LITAF

Chr 16

lipopolysaccharide induced TNF factor

Also known as: PIG7, SIMPLE, TP53I7

NCBI Gene: 9516 ENSG00000189067 UniProt: Q99732

The LITAF protein is a DNA-binding transcription factor that regulates TNF-alpha expression and mediates p53-induced apoptosis. Mutations cause Charcot-Marie-Tooth disease type 1C (CMT1C) through an autosomal dominant inheritance pattern with a dominant-negative mechanism. The pathogenic variants likely disrupt the protein's normal transcriptional regulatory functions, leading to the peripheral neuropathy characteristic of CMT1C.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Lipopolysaccharide is a potent stimulator of monocytes and macrophages, causing secretion of tumor necrosis factor-alpha (TNF-alpha) and other inflammatory mediators. This gene encodes lipopolysaccharide-induced TNF-alpha factor, which is a DNA-binding protein and can mediate the TNF-alpha expression by direct binding to the promoter region of the TNF-alpha gene. The transcription of this gene is induced by tumor suppressor p53 and has been implicated in the p53-induced apoptotic pathway. Mutations in this gene cause Charcot-Marie-Tooth disease type 1C (CMT1C) and may be involved in the carcinogenesis of extramammary Paget's disease (EMPD). Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2014]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.28

Clinical Summary— LITAF

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Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

8 unique Pathogenic / Likely Pathogenic· 151 VUS of 315 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — LITAF

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.28LOEUF

pLI 0.031

Z-score 1.13

OE 0.50 (0.23–1.28)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.22Z-score

OE missense 0.94 (0.80–1.11)

97 obs / 103.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.23–1.28)

0≤0.351.4

Missense OE?0.94 (0.80–1.11)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 3 / 6.0Missense obs/exp: 97 / 103.4Syn Z: -0.18

This gene — mechanism propensity

0.79top 25%

GOF

0.73top 25%

LOF

0.2387th %ile

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

DNprediction above median · 1 literature citation

GOFprediction above median · 1 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

DNThe findings suggested that the W116G Litaf mutation disrupts myelin homeostasis and causes peripheral neuropathy via a combination of toxic gain-of-function and dominant-negative mechanisms.1

GOFThe findings suggested that the W116G Litaf mutation disrupts myelin homeostasis and causes peripheral neuropathy via a combination of toxic gain-of-function and dominant-negative mechanisms.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 23359569 ↗

ClinVar Variant Classifications

315 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic3

VUS151

Likely Benign75

Benign53

Conflicting19

Pathogenic

Likely Pathogenic

151

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	5	0	0	5
Likely Pathogenic	0	3	0	0	3
VUS	5	102	41	3	151
Likely Benign	0	5	25	45	75
Benign	0	4	48	1	53
Conflicting	—				19
Total	5	119	114	49	306

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap LITAF — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →