Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred
- Suleyman Gulsuner1,
- Ayse B Tekinay2,
- Katja Doerschner3,
- Huseyin Boyaci3,
- Kaya Bilguvar4,
- Hilal Unal2,
- Aslihan Ors3,
- Onur Emre Onat1,
- Ergin Atalar5,
- A Nazli Basak6,
- Haluk Topaloglu7,
- Tulay Kansu7,
- Meliha Tan8,
- Uner Tan9,
- Murat Gunel4 and
- Tayfun Ozcelik1,10
- 1 Bilkent University Faculty of Science;
- 2 Bilkent University Institute of Materials Science and Nanotechnology;
- 3 Bilkent University National Research Center for Magnetic Resonance;
- 4 Yale University School of Medicine;
- 5 Bilkent University Faculty of Engineering;
- 6 Boğaziçi University School of Arts and Sciences;
- 7 Hacettepe University Faculty of Medicine;
- 8 Başkent University Faculty of Medicine;
- 9 Çukurova University Faculty of Medicine
- ↵* Corresponding author; email: tozcelik{at}bilkent.edu.tr
Abstract
The biological basis for 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 patient 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 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 co-segregated with the condition in the extended family. The mutation lies in a highly conserved region of WDR81, flanked by an N-terminal neurobeachin 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.
- Received May 11, 2011.
- Accepted August 23, 2011.
- Copyright © 2011, Cold Spring Harbor Laboratory Press
