LMX1A

Chr 1AD

LIM homeobox transcription factor 1 alpha

NCBI Gene: 4009ENSG00000162761UniProt: Q8TE12

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 (By similarity)

Primary Disease Associations & Inheritance

Deafness, autosomal dominant 7MIM #601412
AD
120
ClinVar variants
26
Pathogenic / LP
0.99
pLI score· haploinsufficient
1
Active trials
Clinical Summary— LMX1A
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Gene-Disease Validity (ClinGen)
autosomal dominant nonsyndromic hearing loss · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
26 Pathogenic / Likely Pathogenic· 64 VUS of 120 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.27LOEUF
pLI 0.991
Z-score 4.06
OE 0.09 (0.04–0.27)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.00Z-score
OE missense 0.81 (0.71–0.92)
175 obs / 216.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.09 (0.04–0.27)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.71–0.92)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.92
0≤1.21.6
LoF obs/exp: 2 / 23.0Missense obs/exp: 175 / 216.5Syn Z: 0.56

ClinVar Variant Classifications

120 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
Likely Pathogenic5
VUS64
Likely Benign9
Benign19
Conflicting2
21
Pathogenic
5
Likely Pathogenic
64
VUS
9
Likely Benign
19
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
18
0
21
Likely Pathogenic
1
1
3
0
5
VUS
2
55
6
1
64
Likely Benign
0
2
3
4
9
Benign
0
0
14
5
19
Conflicting
—2
Total3614410120

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

LMX1A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Deafness, autosomal dominant 7

MIM #601412

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
LMX1A inhibits C-Myc expression through ANGPTL4 to exert tumor suppressive role in gastric cancer.
Qian P et al.·PLoS One
2019
Novel Molecular Genetic Etiology of Asymmetric Hearing Loss: Autosomal-Dominant LMX1A Variants.
Lee SY et al.·Ear Hear
2022
A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment.
Schrauwen I et al.·Hum Genet
2018
Update on CD164 and LMX1A genes to strengthen their causative role in autosomal dominant hearing loss.
Oziębło D et al.·Hum Genet
2022
Cloning, expression and genomic structure of human LMX1A, and variant screening in Pima Indians.
Thameem F et al.·Gene
2002
A novel frameshift variant of LMX1A that leads to autosomal dominant non-syndromic sensorineural hearing loss: functional characterization of the C-terminal domain in LMX1A.
Xiao M et al.·Hum Mol Genet
2023Case report
Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction.
Wesdorp M et al.·Hum Genet
2018
Functional roles of Nurr1, Pitx3, and Lmx1a in neurogenesis and phenotype specification of dopamine neurons during in vitro differentiation of embryonic stem cells.
Hong S et al.·Stem Cells Dev
2014Functional
Association of LMX1A genetic polymorphisms with susceptibility to congenital scoliosis in Chinese Han population.
Wu N et al.·Spine (Phila Pa 1976)
2014
Isolation of LMX1a Ventral Midbrain Progenitors Improves the Safety and Predictability of Human Pluripotent Stem Cell-Derived Neural Transplants in Parkinsonian Disease.
de Luzy IR et al.·J Neurosci
2019
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
LMX1A and APOE ɛ Genotype Associations With Working Memory Training Effects in HIV and Non-HIV: A Randomized Controlled Trial.
Chang L et al.·Neurol Neuroimmunol Neuroinflamm
2026🔓 Open Access
Exercise with induced pluripotent stem cells enhances Wnt1-Lmx1a signaling and dopaminergic neurogenesis to alleviate Parkinsonian symptoms.
Arafat A et al.·World J Stem Cells
2025🔓 Open Access
A Novel Missense Variant in LMX1A Leads to Autosomal Dominant Nonsyndromic Hearing Loss.
Chen R et al.·Am J Med Genet A
2026
Exercise combined with induced pluripotent stem cells enhances the Wnt1-Lmx1a loop in the midbrain of Parkinsonian mice to alleviate Parkinsonian symptoms.
Jiang X et al.·World J Stem Cells
2025🔓 Open Access
Silencing of LIM homeodomain transcription factor 1 alpha (Lmx1a) gene caused larval molting failure and adult reproductive deficiency in Henosepilachna vigintioctopunctata.
Liu J et al.·Insect Sci
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Mild Cognitive Impairment

REACT MCI - Repeated Advanced Cognitive Training in Mild Cognitive Impairment

ACTIVE NOT RECRUITING
NCT04792528Phase NASorlandet Hospital HFStarted 2021-05-15
Computerized cognitive training.Generalized brain training / Active control

External Resources

Links to major genomics databases and tools