Browsing by Author "Bilgen, R."
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Item Open Access Abnormal subcortical activity in congenital mirror movement disorder with RAD51 mutation(Turkish Society of Radiology, 2018) Demirayak, Pınar; Onat, Onur Emre; Gevrekci, A. Ö.; Gülsüner, S.; Uysal, H.; Bilgen, R.; Doerschner, Katja; Özçelik, Tayfun; Boyacı, HüseyinPURPOSE Congenital mirror movement disorder (CMMD) is characterized by unintended, nonsuppressible, homologous mirroring activity contralateral to the movement on the intended side of the body. In healthy controls, unilateral movements are accompanied with predominantly contralateral cortical activity, whereas in CMMD, in line with the abnormal behavior, bilateral cortical activity is observed for unilateral motor tasks. However, task-related activities in subcortical structures, which are known to play critical roles in motor actions, have not been investigated in CMMD previously. METHODS We investigated the functional activation patterns of the motor components in CMMD patients. By using linkage analysis and exome sequencing, common mutations were revealed in seven affected individuals from the same family. Next, using functional magnetic resonance imaging (fMRI) we investigated cortical and subcortical activity during manual motor actions in two right-handed affected brothers and sex, age, education, and socioeconomically matched healthy individuals. RESULTS Genetic analyses revealed heterozygous RAD51 c.401C>T mutation which cosegregated with the phenotype in two affected members of the family. Consistent with previous literature, our fMRI results on these two affected individuals showed that mirror movements were closely related to abnormal cortical activity in M1 and SMA during unimanual movements. Furthermore, we have found previously unknown abnormal task-related activity in subcortical structures. Specifically, we have found increased and bilateral activity during unimanual movements in thalamus, striatum, and globus pallidus in CMMD patients. CONCLUSION These findings reveal further neural correlates of CMMD, and may guide our understanding of the critical roles of subcortical structures for unimanual movements in healthy individuals.Item Open Access Identification of a novel missense mutation in RAD51 in a large family with congenital mirror movements(American Society of Human Genetics, 2012-11) Onat, Onur Emre; Gülsüner, Süleyman; Bilgen, R.; Dal, G. M.; Bilguvar, K.; Boyacı, Hüseyin; Doerschner, Katja; Uysal, H.; Günel, M.; Özçelik, TayfunCongenital mirror movements (CMM) are a rare and heterogeneous group of disorders characterized by involuntary contralateral movements of mainly the upper extremities during intentional movements on the opposite side. Isolated cases are usually familial and suggest autosomal dominant inheritance with incomplete penetrance. In two chromosome 18 linked families, causative mutations were identified in DCC (Science 328:592, 2010; MRMV1; MIM:157600). Here, we describe a three-generation consanguineous Turkish family with six members affected by CMM. Linkage analysis with a dominant model and 90 percent penetrance parameters resulted in peaks on 15q13.3-q21.1, 15q26.2, and 19q12 with maximum multipoint LOD scores of 3.6, 2.6, and 2.6, respectively. However, a region of homozygosity segregating with the phenotype was not observed, and thus excluded the possibility of recessive inheritance of the disease allele in this consanguineous family. Whole-exome sequencing of an affected individual uncovered 7 coding, 33 intronic and 3 intergenic novel variants located within the three linkage intervals, which were filtered against the dbSNP132 dataset. Segregation analysis, population filtering using 1000 genomes and EVS data sets, and conservation considerations using prediction tools revealed a novel missense mutation (c.404C>T [p.T134N], RefSeq accession number NM_002875) in exon 5 of RAD51 (MIM:179617), consistent with the dominant inheritance of the disease allele in the family. The mutation resides in the highly conserved AAA (ATPases associated with diverse cellular activities) domain of the protein, and it was not observed in 436 chromosomes from healthy individuals coming from a geographical matched region. Recently, truncating mutations in RAD51 were identified in two families with CMM (Am J Hum Genet 90:301,2012; MRMV2; MIM:614508). Our findings support the totally unexpected role of RAD51 in neurodevelopment and further suggest that alterations of this gene may lead to neurological phenotypes.