Sabine Winkler

Publications (2) View all

• Source

  Available from: Caroline Vance

  Article: Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase.

  John Mitchell, Praveen Paul, Han-Jou Chen, Alex Morris, Miles Payling, Mario Falchi, James Habgood, Stefania Panoutsou, Sabine Winkler, Veronica Tisato, Amin Hajitou, Bradley Smith, Caroline Vance, Christopher Shaw, Nicholas D Mazarakis, Jacqueline de Belleroche
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  ABSTRACT: We report a unique mutation in the D-amino acid oxidase gene (R199W DAO) associated with classical adult onset familial amyotrophic lateral sclerosis (FALS) in a three generational FALS kindred, after candidate gene screening in a 14.52 cM region on chromosome 12q22-23 linked to disease. Neuronal cell lines expressing R199W DAO showed decreased viability and increased ubiquitinated aggregates compared with cells expressing the wild-type protein. Similarly, lentiviral-mediated expression of R199W DAO in primary motor neuron cultures caused increased TUNEL labeling. This effect was also observed when motor neurons were cocultured on transduced astrocytes expressing R199W, indicating that the motor neuron cell death induced by this mutation is mediated by both cell autonomous and noncell autonomous processes. DAO controls the level of D-serine, which accumulates in the spinal cord in cases of sporadic ALS and in a mouse model of ALS, indicating that this abnormality may represent a fundamental component of ALS pathogenesis.
  Proceedings of the National Academy of Sciences 04/2010; 107(16):7556-61. · 9.68 Impact Factor
• Article: Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome.

  Karin R Engelhardt, Sean McGhee, Sabine Winkler, Atfa Sassi, Cristina Woellner, Gabriela Lopez-Herrera, Andrew Chen, Hong Sook Kim, Maria Garcia Lloret, Ilka Schulze, [......], Maria C Pietrogrande, Mehdi Yeganeh, Zeina Baz, Salem Al-Tamemi, Christoph Klein, Jennifer M Puck, Steven M Holland, Edward R B McCabe, Bodo Grimbacher, Talal A Chatila
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  ABSTRACT: The genetic etiologies of the hyper-IgE syndromes are diverse. Approximately 60% to 70% of patients with hyper-IgE syndrome have dominant mutations in STAT3, and a single patient was reported to have a homozygous TYK2 mutation. In the remaining patients with hyper-IgE syndrome, the genetic etiology has not yet been identified. We aimed to identify a gene that is mutated or deleted in autosomal recessive hyper-IgE syndrome. We performed genome-wide single nucleotide polymorphism analysis for 9 patients with autosomal-recessive hyper-IgE syndrome to locate copy number variations and homozygous haplotypes. Homozygosity mapping was performed with 12 patients from 7 additional families. The candidate gene was analyzed by genomic and cDNA sequencing to identify causative alleles in a total of 27 patients with autosomal-recessive hyper-IgE syndrome. Subtelomeric biallelic microdeletions were identified in 5 patients at the terminus of chromosome 9p. In all 5 patients, the deleted interval involved dedicator of cytokinesis 8 (DOCK8), encoding a protein implicated in the regulation of the actin cytoskeleton. Sequencing of patients without large deletions revealed 16 patients from 9 unrelated families with distinct homozygous mutations in DOCK8 causing premature termination, frameshift, splice site disruption, and single exon deletions and microdeletions. DOCK8 deficiency was associated with impaired activation of CD4+ and CD8+T cells. Autosomal-recessive mutations in DOCK8 are responsible for many, although not all, cases of autosomal-recessive hyper-IgE syndrome. DOCK8 disruption is associated with a phenotype of severe cellular immunodeficiency characterized by susceptibility to viral infections, atopic eczema, defective T-cell activation and T(h)17 cell differentiation, and impaired eosinophil homeostasis and dysregulation of IgE.
  The Journal of allergy and clinical immunology 12/2009; 124(6):1289-302.e4. · 9.17 Impact Factor