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.

Fission yeast Atf1 is a member of the ATF/CREB basic leucine zipper (bZIP) family of transcription factors with strong homology to mammalian ATF2. Atf1 regulates transcription in response to stress stimuli and also plays a role in controlling heterochromatin formation and recombination. However, its DNA binding independent role is poorly studied. Here, we report that Atf1 has a distinct role in regulating the anaphasepromoting complex/cyclosome (APC/C) ubiquitin ligase. We have identified atf1؉ as a dose-dependent suppressor of apc5-1, a mutation causing mitotic arrest. Remarkably, the suppression is not dependent upon the bZIP domain and is therefore independent of the ability of Atf1 to bind DNA. Interestingly, Atf1 physically binds the APC/C in vivo. Furthermore, we show that addition of purified Atf1 proteins into a cell-free system stimulates ubiquitylation of cyclin B and securin by the APC/C. These results reveal a novel role for Atf1 in cell cycle control through protein-protein interaction.Ubiquitylation is a post-translational modification that occurs through the action of an enzymatic cascade consisting of three enzymes E1, E2, and E3, and typically controls the proteolysis, localization, or activity of a protein (1). It is a tightly regulated, highly specific and temporally controlled process, and thus plays an important role in many processes such as the cell cycle, signal transduction, transcription, DNA repair, development, and regulation of the immune response.The anaphase-promoting complex/cyclosome (APC/C) 2 is a large (1.5 MDa) multisubunit E3 ubiquitin ligase, which has essential functions in key events during the cell cycle, such as chromosome segregation and mitotic exit by degrading securin/Cut2/Pds1 and cyclin B/Cdc13/Clb2, respectively (2-4). The APC/C belongs to the RING finger family of E3 ubiquitin ligases, which include Ubr1, c-Cbl, and Skp1-Cullin 1-F-box (SCF) complex (5), but unlike other members of this family, it is exceptionally large and complex, consisting of at least 11 conserved subunits. The APC/C appears to consist of two separable subcomplexes which associate independently with the scaffold subunit, Apc1/Cut4 (6). The first subcomplex includes a RING finger subunit Apc11 and a cullin domain subunit Apc2. This subcomplex is capable of ubiquitylating proteins to some extent, but lacks substrate specificity (7-9). The specificity seems to rely on the second subcomplex, consisting of three subunits Apc3/Nuc2/Cdc27, Apc6/Cut9/Cdc16, and Apc8/Cut23/Cdc23, which contain a tetratricopeptide repeat (TPR) domain. A member of the Fizzy family of APC/C activators, Cdh1, has been shown to bind Apc3/Cdc27 via its C-terminal IR motifs and recruit a substrate to the APC/C (10 -12). However, the exact roles of the remaining subunits and other TPR subunits, such as Apc5 and Apc7, are unknown.The activity of the APC/C is regulated in part by the association of the Fizzy family of WD40-containing activator proteins (2-4). There are two major activators during the cell cycle, Fizzy/Slp1/Cdc2...