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Identification of a novel mutation in the APTX gene associated with ataxia-oculomotor apraxia

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      Hereditary ataxias are a clinically and genetically heterogeneous family of disorders defined by the inability to control gait and muscle coordination. Given the nonspecific symptoms of many hereditary ataxias, precise diagnosis relies on molecular genetic testing. To this end, we conducted whole-exome sequencing (WES) on a large consanguineous Iranian family with hereditary ataxia and oculomotor apraxia. WES in five affected and six unaffected individuals resulted in the identification of a homozygous novel stop-gain mutation in the APTX gene (c.739A>T; p.Lys247*) that segregates with the phenotype. Mutations in the APTX (OMIM 606350) gene are associated with ataxia with oculomotor apraxia type 1 (OMIM 208920).

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      Most cited references 24

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      Fast and accurate short read alignment with Burrows–Wheeler transform

      Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals. Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ∼10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package. Availability: Contact:
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        BEDTools: a flexible suite of utilities for comparing genomic features

        Motivation: Testing for correlations between different sets of genomic features is a fundamental task in genomics research. However, searching for overlaps between features with existing web-based methods is complicated by the massive datasets that are routinely produced with current sequencing technologies. Fast and flexible tools are therefore required to ask complex questions of these data in an efficient manner. Results: This article introduces a new software suite for the comparison, manipulation and annotation of genomic features in Browser Extensible Data (BED) and General Feature Format (GFF) format. BEDTools also supports the comparison of sequence alignments in BAM format to both BED and GFF features. The tools are extremely efficient and allow the user to compare large datasets (e.g. next-generation sequencing data) with both public and custom genome annotation tracks. BEDTools can be combined with one another as well as with standard UNIX commands, thus facilitating routine genomics tasks as well as pipelines that can quickly answer intricate questions of large genomic datasets. Availability and implementation: BEDTools was written in C++. Source code and a comprehensive user manual are freely available at Contact:; Supplementary information: Supplementary data are available at Bioinformatics online.
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          The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin.

          The newly recognized ataxia-ocular apraxia 1 (AOA1; MIM 208920) is the most frequent cause of autosomal recessive ataxia in Japan and is second only to Friedreich ataxia in Portugal. It shares several neurological features with ataxia-telangiectasia, including early onset ataxia, oculomotor apraxia and cerebellar atrophy, but does not share its extraneurological features (immune deficiency, chromosomal instability and hypersensitivity to X-rays). AOA1 is also characterized by axonal motor neuropathy and the later decrease of serum albumin levels and elevation of total cholesterol. We have identified the gene causing AOA1 and the major Portuguese and Japanese mutations. This gene encodes a new, ubiquitously expressed protein that we named aprataxin. This protein is composed of three domains that share distant homology with the amino-terminal domain of polynucleotide kinase 3'- phosphatase (PNKP), with histidine-triad (HIT) proteins and with DNA-binding C2H2 zinc-finger proteins, respectively. PNKP is involved in DNA single-strand break repair (SSBR) following exposure to ionizing radiation and reactive oxygen species. Fragile-HIT proteins (FHIT) cleave diadenosine tetraphosphate, which is potentially produced during activation of the SSBR complex. The results suggest that aprataxin is a nuclear protein with a role in DNA repair reminiscent of the function of the protein defective in ataxia-telangiectasia, but that would cause a phenotype restricted to neurological signs when mutant.

            Author and article information

            [1 ]Department of Genetics, Stanford University, Stanford, California 94305, USA;
            [2 ]Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran;
            [3 ]Department of Medical Genetics, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran;
            [4 ]Department of Pediatrics, Stanford University, Stanford, California 94305, USA;
            [5 ]Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran;
            [6 ]Department of Medical Genetics, DeNA Laboratory, Tehran, Iran
            Author notes

            These authors contributed equally to this work.

            Cold Spring Harb Mol Case Stud
            Cold Spring Harb Mol Case Stud
            Cold Spring Harbor Molecular Case Studies
            Cold Spring Harbor Laboratory Press
            November 2017
            : 3
            : 6

            This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted reuse and redistribution provided that the original author and source are credited.

            Pages: 9
            Funded by: National Institutes of Health (NIH) , open-funder-registry 10.13039/100000002;
            Award ID: 1P50HG00773501
            Award ID: 8U54DK10255602
            Funded by: Swiss National Science Foundation (SNSF) , open-funder-registry 10.13039/100000001;
            Award ID: P300PA_161005
            Award ID: P2GEP3_151825
            Research Report


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