LITAF – Charcot-Marie-Tooth Disease

LITAF (lipopolysaccharide-induced TNF-α factor; HGNC:16841) is causally implicated in autosomal dominant Charcot-Marie-Tooth disease (CMT), specifically the demyelinating CMT1C subtype (MONDO:0015626). Patients present with slowly progressive distal muscle weakness, sensory loss, and markedly reduced nerve conduction velocities consistent with a demyelinating neuropathy ([HP:0009830]).

1 Clinical Validity (Strong)

Genetic analyses across 16 unrelated CMT1C probands identified nine distinct missense variants in LITAF, clustered within a conserved C-terminal domain (PMID:15776429). Segregation was demonstrated in six pedigrees encompassing 38 affected relatives (PMID:15122712). Concordant functional studies across multiple models confirm a dominant-negative or loss-of-function mechanism.

• gene_disease_association: Strong — nine pathogenic missense variants in 16 probands, segregation in six families, concordant functional data

2 Genetic Evidence (Strong)

Inheritance is autosomal dominant. A cohort of 192 genetically unexplained CMT patients yielded nine LITAF nucleotide changes in 16 families (PMID:15776429). Segregation analysis in six pedigrees (n = 38 affected) supports penetrance (PMID:15122712). All reported variants are missense substitutions within the LITAF domain. Recurrent c.334G>A (p.Gly112Ser) was identified in 10 individuals across multiple studies (PMID:28164329). No truncating or splicing variants have been reported, and no population-specific founders were detected.

• genetic_evidence: Strong — nine missense variants in 16 probands, segregation in six families, reached ClinGen genetic cap

3 Functional Evidence (Strong)

LITAF encodes an endosomal membrane protein expressed in Schwann cells and peripheral nerves. CMT1C-linked mutations cluster around a transmembrane anchor within a zinc-binding ‘LITAF domain’. Mutant proteins mislocalize from endosomes to the cytosol or mitochondria, form aggregates, and are degraded via proteasome and autophagy pathways (PMID:21896645; PMID:23166352). Patient fibroblasts and CRISPR knockout models exhibit endolysosomal vacuolation, rescued by TRPML1 activation (PMID:33059769). Structural and biophysical studies define LITAF as a monotopic, zinc-binding membrane protein, providing a framework for disease-causing variant clustering (PMID:27582497).

• functional_evidence: Strong — multiple concordant cellular and structural assays demonstrating a loss-of-function and dominant-negative mechanism

4 Conflicting Evidence

The p.Thr49Met (T49M) polymorphism alone is nonpathogenic but may modulate phenotypes when combined with EGR2 variants (PMID:32337334). No studies have refuted the direct association between LITAF variants and CMT1C.

5 Integration & Clinical Utility

LITAF mutations underlie a distinct autosomal dominant demyelinating neuropathy (CMT1C) characterized by endosomal trafficking defects in Schwann cells. Given the clustering of missense variants within a critical membrane-anchoring domain and robust functional concordance, LITAF testing should be included in diagnostic panels for patients with demyelinating CMT, particularly those with conduction blocks.

Key Take-home: LITAF is a validated, clinically actionable gene for autosomal dominant demyelinating CMT, and its inclusion in molecular testing facilitates accurate diagnosis, prognosis, and genetic counseling.

References

• Neurology • 2003 • Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C. PMID:12525712
• Human Mutation • 2005 • SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation. PMID:15776429
• Annals of Neurology • 2004 • SIMPLE mutation in demyelinating neuropathy and distribution in sciatic nerve. PMID:15122712
• Journal of Cell Science • 2011 • Mutations associated with Charcot-Marie-Tooth disease cause SIMPLE protein mislocalization and degradation by the proteasome and aggresome-autophagy pathways. PMID:21896645
• The Journal of Cell Biology • 2012 • Charcot-Marie-Tooth disease-linked protein SIMPLE functions with the ESCRT machinery in endosomal trafficking. PMID:23166352
• Acta Neuropathologica Communications • 2020 • A dysfunctional endolysosomal pathway common to two sub-types of demyelinating Charcot-Marie-Tooth disease. PMID:33059769
• The Biochemical Journal • 2016 • The Charcot Marie Tooth disease protein LITAF is a zinc-binding monotopic membrane protein. PMID:27582497
• Muscle & Nerve • 2017 • Charcot-Marie-Tooth disease type 1C: Clinical and electrophysiological findings for the c.334G>a (p.Gly112Ser) Litaf/Simple mutation. PMID:28164329

Evidence Based Scoring (AI generated)