LITAF – Charcot-Marie-Tooth disease type 1C

Charcot-Marie-Tooth disease type 1C (CMT1C) is a rare, autosomal dominant demyelinating peripheral neuropathy caused by mutations in the LITAF (SIMPLE) gene. Affected individuals present with distal muscle weakness, sensory loss, slow nerve conduction velocities, pes cavus foot deformity, and bilateral foot drop. Electrophysiological and clinical features overlap with CMT1A but generally manifest a milder phenotype with preserved early motor milestones.

Genetic evidence for LITAF in CMT1C includes over 60 affected individuals from at least 16 unrelated families. A cohort of 152 demyelinating neuropathy probands yielded six CMT1C pedigrees (n = 38) with G112S and W116G variants ([PMID:15122712]). Three unrelated Korean families contributed 10 patients harboring p.Gly112Ser ([PMID:35608774]). Four novel missense mutations, including Gly112Ser in two families (total carriers n = 38), were identified among 968 cases ([PMID:16787513]). A mother–son pair with p.Gly112Ser highlights variable expressivity ([PMID:32665875]). Segregation in > 38 affected relatives confirms autosomal dominant transmission.

The variant spectrum is dominated by missense changes clustering within a conserved C-terminal LITAF domain. Key pathogenic alleles include c.334G>A (p.Gly112Ser), c.346T>G (p.Trp116Gly), c.344C>A (p.Thr115Asn), and c.404C>T (p.Pro135Leu). Recurrent p.Gly112Ser has been reported across diverse populations, supporting its role as a founder/recurrent variant.

Functional assays demonstrate that CMT1C-linked LITAF mutations act via combined loss-of-function and dominant-negative mechanisms. SIMPLE mutants mislocalize from endosomal membranes to the cytosol or mitochondria and undergo proteasomal and aggresome-autophagy degradation ([PMID:21896645]). Disrupted recruitment of ESCRT components STAM1, Hrs, and TSG101 impairs endosome-to-lysosome trafficking and prolongs ErbB/ERK1/2 signaling ([PMID:23166352]).

Cellular phenotypes of patient fibroblasts include vacuolation and enlargement of late endocytic compartments, recapitulated by LITAF knockout and reversible by TRPML1 activation with ML-SA1 ([PMID:33059769]). Interaction of SIMPLE with NEDD4 and TSG101 supports its role in lysosomal sorting ([PMID:16118794]).

No conflicting studies refute LITAF’s role in CMT1C. The convergence of genetic segregation and concordant functional data yields a Strong clinical validity classification. Additional evidence, such as animal models, further supports this association but exceeds current ClinGen scoring caps.

Key take-home: Autosomal dominant LITAF missense mutations in a conserved C-terminal domain cause CMT1C, and LITAF sequencing should be included in diagnostic workflows to guide patient management and potential endolysosomal-targeted therapies.

References

• Annals of neurology • 2004 • SIMPLE mutation in demyelinating neuropathy and distribution in sciatic nerve PMID:15122712
• Journal of the peripheral nervous system • 2006 • SIMPLE mutation analysis in dominant demyelinating Charcot-Marie-Tooth disease: three novel mutations PMID:16787513
• 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
• Cureus • 2020 • A Rare Case of Charcot-Marie-Tooth Disease Type 1C With an Unusual Presentation PMID:32665875
• Genes & genomics • 2022 • Identification and clinical characterization of Charcot-Marie-Tooth disease type 1C patients with LITAF p.G112S mutation PMID:35608774
• Neurology • 2003 • Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C PMID:12525712
• 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
• Journal of neuroscience research • 2005 • SIMPLE interacts with NEDD4 and TSG101: evidence for a role in lysosomal sorting and implications for Charcot-Marie-Tooth disease PMID:16118794

Evidence Based Scoring (AI generated)