title: The LITAF/SIMPLE I92V sequence variant results in an earlier age of onset of CMT1A/HNPP diseases.
abstract: Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) represent the most common heritable neuromuscular disorders. Molecular diagnostics of CMT1A/HNPP diseases confirm clinical diagnosis, but their value is limited to the clinical course and prognosis. However, no biomarkers of CMT1A/HNPP have been identified. We decided to explore if the LITAF/SIMPLE gene shared a functional link to the PMP22 gene, whose duplication or deletion results in CMT1A and HNPP, respectively. By studying a large cohort of CMT1A/HNPP-affected patients, we found that the LITAF I92V sequence variant predisposes patients to an earlier age of onset of both the CMT1A and HNPP diseases. Using cell transfection experiments, we showed that the LITAF I92V sequence variant partially mislocalizes to the mitochondria in contrast to wild-type LITAF which localizes to the late endosome/lysosomes and is associated with a tendency for PMP22 to accumulate in the cells. Overall, this study shows that the I92V LITAF sequence variant would be a good candidate for a biomarker in the case of the CMT1A/HNPP disorders.
authors.affiliation: Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5, 02-106, Warsaw, Poland.
authors.forename: Elena
authors.initials: E
authors.lastname: Sinkiewicz-Darol
authors.forename: Andressa Ferreira
authors.initials: AF
authors.lastname: Lacerda
authors.forename: Anna
authors.initials: A
authors.lastname: Kostera-Pruszczyk
authors.forename: Anna
authors.initials: A
authors.lastname: Potulska-Chromik
authors.forename: Beata
authors.initials: B
authors.lastname: Sokołowska
authors.forename: Dagmara
authors.initials: D
authors.lastname: Kabzińska
authors.forename: Craig R
authors.initials: CR
authors.lastname: Brunetti
authors.forename: Irena
authors.initials: I
authors.lastname: Hausmanowa-Petrusewicz
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kochański
mesh_terms: D017668:Age of Onset; D000818:Animals; D001176:Arthrogryposis / Q000150:complications / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D015415:Biomarkers; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000150:complications / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D002522:Chlorocebus aethiops; D005260:Female; D020022:Genetic Predisposition to Disease; D015417:Hereditary Sensory and Motor Neuropathy / Q000150:complications / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009185:Myelin Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D015415:Biomarkers; C118738:LITAF protein, human; D009185:Myelin Proteins; D009687:Nuclear Proteins; C073687:PMP22 protein, human; D014157:Transcription Factors