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Identical point mutations of PMP-22 in Trembler-J mouse and Charcot-Marie-Tooth disease type 1A
L J Valentijn1, F Baas, R A Wolterman
1Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands.
Abstract:
We have investigated the peripheral myelin protein gene, PMP-22, in a family with Charcot-Marie-Tooth disease type 1A (CMT1A). The DNA duplication commonly found in CMT1A was absent in this family, but strong linkage existed between the disease and the CMT1A marker VAW409R3 on chromosome 17p11.2. We found a point mutation in PMP-22 which was completely linked with the disease. The mutation, a proline for leucine substitution in the first putative transmembrane domain, is identical to that recently found in the Trembler-J mouse. The presence of this PMP-22 defect in this CMT1A family and the location of PMP-22 within the DNA duplication associated with CMT1A suggest that both structural alteration and overexpression of PMP-22 may lead to the disease.
Insights
A novel PMP-22 gene mutation causes Charcot-Marie-Tooth disease type 1A (CMT1A) in a family lacking the common DNA duplication. This finding suggests PMP-22 defects, not just duplication, can cause CMT1A.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Charcot-Marie-Tooth disease type 1A (CMT1A) is often caused by a DNA duplication in the peripheral myelin protein gene, PMP-22.
- The genetic basis of CMT1A in families without this duplication requires further investigation.
Purpose of the Study:
- To investigate the genetic cause of CMT1A in a family that does not exhibit the common PMP-22 duplication.
- To identify mutations in the PMP-22 gene linked to the disease in this family.
Main Methods:
- Genetic linkage analysis using CMT1A markers.
- DNA sequencing of the PMP-22 gene to identify point mutations.
Main Results:
- The common PMP-22 DNA duplication was absent in the affected family.
- Strong linkage was observed between the disease and the CMT1A marker VAW409R3 on chromosome 17p11.2.
- A novel point mutation in PMP-22, a proline for leucine substitution in the first transmembrane domain, was identified and completely linked to the disease.
Conclusions:
- A PMP-22 gene mutation, distinct from the common duplication, can cause CMT1A.
- Both structural alterations (mutations) and overexpression of PMP-22 may lead to CMT1A.
- This PMP-22 mutation is identical to one found in the Trembler-J mouse model, highlighting conserved disease mechanisms.