RT Journal
A1 Gulsuner, Suleyman
A1 Tekinay, Ayse B
A1 Doerschner, Katja
A1 Boyaci, Huseyin
A1 Bilguvar, Kaya
A1 Unal, Hilal
A1 Ors, Aslihan
A1 Onat, Onur Emre
A1 Atalar, Ergin
A1 Basak, A Nazli
A1 Topaloglu, Haluk
A1 Kansu, Tulay
A1 Tan, Meliha
A1 Tan, Uner
A1 Gunel, Murat
A1 Ozcelik, Tayfun
T1 Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred
JF Genome Research 
JO Genome Research 
YR 2011 
FD September 01 
DO 10.1101/gr.126110.111 
SP gr.126110.111 
UL http://genome.cshlp.org/content/early/2011/09/01/gr.126110.111.abstract 
AB 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.