Browsing by Author "Tan, M."

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Open Access
Homozygosity mapping and targeted genomic sequencing reveal the game responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred
(Cold Spring Harbor Laboratory Press, 2011) Gulsuner, Süleyman; Tekinay, Ayşe Begüm; Doerschner, Katja; Boyaci, Hüseyin; Bilguvar, K.; Ünal, Hilal; Örs, Aslıhan; Onat, O. Emre; Atalar, Ergin; Basak, A. N.; Topaloglu, H.; Kansu, T.; Tan, M.; Tan, U.; Gunel, M.; Özçelik, Tayfun
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.
Open Access
Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion
(Nature Publishing Group, 2013) Onat, O. E.; Gulsuner, S.; Bilguvar, K.; Basak, A. N.; Topaloglu, H.; Tan, M.; Tan, U.; Gunel, M.; Ozcelik, T.
Cerebellar ataxia, mental retardation and dysequilibrium syndrome is a rare and heterogeneous condition. We investigated a consanguineous family from Turkey with four affected individuals exhibiting the condition. Homozygosity mapping revealed that several shared homozygous regions, including chromosome 13q12. Targeted next-generation sequencing of an affected individual followed by segregation analysis, population screening and prediction approaches revealed a novel missense variant, p.I376M, in ATP8A2. The mutation lies in a highly conserved C-terminal transmembrane region of E1 E2 ATPase domain. The ATP8A2 gene is mainly expressed in brain and development, in particular cerebellum. Interestingly, an unrelated individual has been identified, in whom mental retardation and severe hypotonia is associated with a de novo t(10;13) balanced translocation resulting with the disruption of ATP8A2. These findings suggest that ATP8A2 is involved in the development of the cerebro-cerebellar structures required for posture and gait in humans. © 2013 Macmillan Publishers Limited All rights reserved.
Open Access
Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans
(National Academy of Sciences, 2008) Ozcelik, T.; Akarsu, N.; Uz, E.; Caglayan, S.; Gulsuner, S.; Onat, O. E.; Tan, M.; Tan, U.
Quadrupedal gait in humans, also known as Unertan syndrome, is a rare phenotype associated with dysarthric speech, mental retardation, and varying degrees of cerebrocerebellar hypoplasia. Four large consanguineous kindreds from Turkey manifest this phenotype. In two families (A and D), shared homozygosity among affected relatives mapped the trait to a 1.3-Mb region of chromosome 9p24. This genomic region includes the VLDLR gene, which encodes the very low-density lipoprotein receptor, a component of the reelin signaling pathway involved in neuroblast migration in the cerebral cortex and cerebellum. Sequence analysis of VLDLR revealed nonsense mutation R257X in family A and single-nucleotide deletion c2339delT in family D. Both these mutations are predicted to lead to truncated proteins lacking transmembrane and signaling domains. In two other families (B and C), the phenotype is not linked to chromosome 9p. Our data indicate that mutations in VLDLR impair cerebrocerebellar function, conferring in these families a dramatic influence on gait, and that hereditary disorders associated with quadrupedal gait in humans are genetically heterogeneous.
Open Access
Reply to herz et al. and humprey et al.: genetic heterogeneity of cerebellar hypoplasia with quadruprdal locomotion
(National Academy of Sciences, 2008) Ozcelik, T.; Akarsu, N.; Uz, E.; Caglayan, S.; Gulsuner, S.; Onat, O. E.; Tan, M.; Tan, U.