Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred
- Suleyman Gulsuner1,
- Ayse Begum Tekinay2,
- Katja Doerschner3,4,
- Huseyin Boyaci3,4,
- Kaya Bilguvar5,6,7,
- Hilal Unal2,
- Aslihan Ors4,
- O. Emre Onat1,
- Ergin Atalar4,8,
- A. Nazli Basak9,
- Haluk Topaloglu10,
- Tulay Kansu11,
- Meliha Tan12,
- Uner Tan13,
- Murat Gunel5,6,7 and
- Tayfun Ozcelik1,2,14
- 1Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara 06800, Turkey;
- 2Institute of Materials Science and Nanotechnology, Bilkent University, Ankara 06800, Turkey;
- 3Department of Psychology, Faculty of Economics, Administrative and Social Sciences, Bilkent University, Ankara 06800, Turkey;
- 4National Research Center for Magnetic Resonance, Bilkent University, Ankara 06800 Turkey;
- 5Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510, USA;
- 6Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA;
- 7Department of Genetics, Center for Human Genetics and Genomics and Program on Neurogenetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA;
- 8Department of Electrical and Electronics Engineering, Faculty of Engineering, Bilkent University, Ankara 06800, Turkey;
- 9NDAL Laboratory, School of Arts and Sciences, Bogazici University, Istanbul 34342, Turkey;
- 10Department of Pediatric Neurology, Ihsan Dogramaci Children's Hospital, Ankara 06100, Turkey;
- 11Department of Neurology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey;
- 12Department of Neurology, Baskent University Faculty of Medicine, Ankara 06490, Turkey;
- 13Department of Physiology, Cukurova University Faculty of Medicine, Adana 01330, Turkey
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.
Footnotes
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↵14 Corresponding author.
E-mail tozcelik{at}bilkent.edu.tr.
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.126110.111.
- Received May 11, 2011.
- Accepted August 23, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press
