Non-recurrent SEPT9 duplications cause hereditary neuralgic amyotrophy

ArticleinJournal of Medical Genetics 47(9):601-7 · November 2009with25 Reads
DOI: 10.1136/jmg.2009.072348 · Source: PubMed
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.
    • "In another human disease heterozygous for a septin alteration, hereditary neuralgic amyotrophy, the mutant septin also seems to act dominantly (Kuhlenbäumer et al., 2005; Collie et al., 2010 ). In this case, the alterations do not lie in the GTP-binding domain at all, but instead are substitutions in (Kuhlenbäumer et al., 2005) or duplications (Collie et al., 2010 ) of the extended N terminus of SEPT9. Hence a sequestration-based QC mechanism acting on mutants with misfolded G domains would likely be unable to recognize this class of septin mutants. "
    [Show abstract] [Hide abstract] ABSTRACT: Septin hetero-oligomers polymerize into cytoskeletal filaments with essential functions in many eukaryotic cell types. Mutations within the oligomerization interface that encompasses the GTP-binding pocket of a septin (its "G interface") cause thermo-instability of yeast septin hetero-oligomer assembly, and human disease. When coexpressed with its wild-type counterpart, a G interface mutant is excluded from septin filaments, even at moderate temperatures. We show that this quality control mechanism is specific to G interface mutants, operates during de novo septin hetero-oligomer assembly, and requires specific cytosolic chaperones. Chaperone overexpression lowers the temperature permissive for proliferation of cells expressing a G interface mutant as the sole source of a given septin. Mutations that perturb the septin G interface retard release from these chaperones, imposing a kinetic delay on the availability of nascent septin molecules for higher-order assembly. Unexpectedly, the disaggregase Hsp104 contributes to this delay in a manner that does not require its "unfoldase" activity, indicating a latent "holdase" activity toward mutant septins. These findings provide new roles for chaperone-mediated kinetic partitioning of non-native proteins, and may help explain the etiology of septin-linked human diseases. © 2015 by The American Society for Cell Biology.
    Full-text · Article · Feb 2015
    • "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 "
    [Show abstract] [Hide abstract] 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.
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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), 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. [2010], have been used to explain the generation of a diverse range of complex genomic rearrange- ments [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 Zhang et al., , 2010. For example, DNA replication stalling-induced chromosome breakage has turned out to be an important mechanism causing deletions at chromosomal ends. "
    [Show abstract] [Hide abstract] ABSTRACT: Different types of human gene mutation may vary in size, from structural variants (SVs) to single base-pair substitutions, but what they all have in common is that their nature, size and location are often determined either by specific characteristics of the local DNA sequence environment or by higher order features of the genomic architecture. The human genome is now recognized to contain "pervasive architectural flaws" in that certain DNA sequences are inherently mutation prone by virtue of their base composition, sequence repetitivity and/or epigenetic modification. Here, we explore how the nature, location and frequency of different types of mutation causing inherited disease are shaped in large part, and often in remarkably predictable ways, by the local DNA sequence environment. The mutability of a given gene or genomic region may also be influenced indirectly by a variety of noncanonical (non-B) secondary structures whose formation is facilitated by the underlying DNA sequence. Since these non-B DNA structures can interfere with subsequent DNA replication and repair and may serve to increase mutation frequencies in generalized fashion (i.e., both in the context of subtle mutations and SVs), they have the potential to serve as a unifying concept in studies of mutational mechanisms underlying human inherited disease.
    Full-text · Article · Oct 2011
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