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Modeling Charcot-Marie-Tooth Disease In Vitro by Transfecting Mouse Primary Motoneurons
Published on: January 7, 2019
De novo PMP2 mutations in families with type 1 Charcot-Marie-Tooth disease
William W Motley1, Paulius Palaima2, Sabrina W Yum3
1Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Medicine, Pennsylvania Hospital, University of Pennsylvania, Philadelphia, Pennsylvania 19107, USA.
Abstract:
We performed whole exome sequencing on a patient with Charcot-Marie-Tooth disease type 1 and identified a de novo mutation in PMP2, the gene that encodes the myelin P2 protein. This mutation (p.Ile52Thr) was passed from the proband to his one affected son, and segregates with clinical and electrophysiological evidence of demyelinating neuropathy. We then screened a cohort of 136 European probands with uncharacterized genetic cause of Charcot-Marie-Tooth disease and identified another family with Charcot-Marie-Tooth disease type 1 that has a mutation affecting an adjacent amino acid (p.Thr51Pro), which segregates with disease. Our genetic and clinical findings in these kindred demonstrate that dominant PMP2 mutations cause Charcot-Marie-Tooth disease type 1.
Insights
Dominant mutations in the PMP2 gene cause Charcot-Marie-Tooth disease type 1. This study identified novel PMP2 mutations in families with this demyelinating neuropathy.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Charcot-Marie-Tooth disease type 1 (CMT1) is a group of inherited peripheral neuropathies.
- The genetic causes of many CMT1 cases remain unknown.
- PMP2 encodes the myelin P2 protein, crucial for peripheral nerve function.
Purpose of the Study:
- To identify the genetic basis of Charcot-Marie-Tooth disease type 1 in patients with uncharacterized causes.
- To investigate the role of the PMP2 gene in the pathogenesis of CMT1.
Main Methods:
- Whole exome sequencing was performed on a patient with CMT1.
- Genetic screening of PMP2 was conducted in a cohort of 136 European CMT1 probands.
- Segregation analysis and clinical/electrophysiological evaluations were performed in affected families.
Main Results:
- A de novo mutation (p.Ile52Thr) in PMP2 was identified in a CMT1 patient and segregated with the disease in his family.
- Another PMP2 mutation (p.Thr51Pro) was found in a separate CMT1 family, also segregating with the neuropathy.
- Both identified mutations are located in critical regions of the PMP2 gene.
Conclusions:
- Dominant mutations in the PMP2 gene are a cause of Charcot-Marie-Tooth disease type 1.
- PMP2 mutations lead to a demyelinating peripheral neuropathy.
- These findings expand the genetic landscape of CMT1 and highlight PMP2 as a key disease gene.
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