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The BTBD9 Gene Polymorphisms in Polish Patients with Gilles De La Tourette Syndrome

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The BTBD9 Gene Polymorphisms in Polish Patients with Gilles De La Tourette Syndrome Research Paper Acta Neurobiol Exp 2014, 74: 218–226 The BTBD9 gene polymorphisms in Polish patients with Gilles de la Tourette syndrome Piotr Janik1*, Mariusz Berdyński2, Krzysztof Safranow3, and Cezary Żekanowski2 1Department of Neurology, Medical University of Warsaw, Warsaw, Poland, *Email: [email protected]; 2 Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland; 3Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Szczecin, Poland Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterized by motor and vocal tics. The etiology of the disorder is unknown, although the predominant role of genetic factors has been established. Variants of the BTBD9 gene (rs4714156, rs9296249 and rs9357271) have been reported to be associated with GTS in French Canadian and Chinese Han populations. Therefore, we decided to test the association between GTS and polymorphisms of the BTBD9 gene in Polish patients. Our cohort of GTS cases comprised 162 patients aged 4–54 years (mean age: 19.9±8.7 years; 131 males, 80.9%). The control group consisted of 180 healthy persons aged 14–55 years (mean age: 23.1±2.1 years; 149 males, 82.8%). The rs4714156, rs9296249 and rs9357271 variants of the BTBD9 gene were genotyped. No significant differences were found in minor allele frequencies (MAFs) of the SNPs tested between the two groups. The frequency of MAFs of the genotyped SNPs was lower in GTS patients with Attention Deficit Hyperactivity Disorder (for rs9357271 and rs9296249, P=0.039 and rs4714156, P=0.040) and higher in GTS patients without comorbidities (for rs9357271 and rs9296249 P=0.021 and rs4714156 P=0.025). There was a trend toward an association between the minor allele of the SNPs and mild tics (P=0.089 for rs9357271 and rs9296249, P=0.057 for rs4714156). Despite limitations of the study, including the small number of cases and analyzed SNPs, our results suggest that the examined BTBD9 variants are not associated with GTS risk, but may be associated with comorbidity and tic severity in the Polish population. Key words: Gilles de la Tourette syndrome, tics, BTBD9, genetic variants, single nucleotide polymorphism INTRODUCTION ity, and severity of tics change over time. Tics typi- cally begin around the age of 5–6, reach their worst- Gilles de la Tourette syndrome (GTS) is a child- ever between ages 10 and 12, and then decline in hood-onset neuropsychiatric disorder manifested by severity throughout adolescence (Leckman et al. 1998). tics – brief, repetitive, stereotyped and intermittent Analysis of adulthood tics has revealed that over one- movements (motor tics) or sounds (vocal tics). For a third of children with GTS are completely tic free as GTS diagnosis, both multiple motor and one or more adults, slightly less than half have minimal to mild vocal tics must be present at some time during the ill- tics, and less than a quarter have moderate or stronger ness. They must be present for at least 12 months with- tics. These results contrast with their worst-ever period out any tic-free period of more than three consecutive where all individuals experience at least moderate tics months, the onset of tics must be before the age of 18 (Bloch et al. 2006, Spencer et al. 1999). years, and other causes of tics, such as substance In addition to tics, many patients with GTS exhibit intoxication or general medical condition have to be a variety of mental disorders and behavioral symptoms excluded (American Psychiatric Association 2000). such as attention deficit hyperactivity disorder (ADHD), The anatomical location, number, frequency, complex- obsessive compulsive disorder (OCD), poor impulse control, conduct disorder, oppositional defiant disor- Correspondence should be addressed to P. Janik der, anxiety, depression, temper outbursts, rage attacks, Email: [email protected] self-injuries, and inappropriate sexual behavior (Janik Received 04 February 2013, accepted 10 February 2014 et al. 2007). Similarly to tics, symptoms of ADHD and © 2014 by Polish Neuroscience Society - PTBUN, Nencki Institute of Experimental Biology Polymorphisms of the BTBD9 gene in GTS 219 OCD may fluctuate over time. ADHD usually occurs also influence the metabolism of iron. Some such vari- before the tic onset. Hyperactivity symptoms generally ants may reduce the iron content in the ventral mid- improve during adolescence, whereas inattention brain (Jones et al. 2003), which is consistent with lower symptoms often persist into adulthood (Faraone et al. ferritin and serum iron levels in patients with GTS 2006). OCD has an onset around the time the tics reach (Gorman et al. 2006). their worst-ever intensity, but symptoms may also Riviere and colleagues (2009) have reported three appear de novo during adolescence and early adult- intronic SNPs (rs4714156, rs9296249, rs9357271) with- hood (Bloch et al. 2006). in the BTBD9 gene associated with GTS in the French The worldwide prevalence of GTS has been reported Canadian population. Another study that examined the to be about 1% of all children between the age of 5 and association between variants of the BTBD9 gene and 18 (Robertson 2008) and ten times less in adults due to GTS has revealed that only the rs9296249 variant, but the natural course of tics (Burd et al. 1986). Many not rs4714156 or rs9357271, is associated with GTS in patients with GTS do not require treatment for their the Chinese Han population (Guo et al. 2012). tics, since they do not interfere with daily life. Some The aim of this study was to further analyze three patients with very mild tics are not even aware of being SNPs of the BTBD9 gene rs4714156, rs9296249, and ill. Indeed, only a minority of individuals with tics rs9357271, that showed an association with GTS in the seek medical advice (Robertson 2008). Thus, despite population mentioned, and to determine whether they the relatively high prevalence of GTS in the general could be involved in the etiology of GTS in Polish population the disorder is considered rare in the clini- patients. cal setting. The etiology of GTS remains unknown, although a METHODS significant contribution of genetic factors has been established. The failure of family and candidate gene Study participants studies to identify a precise linkage with GTS has led investigators to examine polymorphism associations. The cohort of GTS cases comprised 162 patients Numerous independent studies in different popula- aged 4–54 years (mean age: 19.9±8.7 years; 131 tions have sought to identify GTS-associated single males (80.9%), 75 children and 87 adult patients nucleotide polymorphisms (SNPs) in many genes. defined as ≥18 years, 53.7%). The family history Recently, variants of the BTBD9 gene (OMIM 611237) was positive in 80 (49.7%) patients, and was un k nown have been reported to be associated with restless legs for one patient. The mean age of tic onset was syndrome and GTS (Winkelmann et al. 2007, Riviere 7.5±3.2 years. 125 (77.2%) patients had at least one et al. 2009, Guo et al. 2012). The BTBD9 gene, coding of the following comorbidities: ADHD n=63 (38.9%), for BTB/POZ domain-containing protein, maps on OCD/OCB n=70 (43.2%), Learning Disorder n=51 chromosome 6 at 6p21, and is highly expressed in the (31.5%), Mood Disorder n=25 (15.4%), Anxiety amygdale, cerebellum, hippocampus, and caudate and Disorder n=34 (21.0%), Conduct Disorder n=12 subthalamic nuclei, as well as outside the brain, in the (7.4%), while 37 (22.8%) had no comorbid mental heart, kidneys, pancreas, and liver. Eight alternative disorders. None of the GTS patients included into BTBD9 transcripts have been described, resulting in the study had symptoms of restless legs syndrome. seven protein isoforms, 92-612 amino acids long. The As a control group we enrolled 180 unrelated, ethni- BTB/POZ domain is a known protein–protein interac- cally and gender matched individuals with no diag- tion motif, but the function of the protein remains nosed mental, neurological or general disorder, aged largely unknown. Other proteins containing the BTB/ 14–55 years (mean age: 23.1±2.1 years; 149 males, POZ domain function in transcription repression, 82.8%). The patients were evaluated for the clinical cytoskeleton regulation, tetramerization, gating of ion diagnosis of GTS and comorbid mental disorders channels, and ubiquitin-dependent protein degradation according to DSM-IV-TR (American Psychiatric (Stogios et al. 2005). The molecular nature of the Association 2000). Obsessive Compulsive Behavior BTBD9 protein and the universal occurrence of the (OCB) was diagnosed when obsessions and compul- domain in question make the assignment of a specific sions were present but did not meet the criteria of function difficult at present. The BTBD9 variants may DSM-IV-TR. 220 P. Janik et al. Table I Frequencies of haplotypes derived from three BTBD9 SNPs Number Frequency GTS vs. Control Haplotypea GTS Control GTS Control Chi2 Pb TTC 262 282 0.81 0.78 0.671 0.413 CCT 59 74 0.18 0.21 0.599 0.439 CCC 3 4 0.01 0.01 0.058 0.810 (GTS) Gilles de la Tourette syndrome; (SNPs) single nucleotide polymorphisms. aHaplotype includes 3 loci in order: rs9357271-rs9296249-rs4714156, bchi-square test. Assessment of tic severity with age of tic onset was analyzed with Kruskal- Wallis test. Haploview 4.2 program was used for hap- The tic severity was determined retrospectively lotype analysis and Statistica 10 for other calculations. based on reports from parents or patients and defined The significance level was set at P<0.05. descriptively as mild, moderate or intensive. Mild tics were diagnosed if they were not related to physical or RESULTS mental discomfort, problems in relations with peers, lower-than-expected academic achievements or a need Genotypic and allelic association analysis of treatment.
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