000
15:101010448:A:AC	acceptor_loss	1.0000
15:101010448:A:AG	acceptor_gain	1.0000
15:101010448:AG:A	acceptor_gain	1.0000
15:101010449:G:GT	acceptor_gain	1.0000
15:101010449:GG:G	acceptor_gain	1.0000
15:101010449:GGC:G	acceptor_gain	1.0000
15:101010449:GGCT:G	acceptor_gain	1.0000
15:101010449:GGCTA:G	acceptor_gain	1.0000
15:101010672:A:AG	acceptor_gain	1.0000
15:101010673:G:GA	acceptor_gain	1.0000
15:101010673:GCC:G	acceptor_gain	1.0000
15:101011994:C:CA	acceptor_gain	1.0000
15:101011998:A:AG	acceptor_gain	1.0000

AlphaMissense

13206 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:101055048:A:T	D1386V	1.000
15:101055117:A:T	D1409V	1.000
15:101014376:T:A	W494R	0.999
15:101014376:T:C	W494R	0.999
15:101024905:T:A	W724R	0.999
15:101024905:T:C	W724R	0.999
15:101045986:T:C	L990P	0.999
15:101055048:A:C	D1386A	0.999
15:101055048:A:G	D1386G	0.999
15:101055049:C:A	D1386E	0.999
15:101055049:C:G	D1386E	0.999
15:101055055:G:C	K1388N	0.999
15:101055055:G:T	K1388N	0.999
15:101055116:G:C	D1409H	0.999
15:101055117:A:C	D1409A	0.999
15:101055117:A:G	D1409G	0.999
15:101055118:C:A	D1409E	0.999
15:101055118:C:G	D1409E	0.999
15:101055167:G:C	G1426R	0.999
15:101056865:T:C	F1448L	0.999
15:101056867:C:A	F1448L	0.999
15:101056867:C:G	F1448L	0.999
15:101008852:T:A	W260R	0.998
15:101008852:T:C	W260R	0.998
15:101008969:T:A	W299R	0.998
15:101008969:T:C	W299R	0.998
15:101021101:T:C	L553P	0.998
15:101021170:T:C	L576P	0.998
15:101022463:G:C	G645R	0.998
15:101025998:G:T	G756W	0.998

dbSNP variants (sampled 300 via entrez): RS1000014572 (15:100945870 G>A,C,T), RS1000056483 (15:100995322 C>A,T), RS1000063091 (15:100954414 A>T), RS1000073821 (15:100994299 A>T), RS1000082001 (15:101069613 T>C), RS1000094949 (15:100921811 C>G), RS1000097370 (15:101062647 C>T), RS1000098710 (15:100950186 G>A), RS1000100648 (15:101036051 T>C), RS1000140964 (15:101050753 C>G,T), RS1000145836 (15:100961132 G>A), RS1000218584 (15:101014768 C>T), RS1000233189 (15:101000978 C>T), RS1000243471 (15:101064885 G>C), RS1000291681 (15:100944314 T>G)

Disease associations

OMIM: gene MIM:610986 | disease phenotypes: MIM:615198

GenCC curated gene-disease

Disease	Classification	Inheritance
osteosclerotic metaphyseal dysplasia	Strong	Autosomal recessive

Mondo (1): osteosclerotic metaphyseal dysplasia (MONDO:0014080)

Orphanet (1): Osteosclerotic metaphyseal dysplasia (Orphanet:500548)

HPO phenotypes

14 total (14 of 14 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001508	Failure to thrive
HP:0003155	Elevated circulating alkaline phosphatase concentration
HP:0003593	Infantile onset
HP:0004576	Sclerotic vertebral endplates
HP:0011001	Increased bone mineral density
HP:0100255	Metaphyseal dysplasia
HP:0100923	Clavicular sclerosis
HP:0100959	Dense metaphyseal bands

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001806_23	Corneal structure	6.000000e-19
GCST003856_6	Central corneal thickness	4.000000e-07
GCST005667_15	Central corneal thickness	2.000000e-23
GCST006366_9	Central corneal thickness	4.000000e-06
GCST008163_405	Height	2.000000e-06
GCST009414_18	Central corneal thickness	1.000000e-13
GCST009414_20	Central corneal thickness	2.000000e-17
GCST011956_147	Systemic lupus erythematosus	2.000000e-08
GCST90000654_63	Central corneal thickness	4.000000e-34

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004345	corneal topography
EFO:0005213	central corneal thickness

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Leucine-rich repeat kinase (LRRK) family

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
entinostat	increases expression, affects cotreatment	2
Arsenic Trioxide	affects binding, decreases reaction, increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation, affects methylation	2
Tretinoin	decreases expression	2
bisphenol A	affects cotreatment, increases methylation	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
nickel sulfate	increases expression	1
4-aminophenylarsenoxide	decreases reaction, affects binding	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases methylation	1
(+)-JQ1 compound	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	affects methylation	1
Calcitriol	increases expression, affects cotreatment	1
Formaldehyde	decreases expression	1
Methapyrilene	decreases methylation	1
Smoke	decreases expression	1
Testosterone	increases expression, affects cotreatment	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1W6	Abcam HeLa LRRK1 KO	Cancer cell line	Female
CVCL_SW00	HAP1 LRRK1 (-) 1	Cancer cell line	Male
CVCL_SW01	HAP1 LRRK1 (-) 2	Cancer cell line	Male
CVCL_SW02	HAP1 LRRK1 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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