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A novel frameshift mutation in PMP22 accounts for hereditary neuropathy with liability to pressure palsies
P Young1, H Wiebusch, F Stögbauer
1Klinik und Poliklinik für Neurologie, Westfähische Wilhelms-Universität, Münster, Germany.
Abstract:
Peripheral myelin protein PMP22 deficiency is associated with hereditary neuropathy with liability to pressure palsies (HNPP). Most HNPP cases are caused by a 1.5-megabase deletion in chromosome 17p11.2-12, a region that contains the PMP22 gene, whereas point mutations leading to HNPP are extremely rare. We have identified a family with clinical and electrophysiologic features of HNPP,in which all affected members are heterozygous carriers of a single base insertion in codon 94. This mutation is predicted to alter the reading frame and to result in a delayed termination signal. We conclude that the functional consequences of the frameshift are equivalent to those of the PMP22 deletion allele.
Insights
A rare frameshift mutation in the PMP22 gene causes hereditary neuropathy with liability to pressure palsies (HNPP). This genetic finding offers new insights into the molecular basis of HNPP, similar to common deletions.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Hereditary neuropathy with liability to pressure palsies (HNPP) is typically linked to deletions in the PMP22 gene on chromosome 17p11.2-12.
- Point mutations in PMP22 causing HNPP are exceptionally uncommon.
- Understanding the genetic basis of HNPP is crucial for diagnosis and potential therapeutic strategies.
Purpose of the Study:
- To identify the genetic cause of HNPP in a family presenting with typical clinical and electrophysiologic features.
- To investigate the molecular mechanism of a novel PMP22 mutation.
- To compare the functional impact of this mutation with known PMP22 deletion alleles.
Main Methods:
- Clinical evaluation and electrophysiologic studies of affected family members.
- DNA sequencing to identify mutations in the PMP22 gene.
- In silico analysis to predict the effect of the identified mutation on protein structure and function.
Main Results:
- A novel single base insertion in codon 94 of the PMP22 gene was identified in all affected individuals.
- This insertion causes a frameshift mutation, predicted to lead to a premature and altered termination signal.
- Affected individuals exhibited clinical and electrophysiologic characteristics consistent with HNPP.
Conclusions:
- A PMP22 frameshift mutation can cause HNPP, challenging the notion that only deletions are significant.
- The functional consequences of this PMP22 frameshift mutation are comparable to those of the common deletion allele.
- This discovery expands the spectrum of genetic defects underlying HNPP and highlights the importance of PMP22 dosage and integrity.