MITF

Chr 3ARAD

melanocyte inducing transcription factor

ENSG00000187098 UniProt: O75030 OMIM: 156845

MITF encodes a transcription factor that serves as a master regulator of melanocyte survival and differentiation, binding to promoter regions of pigmentation genes like tyrosinase to control melanin production. Mutations cause auditory-pigmentary syndromes including Waardenburg syndrome type 2A, Tietz albinism-deafness syndrome, and COMMAD syndrome, with both autosomal dominant and autosomal recessive inheritance patterns reported. The gene is highly constrained against loss-of-function variants (pLI 0.98, LOEUF 0.31), reflecting its critical role in melanocyte development and pigmentation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAR/ADLOEUF 0.314 OMIM phenotypes

Clinical Summary— MITF

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Gene-Disease Validity (ClinGen)

Waardenburg syndrome type 2 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.31LOEUF

pLI 0.981

Z-score 4.38

OE 0.13 (0.07–0.31)

Highly constrained

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

Missense Constraint

1.47Z-score

OE missense 0.77 (0.69–0.85)

243 obs / 316.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.13 (0.07–0.31)

0≤0.351.4

Missense OE0.77 (0.69–0.85)

0≤0.61.4

Synonymous OE0.96

0≤1.21.6

LoF obs/exp: 4 / 29.8Missense obs/exp: 243 / 316.5Syn Z: 0.36

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMITF-related Waardenburg syndromeLOFAD

limitedMITF-related melanoma, cutaneous malignantGOFAD

definitiveMITF-related Tietz syndromeOTHERAD

strongMITF-related coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD syndrome)LOFAR

0.5674th %ile

GOF

0.3590th %ile

LOF

0.75top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.31

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNBiochemical and functional data for one of the probands demonstrate that mutations do not affect dimerization of MITF with other MiT family transcription factors but rather alter nuclear migration and DNA binding of homo- and heterodimers and thus allow the mutant alleles to act as dominant negativePMID:27889061

LOFBiallelic Mutations in MITF Cause Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism, and DeafnessPMID:27889061

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.