Alternative Splicing in the Human PMP22 Gene: Implications in CMT1A Neuropathy.
CMT1A patients commonly share PMP22 genetic overloading but they show phenotypic heterogeneity and variability in PMP22 mRNA and protein expression. Moreover, PMP22 mRNA levels do not correlate with clinical outcome measures in these patients, suggesting their uselessness as a disease biomarker. Thus, in-depth analysis of PMP22 transcription and translation might help to define its pathogenic role in CMT1A. We focused on the alternative splicing of PMP22 gene to verify whether mRNA processing is altered in CMT1A. We identified three new PMP22 transcripts enriched in human sural nerve biopsies. One of them was an untranslated variant, whereas the other two originated from a PMP22 undescribed exon and encoded for a new putative protein localized in the endoplasmic reticulum. As splicing events in the PMP22 gene are differently regulated in tissues and during development, we analyzed the levels of PMP22 transcripts and their splicing pattern in human and experimental CMT1A. We found an altered PMP22 splicing ratio in the CMT1A rat. In addition, we showed a remarkable derangement in rat QKI expression, which is a critical regulator of splicing during myelination. Overall, our data suggest that an alteration of mRNA processing could be a pathogenic mechanism in CMT1A.
Department of Neurosciences, Rehabilitation Ophthalmology, Genetics and Maternal-Infantile Sciences (DINOGMI) and CEBR, University of Genoa, Genoa, Italy.
Davide
D
Visigalli
IRCCS AOU San Martino - IST, Genoa, Italy.
Patrizio
P
Castagnola
Department of Neurosciences, Rehabilitation Ophthalmology, Genetics and Maternal-Infantile Sciences (DINOGMI) and CEBR, University of Genoa, Genoa, Italy.
Giovanna
G
Capodivento
Department of Neurosciences, Rehabilitation Ophthalmology, Genetics and Maternal-Infantile Sciences (DINOGMI) - Section of Medical Genetics, University of Genoa IRCCS AOU San Martino-IST, UOC Medical Genetics, Genoa, Italy.
Alessandro
A
Geroldi
Department of Neurosciences, Rehabilitation Ophthalmology, Genetics and Maternal-Infantile Sciences (DINOGMI) - Section of Medical Genetics, University of Genoa IRCCS AOU San Martino-IST, UOC Medical Genetics, Genoa, Italy.
Emilia
E
Bellone
Department of Neurosciences, Rehabilitation Ophthalmology, Genetics and Maternal-Infantile Sciences (DINOGMI) and CEBR, University of Genoa, Genoa, Italy.
Gianluigi
G
Mancardi
Clinic of Central and Peripheral Degenerative Neuropathies Unit, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy.
Davide
D
Pareyson
Department of Neurosciences, Rehabilitation Ophthalmology, Genetics and Maternal-Infantile Sciences (DINOGMI) and CEBR, University of Genoa, Genoa, Italy.
Angelo
A
Schenone
Department of Neurosciences, Rehabilitation Ophthalmology, Genetics and Maternal-Infantile Sciences (DINOGMI) and CEBR, University of Genoa, Genoa, Italy.
Lucilla
L
Nobbio
D017398:Alternative Splicing; D000818:Animals; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics; D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D008822:Mice, Transgenic; D009185:Myelin Proteins / Q000235:genetics* / Q000378:metabolism; D010525:Peripheral Nerves / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000235:genetics; D051381:Rats
C109561:CDRT1 protein, human; D009185:Myelin Proteins; C073687:PMP22 protein, human; D011506:Proteins
CMT1A; PMP22; QKI; alternative splicing; neuropathy; patients; protein isoform