NEK1 Variants in a Cohort of Italian Patients With Amyotrophic Lateral Sclerosis
Nilo RivaLaura PozziTommaso RussoGiovanni Battista PipitoneParide SchitoTeuta DomiFederica AgostaAngelo QuattriniPaola CarreraMassimo Filippi
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In the last few years, different studies highlighted a significant enrichment of NEK1 loss of function (LoF) variants in amyotrophic lateral sclerosis (ALS), and an additional role for the p.Arg261His missense variant in the disease susceptibility. Several other missense variants have been described so far, whose pathogenic relevance remains however unclear since many of them have been reported in both patients and controls. This study aimed to investigate the presence of NEK1 variants and their correlation with phenotype in a cohort of Italian patients with ALS.We sequenced a cohort of 350 unrelated Italian patients with ALS by next-generation sequencing (NGS) and then we analyzed the clinical features of NEK1 carriers.We detected 20 different NEK1 rare variants (four LoF and 16 missense) in 33 unrelated patients with sporadic ALS (sALS). The four LoF variants (two frameshift and two splice-site variants) were all novel. The p.Arg261His missense variant was enriched in the patients' cohort (p < 0.001). Excluding this variant from counting, the difference in the frequency of NEK1 rare missense variants between patients and controls was not statistically significant. NEK1 carriers had a higher frequency of flail arm (FA) phenotype compared with the other patients of the cohort (29.2% vs. 6.4%). Nine NEK1 carriers (37.5%) also harbored variants in other ALS-related genes.This study confirms that NEK1 LoF and p.Arg261. His missense variants are associated with ALS in an Italian ALS cohort and suggests a correlation between the presence of NEK1 variants and FA phenotype.BACKGROUND To explore frameshift mutations in the Bax and TGFβRII genes and the relationship between frameshift mutations and microsatellite alterations in lung cancer. METHODS Frameshift mutations and microsatellite alterations were detected in 50 primary lung cancer tissues by PCR,8% denature polyacrylamide gel electrophoresis and silver staining. RESULTS Bax gene (G)₈ frameshift mutations were detected in 12 cases (24%，12/50),and all were base deletion mutations.Bax frameshift mutations correlated with microsatellite alterations (P<0.05).TGFβRII (A)₁₀ frameshift mutations were not found. CONCLUSIONS Bax gene frameshift mutations are found in lung cancer,and closely correlate with microsatellite alterations.Bax gene and microsatellite might play a certain role in carcinogenesis of lung cancer.
Microsatellite Instability
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ALS : amyotrophic lateral sclerosis UMN : upper motor neuron LMN : lower motor neuron fALS : familial amyotrophic lateral sclerosis sALS : sporadic amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) reflects a heterogeneous group of neurodegenerative disorders unified by
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Abstract Motivation: Cancer researchers seeking immunotherapy targets in cancer cells need tools to locate highly expressed proteins unique to cancer cells. Missense mutation and frameshift location reporter (MMuFLR), a Galaxy-based workflow, analyzes next-generation sequencing paired read RNA-seq output to reliably identify small frameshift mutations and missense mutations in highly expressed protein-coding genes. MMuFLR ignores known SNPs, low quality reads and poly-A/T sequences. For each frameshift and missense mutation identified, MMuFLR provides the location and sequence of the amino acid substitutions in the novel protein candidates for direct input into epitope evaluation tools. Availability: http://toolshed.g2.bx.psu.edu/ Contact: rath0096@umn.edu or johns198@umn.edu Supplementary information: Supplementary data are available at Bioinformatics online.
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In his influential book “Evolution by Gene Duplication”, Ohno postulated that frameshift mutation could lead to a new function after duplication, but frameshift mutation is generally thought to be deleterious, and thus drew little attention in functional innovation in duplicate evolution. To this end, we here report an exhaustive survey of the genomes of human, mouse, zebrafish, and fruit fly. We identified 80 duplicate genes that involved frameshift mutations after duplication. The frameshift mutation preferentially located close to the C-terminus in most cases (55/88), which indicated that a frameshift mutation that changed the reading frame in a small part at the end of a duplicate may likely have contributed to adaptive evolution (e.g., human genes NOTCH2NL and ARHGAP11B) otherwise too deleterious to survive. A few cases (11/80) involved multiple frameshift mutations, exhibiting various patterns of modifications of the reading frame. Functionality of duplicate genes involving frameshift mutations was confirmed by sequence characteristics and expression profile, suggesting a potential role of frameshift mutation in creating functional novelty. We thus showed that genomes have non-negligible numbers of genes that have experienced frameshift mutations following gene duplication. Our results demonstrated the potential importance of frameshift mutations in molecular evolution, as Ohno verbally argued 50 years ago.
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This corrigendum corrects the following article. In the article "Spectrum of amyloglucosidase mutations in Asian Indian patients with Glycogen storage disease type III. Am J Med Genet Part A. 2020;182A:1190–1200", the authors would like to state that there are two typos that should be corrected in their article and are requesting an addition of a corrigendum to the manuscript. The following errors should be corrected: 1. The variation identified in case no 56 should be c.4098T>G, instead of c.4099T>G in Table 1 on pages 1192–1193, and in the section 3.2.2 novel variants on page 1195. Group1 Variants (frameshift, nonsense, splice site) G1 IIIa c.3526A>T p.Lys1176* Nonsense G47 IIIa G3§ IIIa c.1632dupG p.Asn545Glufs*11 Frame shift G3C§ IIIa G4 IIIa c.1735 + 1G>T Splice variant G9 IIIa c.3755delA p.Asn1252Ilefs*38 Frame shift G26 IIIa G14 IIIa G36 IIIa c.2362_2392 dup31 p.Gly798Alafs*3 Frame shift G37 IIIa c.428G>A p.Trp143* Nonsense G56 IIIa G69 IIIa Group2 variants (missense and compound heterozygous) c.1880A>G p.Asp627Gly Missense c.4331A>G p.Asn1444Ser Missense c.3069G>A, p.Trp1023* Nonsense/ c.4353G>T p.Trp1451Cys Missense c.3083 + 1G>A splice variant c.2362_2392dup31 p.Gly798Alafs*3 Frameshift/ c.3444C>G p.Tyr1148* Nonsense c.4334A>G p.Tyr1445Cys Missense/ c.3444C>G, pTyr1148* Nonsense c.2362_2392dup31 p.Gly798Alafs*3 Frameshift/ c.4334A>G p.Tyr1445Cys Missense 2. Similarly, the second change in the siblings Case nos. G61 and G61C should be c.3444C>G instead of c.3444A>G in Table 1 on pages 1192–1193.
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Abstract Phosphorylated TDP-43 (pTDP-43) aggregates in the cytoplasm of motor neurons and neuroglia in the brain are one of the pathological hallmarks of amyotrophic lateral sclerosis. Although the axons exceed the total volume of motor neuron soma by several orders of magnitude, systematic studies investigating the presence and distribution of pTDP-43 aggregates within motor nerves are still lacking. The aim of this study is to define the TDP-43/pTDP-43 pathology in diagnostic motor nerve biopsies performed on a large cohort of patients presenting with a lower motor neuron syndrome and to assess whether this might be a discriminating tissue biomarker for amyotrophic lateral sclerosis and non-amyotrophic lateral sclerosis cases. We retrospectively evaluated 102 lower motor neuron syndrome patients referred to our centre for a diagnostic motor nerve biopsy. Histopathological criteria of motor neuron disease and motor neuropathy were applied by two independent evaluators, who were blind to clinical data. TDP-43 and pTDP-43 were evaluated by immunohistochemistry, and results compared to final clinical diagnosis. We detected significant differences between amyotrophic lateral sclerosis and non-amyotrophic lateral sclerosis cases in pTDP-43 expression in myelinated fibres: axonal accumulation was detected in 98.2% of patients with amyotrophic lateral sclerosis versus 30.4% of non-amyotrophic lateral sclerosis samples (P < 0.0001), while concomitant positive staining in Schwan cell cytoplasm was found in 70.2% of patients with amyotrophic lateral sclerosis versus 17.4% of patients who did not have amyotrophic lateral sclerosis (P < 0.001). Importantly, we were also able to detect pTDP-43 aggregates in amyotrophic lateral sclerosis cases displaying normal features at standard histopathological analysis. Our findings demonstrated that a specific pTDP-43 signature is present in the peripheral nervous system of patients with amyotrophic lateral sclerosis, and could be exploited as a specific, accessible tissue biomarker. The detection of pTDP-43 aggregates within motor nerves of living patients with amyotrophic lateral sclerosis, occurring before axonal degeneration, suggests that this is an early event that may contribute to amyotrophic lateral sclerosis pathogenesis.
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Frameshift mutations occur when the coding region of a gene is altered by addition or deletion of a number of base pairs that is not a multiple of three. The occurrence of a deletion versus an insertion type of frameshift depends on the nature of the transient intermediate structure formed during DNA synthesis. Extrahelical bases on the template strand give rise to deletions, whereas extrahelical bases on the strand being synthesized produce insertions. We previously used reversion of a +1 frameshift mutation to analyze the role of the mismatch repair (MMR) machinery in correcting −1 frameshift intermediates within a defined region of the yeast LYS2gene. In this study, we have used reversion of a −1 frameshift mutation within the same region of LYS2 to analyze the role of the MMR machinery in the correction of frameshift intermediates that give rise to insertion events. We found that insertion and deletion events occur at similar rates but that the reversion spectra are very different in both the wild-type and MMR-defective backgrounds. In addition, analysis of the +1 spectra revealed novel roles for Msh3p and Msh6p in removing specific types of frameshift intermediates.
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