Journal article
SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation
Human mutation, Vol.25(4), pp.372-383
04/2005
DOI: 10.1002/humu.20153
PMID: 15776429
Abstract
Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited peripheral neuropathies characterized by progressive weakness and atrophy of distal limb muscles. Recently, SIMPLE/LITAF was shown to be responsible for an autosomal dominant demyelinating form of CMT linked to 16p (CMT1C). Although two transcripts encoding different proteins (SIMPLE and LITAF) have been reported from the same gene, we could not confirm the existence of LITAF. Here we show that the LITAF transcript appears to result from a DNA sequencing error. We screened the SIMPLE gene for mutations in a cohort of 192 patients with CMT or related neuropathies, each of whom tested negative for other known genetic causes of CMT. In 16 unrelated CMT families we identified nine different nucleotide variations in SIMPLE that were not detected in control chromosomes. SIMPLE mutations can occur de novo, associated with sporadic CMT1 and may convey both demyelinating and axonal forms. Bioinformatics analyses and other observations of SIMPLE suggest that 1) it could be a member of the RING finger motif-containing subfamily of E3 ubiquitin ligases that are associated with the ubiquitin-mediated proteasome processing pathway, 2) it could interact through its PPXY motifs with a WW domain containing protein, for instance with NEDD4, an E3 ubiquitin ligase, and 3) it could interact through the PSAP motif with TSG10, a protein associated with endosomal multivesicular protein sorting. Since both SIMPLE and Hrs are endosomal proteins and have both PPXY and P(S/T)AP motifs, we hypothesize that SIMPLE, like Hrs, is potentially a clathrin adaptor aiding in the retention of ubiquitinated proteins on to the endosomes. Thus the potential E3 ubiquitin ligase activity of SIMPLE, alteration in its interactions with NEDD4 or TSG101, or changes in its properties as a clathrin coat adaptor may underlie the pathogenesis of Charcot-Marie-Tooth disease.
Details
- Title: Subtitle
- SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation
- Creators
- Gulam Mustafa Saifi - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USAKinga SzigetiWojciech WiszniewskiMichael E ShyKaren KrajewskiIrena Hausmanowa-PetrusewiczAndrzej KochanskiSuzanne ReeserPedro ManciasIan ButlerJames R Lupski
- Resource Type
- Journal article
- Publication Details
- Human mutation, Vol.25(4), pp.372-383
- Publisher
- United States
- DOI
- 10.1002/humu.20153
- PMID
- 15776429
- ISSN
- 1059-7794
- eISSN
- 1098-1004
- Grant note
- R01NS27042 / NINDS NIH HHS
- Language
- English
- Date published
- 04/2005
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984020756002771
Metrics
21 Record Views