title: A novel synonymous mutation in the MPZ gene causing an aberrant splicing pattern and Charcot-Marie-Tooth disease type 1b.
abstract: Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy with a heterogeneous genetic background. Here, we describe two CMT1B families with a mild sensory-motor neuropathy and a novel synonymous variant (c.309G > T, p.G103G) in exon 3 of the MPZ gene. Next generation sequencing analysis on a 94 CMT gene panel showed no mutations in other disease genes. In vitro splicing assay and mRNA expression analysis indicated that the c.309T variant enhances a cryptic donor splice site at position c.304 resulting in the markedly increased expression of the r.304_448del alternative transcript in patients' cells. This transcript is predicted to encode a truncated P0 protein (p.V102Cfs11*) lacking the transmembrane domain, thus suggesting a possible haploinsufficiency mechanism for this mutation. This is the third reported synonymous MPZ variant associated with CMT1 and affecting splicing. These data confirm the functional impact of synonymous variants on MPZ splicing and their possible role as disease-causing mutations rather than silent polymorphisms.
authors.affiliation: Human Genetics Laboratory, Department of Health Sciences, Amedeo Avogadro University, Via Solaroli 17, 28100 Novara, Italy; Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Amedeo Avogadro University, Novara, Italy. Electronic address: lucia.corrado@med.unipmn.it.
authors.forename: L
authors.initials: L
authors.lastname: Corrado
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Disease, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20133 Milano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Magri
authors.affiliation: Human Genetics Laboratory, Department of Health Sciences, Amedeo Avogadro University, Via Solaroli 17, 28100 Novara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bagarotti
authors.affiliation: Department of Neurology, Amedeo Avogadro University, Corso Mazzini 18, 28100 Novara, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Carecchio
authors.affiliation: Unit of Clinic of Central and Peripheral Degenerative Neuropathies, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20133 Milano, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Piscosquito
authors.affiliation: Unit of Clinic of Central and Peripheral Degenerative Neuropathies, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20133 Milano, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Pareyson
authors.affiliation: Department of Neurology, Amedeo Avogadro University, Corso Mazzini 18, 28100 Novara, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Varrasi
authors.affiliation: Department of Neurology, Amedeo Avogadro University, Corso Mazzini 18, 28100 Novara, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Vecchio
authors.affiliation: Human Genetics Laboratory, Department of Health Sciences, Amedeo Avogadro University, Via Solaroli 17, 28100 Novara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Zonta
authors.affiliation: Department of Neurology, Amedeo Avogadro University, Corso Mazzini 18, 28100 Novara, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Cantello
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Disease, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20133 Milano, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Taroni
authors.affiliation: Human Genetics Laboratory, Department of Health Sciences, Amedeo Avogadro University, Via Solaroli 17, 28100 Novara, Italy; Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Amedeo Avogadro University, Novara, Italy.
authors.forename: S
authors.initials: S
authors.lastname: D'Alfonso
mesh_terms: D000293:Adolescent; D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism*; D005091:Exons; D005190:Family; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D018993:Myelin P0 Protein / Q000235:genetics* / Q000378:metabolism*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: C560547:MPZ protein, human; D018993:Myelin P0 Protein; D012333:RNA, Messenger
keywords: CMT; MPZ; P(0); RNA splicing; Synonymous mutation