SIMPLE mutations in CMT and the potential role of its protein product in protein

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Hum Mutat. 2005 Mar 17;25(4):372-383

SIMPLE mutations in Charcot-Marie-Tooth disease and the potential

role of its protein product in protein degradation.

Saifi GM, Szigeti K, Wiszniewski W, Shy ME, Krajewski K, Hausmanowa-

Petrusewicz I, Kochanski A, Reeser S, Mancias P, I, Lupski JR.

Department of Molecular and Human Genetics, Baylor College of

Medicine, Houston, Texas.

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.