LMX1A

Summary

LMX1A (LIM homeobox transcription factor 1 alpha, HGNC:6653) is a protein-coding gene on chromosome 1q23.3, encoding LIM homeobox transcription factor 1-alpha (Q8TE12). Acts as a transcriptional activator by binding to an A/T-rich sequence, the FLAT element, in the insulin gene promoter.

This gene encodes a homeodomain and LIM-domain containing protein. The encoded protein is a transcription factor that acts as a positive regulator of insulin gene transcription. This gene also plays a role in the development of dopamine producing neurons during embryogenesis. Mutations in this gene are associated with an increased risk of developing Parkinson’s disease. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 4009 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant nonsyndromic hearing loss (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 102 total — 4 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 2
• Transcription factor: yes — 12 downstream targets (CollecTRI)
• MANE Select transcript: NM_177398

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6653
Approved symbol	LMX1A
Name	LIM homeobox transcription factor 1 alpha
Location	1q23.3
Locus type	gene with protein product
Status	Approved
Aliases	LMX1.1
Ensembl gene	ENSG00000162761
Ensembl biotype	protein_coding
OMIM	600298
Entrez	4009

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000294816, ENST00000342310, ENST00000367893, ENST00000489443

RefSeq mRNA: 2 — MANE Select: NM_177398 NM_001174069, NM_177398

CCDS: CCDS1247

Canonical transcript exons

ENST00000342310 — 9 exons

Exon	Start	End
ENSE00001068374	165213641	165213813
ENSE00001158602	165249408	165249640
ENSE00001158610	165353076	165353262
ENSE00001291550	165355484	165355581
ENSE00001407570	165356355	165356715
ENSE00002074628	165201867	165204040
ENSE00003507619	165210699	165210776
ENSE00003538391	165208063	165208132
ENSE00003628521	165205864	165206034

Expression profiles

Bgee: expression breadth broad, 92 present calls, max score 78.93.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.0534 / max 86.4825, expressed in 128 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15715	0.5455	102
15713	0.1843	61
15717	0.1638	63
15716	0.1192	48
15714	0.0407	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.93	gold quality
sperm	CL:0000019	63.30	silver quality
apex of heart	UBERON:0002098	59.78	gold quality
hindlimb stylopod muscle	UBERON:0004252	57.58	gold quality
pituitary gland	UBERON:0000007	57.46	gold quality
adenohypophysis	UBERON:0002196	56.17	gold quality
mucosa of stomach	UBERON:0001199	55.78	gold quality
left testis	UBERON:0004533	54.25	gold quality
rectum	UBERON:0001052	53.86	gold quality
right testis	UBERON:0004534	53.73	gold quality
testis	UBERON:0000473	53.31	gold quality
subcutaneous adipose tissue	UBERON:0002190	51.48	gold quality
calcaneal tendon	UBERON:0003701	50.70	gold quality
duodenum	UBERON:0002114	50.32	gold quality
colonic epithelium	UBERON:0000397	49.71	gold quality
lower esophagus muscularis layer	UBERON:0035833	48.00	gold quality
lower esophagus	UBERON:0013473	47.82	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	47.75	gold quality
skeletal muscle tissue	UBERON:0001134	46.81	gold quality
muscle of leg	UBERON:0001383	46.69	gold quality
tendon	UBERON:0000043	46.65	silver quality
muscle tissue	UBERON:0002385	46.45	gold quality
adipose tissue	UBERON:0001013	45.46	gold quality
ventricular zone	UBERON:0003053	45.39	gold quality
substantia nigra	UBERON:0002038	45.06	gold quality
gastrocnemius	UBERON:0001388	44.89	gold quality
cortical plate	UBERON:0005343	44.75	gold quality
midbrain	UBERON:0001891	44.40	gold quality
ectocervix	UBERON:0012249	44.23	gold quality
small intestine	UBERON:0002108	43.47	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.39

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

12 targets.

Target	Regulation
CDKN1B
CUX2	Activation
HES1
IAPP
LMX1A	Activation
LMX1B	Activation
MSX1	Activation
NEUROG2	Activation
NR4A2	Activation
PITX3	Activation
SLC6A3
WNT1	Activation

JASPAR motifs

Motif	Name	Family
MA0702.1	LMX1A	HD-LIM
MA0702.2	LMX1A	HD-LIM
MA0702.3	LMX1A	HD-LIM

JASPAR matrix evidence (PMIDs): PMID:18585360, PMID:18585359

Upstream regulators (CollecTRI, top): EZH2, FOXA1, FOXA2, LMX1A, LMX1B, NKX2-2, SP1, WNT1, WNT3

miRNA regulators (miRDB)

135 targeting LMX1A, 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-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548N	99.98	71.94	4170
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-570-3P	99.96	72.41	4910
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-548AB	99.95	71.31	3488

Literature-anchored findings (GeneRIF, showing 31)

• Did not find evidence for association of any LMX1A SNPs with type 2 diabetes mellitus (T2DM) and conclude that LMX1A does not contribute significantly to T2DM etiology in Pima Indians. (PMID:12062816)
• Lmx1a expression is necessary for the expression of bone morphogenetic protein (BMP), and for the normal generation and differentiation of the dorsal-most spinal cord neurons, the dl1 interneurons. (PMID:15183721)
• Lmx1a may be critical to the development of midbrain dopamine neurons from human embryonic stem cells. (PMID:18832589)
• Data show that three single nucleotide polymor in LMX1A and one in LMX1B are associated with Parkinson’s disease. (PMID:19189040)
• Genetic variation in LMX1A may increase the risk of developing schizophrenia. (PMID:20570600)
• LMX1A may be a potential biomarker for gastric cancer. (PMID:21159062)
• One single nucleotide polymorphisms of lmx1a was strongly associated with the magnitude of training-related gains in verbal working memory (PMID:21435346)
• The Lmx1a can induce desired neuronal lineages from most expressing neural progenitor cells by a mechanism resembling developmental binary cell-fate switching. (PMID:21624811)
• Higher immunostaining intensity for OPN and LMX1A correlated with WHO grades for meningiomas and some gliomas. Contrary to our expectations, LMX1A staining in WHO grade IV gliomas was shown to be weaker than in WHO grade III tumours. (PMID:22882568)
• higher expression is associated with more advanced neoplasm staging in Chinese patients with pancreatic ductal adenocarcinomas (PMID:23165334)
• these data imply that Sp1 and EZH2 may activate LMX1A expression upon oncogenic stress during cervical cancer development. (PMID:24018208)
• LMX1A is weakly methylated in cervical adenocarcinomas compared with controls, in a metastatic stage of cervical cancer. (PMID:24407576)
• SNPs of the LMX1A gene might be associated with the susceptibility to congenital scoliosis and different clinical phenotypes in the Chinese Han population. (PMID:25099324)
• To our best knowledge, this is the first report demonstrating the application of TAT-LMX1A recombinant protein to enhance hESC differentiation to DA as shown by the expression of DA specific makers. (PMID:25380985)
• Lmx1a and Lmx1b expression persists in mature dopaminergic neurons of the substantia nigra pars compacta and the ventral tegmental area. [Review] (PMID:26526610)
• Polymorphisms of dopamine pathway gene aLMX1A is associated with cognitive performance in Bipolar disorder. (PMID:26534905)
• Study revealed an anti-metastatic role of LMX1A in gastric cancer which is mediated by the negative regulation of beta-catenin signaling target genes. (PMID:27061089)
• The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. (PMID:29754270)
• Our results suggest that LMX1A is involved in both human autosomal recessive and dominant sensorineural hearing impairmen (PMID:29971487)
• miR-9 selectively targets LMX1A to promote gastric cancer cell progression. (PMID:30262143)
• Our results indicate an important influence of the neurodevelopment genes, PBX1, LMX1A, and SLITRK1 in obsessive-compulsive disorder susceptibility (PMID:30377043)
• Knockdown of LncRNA SCAMP1 suppressed malignant biological behaviours of glioma cells via modulating miR-499a-5p/LMX1A/NLRC5 pathway. (PMID:31207033)
• Knockdown of ANGPTL4 rescued the tumor suppressive phenotype of LMX1A overexpression, which indicated that LMX1A upregulates ANGPTL4 to exert its role. Mechanistically, we found that LMX1A inhibited the expression of the oncogene C-Myc, which is alleviated by ANGPTL4 knockdown. (PMID:31557193)
• LINC00682 inhibits gastric cancer cell progression via targeting microRNA-9-LMX1A signaling axis. (PMID:31822638)
• Circular RNA circMTO1 Suppresses RCC Cancer Cell Progression via miR9/LMX1A Axis. (PMID:32207384)
• Epigenetic Silencing of LMX1A Contributes to Cancer Progression in Lung Cancer Cells. (PMID:32751497)
• Novel genotype-phenotype correlation of functionally characterized LMX1A variants linked to sensorineural hearing loss. (PMID:32840933)
• Update on CD164 and LMX1A genes to strengthen their causative role in autosomal dominant hearing loss. (PMID:35254497)
• Novel Molecular Genetic Etiology of Asymmetric Hearing Loss: Autosomal-Dominant LMX1A Variants. (PMID:35711095)
• ceRNA network of lncRNA MIR210HG/miR-377-3p/LMX1A in malignant proliferation of glioma cells. (PMID:36197580)
• Forced LMX1A expression induces dorsal neural fates and disrupts patterning of human embryonic stem cells into ventral midbrain dopaminergic neurons. (PMID:38759646)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	lmx1al	ENSDARG00000077915
mus_musculus	Lmx1a	ENSMUSG00000026686
rattus_norvegicus	Lmx1a	ENSRNOG00000004642

Paralogs (20): FHL1 (ENSG00000022267), LMO3 (ENSG00000048540), LHX5 (ENSG00000089116), ZFHX4 (ENSG00000091656), LHX2 (ENSG00000106689), LHX6 (ENSG00000106852), LHX3 (ENSG00000107187), LHX4 (ENSG00000121454), LMO2 (ENSG00000135363), ZFHX2 (ENSG00000136367), LMX1B (ENSG00000136944), ZFHX3 (ENSG00000140836), LMO4 (ENSG00000143013), LHX9 (ENSG00000143355), CRIP3 (ENSG00000146215), LHX8 (ENSG00000162624), LMO1 (ENSG00000166407), CRIP2 (ENSG00000182809), CRIP1 (ENSG00000213145), LHX1 (ENSG00000273706)

Protein

Protein identifiers

LIM homeobox transcription factor 1-alpha — Q8TE12 (reviewed: Q8TE12)

Alternative names: LIM/homeobox protein 1.1, LIM/homeobox protein LMX1A

All UniProt accessions (1): Q8TE12

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional activator by binding to an A/T-rich sequence, the FLAT element, in the insulin gene promoter. Required for development of the roof plate and, in turn, for specification of dorsal cell fates in the CNS and developing vertebrae.

Subcellular location. Nucleus.

Tissue specificity. Isoform 1 is expressed in many tissues. Not found in heart, liver, spleen and testis. Relatively highly expressed in fetal brain. Isoform LMX1A-4AB is expressed in testis.

Disease relevance. Deafness, autosomal dominant, 7 (DFNA7) [MIM:601412] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA7 is a progressive form with highly variable age at onset and severity, even within families. The age at onset ranges from congenital to mid-adulthood. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TE12-1	1	yes
Q8TE12-2	LMX1A-4AB

RefSeq proteins (2): NP_001167540, NP_796372* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR001781	Znf_LIM	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR042688	Lmx1a_LIM1	Domain
IPR050453	LIM_Homeobox_TF	Family

Pfam: PF00046, PF00412

UniProt features (15 total): sequence variant 4, helix 3, domain 2, region of interest 2, chain 1, DNA-binding region 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8IK5	X-RAY DIFFRACTION	1.99
8IKE	X-RAY DIFFRACTION	2.6
8ILW	X-RAY DIFFRACTION	2.71

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TE12-F1	69.93	0.39

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 168 (showing top): GOBP_MEMORY, GOBP_DENTATE_GYRUS_DEVELOPMENT, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_COGNITION, GOBP_BEHAVIOR, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_GROWTH, GOBP_NEUROGENESIS, LHX3_01, GGGTGGRR_PAX4_03, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_HIPPOCAMPUS_DEVELOPMENT

GO Biological Process (20): regulation of cell growth (GO:0001558), regulation of transcription by RNA polymerase II (GO:0006357), axon guidance (GO:0007411), memory (GO:0007613), locomotory behavior (GO:0007626), dentate gyrus development (GO:0021542), cerebellum development (GO:0021549), neuron differentiation (GO:0030182), olfactory behavior (GO:0042048), negative regulation of neuron differentiation (GO:0045665), positive regulation of transcription by RNA polymerase II (GO:0045944), synapse organization (GO:0050808), dopaminergic neuron differentiation (GO:0071542), midbrain dopaminergic neuron differentiation (GO:1904948), regulation of DNA-templated transcription (GO:0006355), central nervous system development (GO:0007417), regulation of gene expression (GO:0010468), hippocampus development (GO:0021766), central nervous system neuron differentiation (GO:0021953), midbrain development (GO:0030901)

GO Molecular Function (7): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), metal ion binding (GO:0046872), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	4
neuron differentiation	3
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
regulation of DNA-templated transcription	1
axonogenesis	1
neuron projection guidance	1
learning or memory	1
behavior	1
hippocampus development	1
metencephalon development	1
cell differentiation	1
generation of neurons	1
chemosensory behavior	1
negative regulation of cell differentiation	1
regulation of neuron differentiation	1
positive regulation of DNA-templated transcription	1
cell junction organization	1
central nervous system neuron differentiation	1
midbrain development	1
dopaminergic neuron differentiation	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
nervous system development	1
system development	1
gene expression	1
regulation of macromolecule biosynthetic process	1
pallium development	1
limbic system development	1
central nervous system development	1
brain development	1
transcription cis-regulatory region binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1

Protein interactions and networks

STRING

1186 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LMX1A	NEUROG2	Q9H2A3	871
LMX1A	NR4A2	P43354	849
LMX1A	FOXA2	Q9Y261	801
LMX1A	ASCL1	P50553	800
LMX1A	MSX1	P28360	799
LMX1A	WNT1	P04628	757
LMX1A	NKX2-2	O95096	754
LMX1A	OTX2	P32243	736
LMX1A	TH	P07101	685
LMX1A	KCNJ6	P48051	685
LMX1A	SHH	Q15465	677
LMX1A	PAX2	Q02962	677
LMX1A	ALX3	O95076	640
LMX1A	DDC	P20711	626
LMX1A	SLC6A3	Q01959	622
LMX1A	FGF8	P55075	622

IntAct

6 interactions, top by confidence:

A	B	Type	Score
LMX1A	GRB2	psi-mi:“MI:0915”(physical association)	0.570
GRB2	LMX1A	psi-mi:“MI:0915”(physical association)	0.570
rep	LMX1A	psi-mi:“MI:0915”(physical association)	0.490

BioGRID (10): LMX1A (Two-hybrid), GRB2 (Affinity Capture-Luminescence), TCF3 (Two-hybrid), LMX1A (Two-hybrid), TCF3 (Reconstituted Complex), LMX1A (Reconstituted Complex), LMX1A (Reconstituted Complex), LHX3 (Reconstituted Complex), LHX3 (Affinity Capture-Western), LMX1A (Two-hybrid)

ESM2 similar proteins: A5PMU4, O60663, O75541, O88609, O97581, P29674, P36200, P48742, P50211, P50212, P50480, P50481, P52889, P53405, P53406, P53407, P53408, P53409, P53410, P53411, P53412, P53413, P53776, P61371, P61372, P61373, P61374, P61375, P61376, P63006, P63007, P63008, Q04650, Q32KS7, Q5IS44, Q5IS89, Q60564, Q6H8Q1, Q6KC51, Q6PD05

Diamond homologs: A0A1L8F1M4, A0M8R4, A0M8S5, A0M8U6, A1Z6W3, A8WH69, O43294, O43900, P47226, Q00PK1, Q04650, Q07DW1, Q07DX3, Q07DY3, Q07DZ4, Q07E27, Q07E40, Q07E51, Q09YI0, Q09YJ2, Q09YK3, Q09YL5, Q09YN8, Q108U9, Q174I2, Q17QE2, Q28FG2, Q292U2, Q292U5, Q2IBA3, Q2IBC3, Q2IBH0, Q2LAP6, Q2QL92, Q2QLA1, Q2QLB2, Q2QLC3, Q2QLE3, Q2QLF4, Q2QLG8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
LMX1A	“form complex”	NLI/Lmx1.1/Isl1	binding
LMX1A	“up-regulates quantity by expression”	CUX2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	5
Uncertain significance	63
Likely benign	9
Benign	18

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1705342	NM_177398.4(LMX1A):c.595A>G (p.Arg199Gly)	Pathogenic
1723178	NM_177398.4(LMX1A):c.622C>T (p.Arg208Ter)	Pathogenic
812515	NM_177398.4(LMX1A):c.721G>C (p.Val241Leu)	Pathogenic
812516	NM_177398.4(LMX1A):c.290G>C (p.Cys97Ser)	Pathogenic
1687337	NM_177398.4(LMX1A):c.331del (p.Gln111fs)	Likely pathogenic
2503455	NM_177398.4(LMX1A):c.937C>T (p.Arg313Ter)	Likely pathogenic
2576012	NM_177398.4(LMX1A):c.766C>T (p.Arg256Ter)	Likely pathogenic
3601196	NM_177398.4(LMX1A):c.596G>A (p.Arg199Lys)	Likely pathogenic
4813826	NM_177398.4(LMX1A):c.390_391delinsAT (p.Lys131Ter)	Likely pathogenic

SpliceAI

2888 predictions. Top by Δscore:

Variant	Effect	Δscore
1:165205858:TCTTA:T	donor_loss	1.0000
1:165205859:CTTAC:C	donor_loss	1.0000
1:165205860:TTACC:T	donor_loss	1.0000
1:165205861:TA:T	donor_loss	1.0000
1:165205862:A:T	donor_loss	1.0000
1:165205863:C:CG	donor_loss	1.0000
1:165206030:CTGAG:C	acceptor_gain	1.0000
1:165206031:TGAG:T	acceptor_gain	1.0000
1:165206031:TGAGC:T	acceptor_loss	1.0000
1:165206032:GAG:G	acceptor_gain	1.0000
1:165206034:GC:G	acceptor_loss	1.0000
1:165206035:C:CC	acceptor_gain	1.0000
1:165206035:CT:C	acceptor_loss	1.0000
1:165206037:G:C	acceptor_gain	1.0000
1:165208133:C:CC	acceptor_gain	1.0000
1:165213643:T:A	donor_gain	1.0000
1:165213666:T:TA	donor_gain	1.0000
1:165213814:C:A	acceptor_loss	1.0000
1:165213815:T:A	acceptor_loss	1.0000
1:165232612:A:C	acceptor_gain	1.0000
1:165249404:TCACC:T	donor_loss	1.0000
1:165249405:CACCT:C	donor_loss	1.0000
1:165249406:A:AG	donor_loss	1.0000
1:165353074:A:AC	donor_gain	1.0000
1:165353075:C:CC	donor_gain	1.0000
1:165353075:CTT:C	donor_gain	1.0000
1:165353075:CTTCT:C	donor_gain	1.0000
1:165355479:CTCA:C	donor_loss	1.0000
1:165355481:CACCC:C	donor_loss	1.0000
1:165355482:A:AC	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000005810 (1:165355980 T>A), RS1000015353 (1:165271915 C>T), RS1000044796 (1:165271684 T>C), RS1000052172 (1:165349696 C>A,T), RS1000091407 (1:165202559 T>C), RS1000095812 (1:165228127 T>G), RS1000121800 (1:165355658 G>A), RS1000129608 (1:165343652 C>T), RS1000135358 (1:165288907 T>A), RS1000157363 (1:165247469 A>C,G,T), RS1000179389 (1:165205461 T>C), RS1000195286 (1:165295055 C>A), RS1000212504 (1:165217023 T>A), RS1000239398 (1:165229706 A>G,T), RS1000308804 (1:165249709 A>G)

Disease associations

OMIM: gene MIM:600298 | disease phenotypes: MIM:601412, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant nonsyndromic hearing loss	Definitive	Autosomal dominant
autosomal dominant nonsyndromic hearing loss 7	Strong	Autosomal dominant
Mobius syndrome	Limited	Autosomal dominant
hearing loss, autosomal recessive	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
autosomal dominant nonsyndromic hearing loss	Definitive	AD

Mondo (6): autosomal dominant nonsyndromic hearing loss 7 (MONDO:0011074), schizophrenia (MONDO:0005090), sensorineural hearing loss disorder (MONDO:0020678), Mobius syndrome (MONDO:0008006), hearing loss, autosomal recessive (MONDO:0019588), autosomal dominant nonsyndromic hearing loss (MONDO:0019587)

Orphanet (2): Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

2 total (4 of 2 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0005101	High-frequency hearing impairment
HP:0100753	Schizophrenia
HP:0000407	Sensorineural hearing impairment

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000924_5	Response to acetaminophen (hepatotoxicity)	6.000000e-07
GCST002408_18	Response to methotrexate in juvenile idiopathic arthritis	6.000000e-06
GCST005024_15	Pursuit maintenance gain	4.000000e-06
GCST006275_1	Vestibular neuritis	8.000000e-11
GCST006473_6	Diffusing capacity of the lung for carbon monoxide traits	8.000000e-07
GCST006976_88	Macular thickness	4.000000e-09
GCST008811_3	Alcohol consumption (drinks per week)	8.000000e-09
GCST012442_29	Age-related hearing impairment	2.000000e-10
GCST90020028_628	Hip circumference adjusted for BMI	7.000000e-09
GCST90020028_629	Hip circumference adjusted for BMI	6.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008433	pursuit maintenance gain measurement
EFO:0009369	diffusing capacity of the lung for carbon monoxide
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D020331	Mobius Syndrome	C07.465.299.825; C10.292.319.825; C10.292.562.700.375.750; C11.590.436.400.750; C16.131.077.578; C16.614.595
C563321	Deafness, Autosomal Dominant 7 (supp.)
C564609	Deafness, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Vorinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, affects methylation	1
decabromobiphenyl ether	decreases expression	1
arsenite	increases methylation	1
sodium arsenite	decreases expression	1
tetrabromobisphenol A	decreases expression	1
N-acetyl-4-benzoquinoneimine	affects response to substance	1
1,1,2,2-tetrabromoethane	affects response to substance	1
tetrachlorodian	decreases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
rofecoxib	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
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects cotreatment, affects methylation	1
Cadmium	decreases expression, increases abundance	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	affects expression	1
Aflatoxin B1	increases methylation	1
Asbestos, Serpentine	decreases methylation	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A3Y3	SEES3-1V human LMX1A, clone1	Embryonic stem cell	Male
CVCL_A3Y4	SEES3-1V human LMX1A, clone2	Embryonic stem cell	Male
CVCL_A3Y5	SEES3-1V human LMX1A, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety