Non-recurrent SEPT9 duplications cause hereditary neuralgic amyotrophy
ABSTRACT Genomic copy number variants have been shown to be responsible for multiple genetic diseases. Recently, a duplication in septin 9 (SEPT9) was shown to be causal for hereditary neuralgic amyotrophy (HNA), an episodic peripheral neuropathy with autosomal dominant inheritance. This duplication was identified in 12 pedigrees that all shared a common founder haplotype.
Based on array comparative genomic hybridisation, we identified six additional heterogeneous tandem SEPT9 duplications in patients with HNA that did not possess the founder haplotype. Five of these novel duplications are intragenic and result in larger transcript and protein products, as demonstrated through reverse transcription-PCR and western blotting. One duplication spans the entire SEPT9 gene and does not generate aberrant transcripts and proteins. The breakpoints of all the duplications are unique and contain regions of microhomology ranging from 2 to 9 bp in size. The duplicated regions contain a conserved 645 bp exon within SEPT9 in which HNA-linked missense mutations have been previously identified, suggesting that the region encoded by this exon is important to the pathogenesis of HNA.
Together with the previously identified founder duplication, a total of seven heterogeneous SEPT9 duplications have been identified in this study as a causative factor of HNA. These duplications account for one third of the patients in our cohort, suggesting that duplications of various sizes within the SEPT9 gene are a common cause of HNA.
- SourceAvailable from: Hauke Werner
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- "Septins can assemble into filaments and have been implicated in regulating microtubules and vesicle trafficking (Peterson and Petty, 2010). Duplication of the whole SEPT9 gene causes the neuropathy HNA (Collie et al., 2010), and point mutations (Kuhlenbäumer et al., 2005) dramatically increase SEPT9–mRNA translation (McDade et al., 2007), suggesting that the "
ABSTRACT: Peripheral nerve myelin facilitates rapid impulse conduction and normal motor and sensory functions. Many aspects of myelin biogenesis, glia-axonal interactions, and nerve homeostasis are poorly understood at the molecular level. We therefore hypothesized that only a fraction of all relevant myelin proteins has been identified so far. Combining gel-based and gel-free proteomic approaches, we identified 545 proteins in purified mouse sciatic nerve myelin, including 36 previously known myelin constituents. By mass spectrometric quantification, the predominant P0, periaxin, and myelin basic protein constitute 21, 16, and 8% of the total myelin protein, respectively, suggesting that their relative abundance was previously misestimated due to technical limitations regarding protein separation and visualization. Focusing on tetraspan-transmembrane proteins, we validated novel myelin constituents using immuno-based methods. Bioinformatic comparison with mRNA-abundance profiles allowed the categorization in functional groups coregulated during myelin biogenesis and maturation. By differential myelin proteome analysis, we found that the abundance of septin 9, the protein affected in hereditary neuralgic amyotrophy, is strongly increased in a novel mouse model of demyelinating neuropathy caused by the loss of prion protein. Finally, the systematic comparison of our compendium with the positions of human disease loci allowed us to identify several candidate genes for hereditary demyelinating neuropathies. These results illustrate how the integration of unbiased proteome, transcriptome, and genome data can contribute to a molecular dissection of the biogenesis, cell biology, metabolism, and pathology of myelin.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 11/2011; 31(45):16369-86. DOI:10.1523/JNEUROSCI.4016-11.2011 · 6.75 Impact Factor
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- "Replication slippage or template switching during replication account for both small and large deletions and duplications with terminal microhomologies (Fig. 1). Recently, relevant replicationbased models including serial replication slippage (SRS) [Chen et al., 2005a, b, c], fork stalling and template switching (FoSTes) [Lee et al., 2007], and microhomology-mediated break-induced replication (MMBIR) [Hastings et al., 2009], which were collectively termed microhomology-mediated replication-dependent recombination (MMRDR) by Chen et al. , have been used to explain the generation of a diverse range of complex genomic rearrangements [Bauters et al., 2008; Carvalho et al., 2009; Chauvin et al., 2009; Collie et al., 2010; Koumbaris et al., 2011; Sheen et al., 2007; Vissers et al., 2009; Zhang et al., 2009, 2010]. For example, DNA replication stalling-induced chromosome breakage has turned out to be an important mechanism causing deletions at chromosomal ends. "
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