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      Homozygosity mapping and targeted genomic sequencing reveal the game responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred

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      Author(s)
      Gulsuner, Süleyman
      Tekinay, Ayşe Begüm
      Doerschner, Katja
      Boyaci, Hüseyin
      Bilguvar, K.
      Ünal, Hilal
      Örs, Aslıhan
      Onat, O. Emre
      Atalar, Ergin
      Basak, A. N.
      Topaloglu, H.
      Kansu, T.
      Tan, M.
      Tan, U.
      Gunel, M.
      Özçelik, Tayfun
      Date
      2011
      Source Title
      Genome Research
      Print ISSN
      1088-9051
      Publisher
      Cold Spring Harbor Laboratory Press
      Volume
      21
      Pages
      1995 - 2003
      Language
      English
      Type
      Article
      Item Usage Stats
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      84
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      Abstract
      The biological basis for the development of the cerebro-cerebellar structures required for posture and gait in humans is poorly understood. We investigated a large consanguineous family from Turkey exhibiting an extremely rare phenotype associated with quadrupedal locomotion, mental retardation, and cerebro-cerebellar hypoplasia, linked to a 7.1-Mb region of homozygosity on chromosome 17p13.1-13.3. Diffusion weighted imaging and fiber tractography of the patients' brains revealed morphological abnormalities in the cerebellum and corpus callosum, in particular atrophy of superior, middle, and inferior peduncles of the cerebellum. Structural magnetic resonance imaging showed additional morphometric abnormalities in several cortical areas, including the corpus callosum, precentral gyrus, and Brodmann areas BA6, BA44, and BA45. Targeted sequencing of the entire homozygous region in three affected individuals and two obligate carriers uncovered a private missense mutation, WDR81 p.P856L, which cosegregated with the condition in the extended family. The mutation lies in a highly conserved region of WDR81, flanked by an N-terminal BEACH domain and C-terminal WD40 beta-propeller domains. WDR81 is predicted to be a transmembrane protein. It is highly expressed in the cerebellum and corpus callosum, in particular in the Purkinje cell layer of the cerebellum. WDR81 represents the third gene, after VLDLR and CA8, implicated in quadrupedal locomotion in humans.
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      http://hdl.handle.net/11693/12160
      Published Version (Please cite this version)
      http://dx.doi.org/10.1101/gr.126110.111
      Collections
      • Aysel Sabuncu Brain Research Center (BAM) 213
      • Department of Electrical and Electronics Engineering 3702
      • Department of Molecular Biology and Genetics 468
      • Department of Psychology 191
      • Institute of Materials Science and Nanotechnology (UNAM) 1930
      • Nanotechnology Research Center (NANOTAM) 1063
      • National Magnetic Resonance Research Center (UMRAM) 218
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