title: Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred.
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.
authors: Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara 06800, Turkey.
authors: Suleyman
authors: S
authors: Gulsuner
authors: Ayse Begum
authors: AB
authors: Tekinay
authors: Katja
authors: K
authors: Doerschner
authors: Huseyin
authors: H
authors: Boyaci
authors: Kaya
authors: K
authors: Bilguvar
authors: Hilal
authors: H
authors: Unal
authors: Aslihan
authors: A
authors: Ors
authors: O Emre
authors: OE
authors: Onat
authors: Ergin
authors: E
authors: Atalar
authors: A Nazli
authors: AN
authors: Basak
authors: Haluk
authors: H
authors: Topaloglu
authors: Tulay
authors: T
authors: Kansu
authors: Meliha
authors: M
authors: Tan
authors: Uner
authors: U
authors: Tan
authors: Murat
authors: M
authors: Gunel
authors: Tayfun
authors: T
authors: Ozcelik
mesh_terms: D000328:Adult; D002531:Cerebellum; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D005260:Female; D005684:Gait / Q000235:genetics*; D030342:Genetic Diseases, Inborn / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D056426:Genetic Loci; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D011187:Posture; D011859:Radiography; D014421:Turkey