Cerebellar Agenesis and Bilateral Polimicrogyria Associated with Rare Variants of CUB and Sushi Multiple Domains 1 Gene (CSMD1): A Longitudinal Neuropsychological and Neuroradiological Case Study.

Cerebellar agenesis is an extremely rare condition characterized by a near complete absence of the cerebellum. The pathogenesis and molecular basis remain mostly unknown. We report the neuroradiological, molecular, neuropsychological and behavioral characterization of a 5-year-old girl, with cerebellar agenesis associated with parietal and peri-Sylvian polymicrogyria, followed-up for 10 years at four time points. Whole exome sequencing identified two rare variants in CSMD1, a gene associated with neurocognitive and psychiatric alterations. Mild intellectual impairment, cerebellar ataxia and deficits in language, memory and executive functions, with relatively preserved adaptive and psychopathological domains, were initially showed. Phonological awareness and verbal memory declined at 11 years of age, and social and anxiety problems emerged. Adaptive and psychopathological characteristics dramatically worsened at 15 years. In summary, the developmental clinical outcome showed impairment in multiple cognitive functions in childhood, with a progressive decline in cognitive and adaptive abilities and the emergence of psychopathological symptoms in adolescence. The observed phenotype could be the result of a complex interplay between cerebellar abnormality, brain malformation and the relations with CSMD1 variants. These findings may provide insights into the developmental clinical outcomes of a co-occurrence between rare brain malformation and rare genetic variants associated to neurodevelopmental disorders.

Relationship between CSMD1 gene polymorphism and schizophrenia and cognitive function / 中华行为医学与脑科学杂志

Objective:To explore the relevance of the three polymorphic loci in the CUB and SUSHI multiple domains 1(CSMD1) gene with schizophrenia and its cognitive function.Methods:Polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP) was used to detect CSMD1 gene polymorphism in 109 schizophrenia patients(case group) and 109 healthy controls(control group), and the cognitive function was evaluated by Montreal cognitive assessment (MoCA). The allele and genotype frequencies between the case group and the control group were statistically analyzed by SPSS 19.0 software.Results:(1)There were significant differences in the distribution of genotype AA, AC, CC (case group: AA, 51(46.79%), AC, 43(39.45%), CC, 15(13.76%); control group: AA, 22(20.18%), AC, 58(53.21%), CC, 29(26.61%), χ2 =18.203, P<0.001) and allele frequencies (case group: A, 145 (66.51%), C, 73 (33.49%); control group: A, 102(46.79%), C, 116(53.21%), χ2=17.269, P<0.001, OR=0.443, 95% CI: 0.301-0.652) at rs10503253 loci between the case group and the control group.(2) Differences in allele frequencies at the rs10503253 loci were associated with the visual space and executive dysfunction in the case group ( χ2=6.470, P=0.011, OR=2.089, 95% CI: 1.179-3.702). (3) Differences in allele frequencies at the rs17405197 loci were associated with language dysfunction in the case group ( χ2=9.468, P=0.002, OR=0.415, 95% CI: 0.235-0.731). (4) Differences in allele frequencies at the rs2740931 loci were associated with language dysfunction in the case group ( χ2=5.094, P=0.024, OR=2.016, 95% CI: 1.091-3.726). Conclusion:CSMD1 gene polymorphism may be a risk factor for the onset of schizophrenia, associated with symptoms of cognitive dysfunction in schizophrenia.

Genome-Wide Association Study of Smoking Behavior Traits in a Chinese Han Population.

Tobacco use is one of the leading causes of preventable disease worldwide. Genetic studies have elucidated numerous smoking-associated risk loci in American and European populations. However, genetic determinants for cigarette smoking in Chinese populations are under investigated. In this study, a whole-genome sequencing (WGS)-based genome-wide association study (GWAS) was performed in a Chinese Han population comprising 620 smokers and 564 nonsmokers. Thirteen single-nucleotide polymorphisms (SNPs) of the raftlin lipid linker 1 (RFTN1) gene achieved genome-wide significance levels (P < 5 x 10-8) for smoking initiation. The rs139753473 from RFTN1 and six other suggestively significant loci from CUB and sushi multiple domains 1 (CSMD1) gene were also associated with cigarettes per day (CPD) in an independent Chinese sample consisting of 1,329 subjects (805 smokers and 524 nonsmokers). When treating males separately, associations between smoking initiation and PCAT5/ANKRD30A, two genes involved in cancer development, were identified and replicated. Within RFTN1, two haplotypes (i.e., C-A-C-G and A-G-T-C) formed by rs796812630-rs796584733-rs796349027-rs879511366 and three haplotypes (i.e., T-T-C-C-C, T-T-A-T-T, and C-A-A-T-T) formed by rs879401109-rs879453873-rs75180423-rs541378415-rs796757175 were strongly associated with smoking initiation. In addition, we also revealed two haplotypes (i.e., C-A-G-G and T-C-T-T derived from rs4875371-rs4875372-rs17070935-rs11991366) in the CSMD1 gene showing a significant association with smoking initiation. Further bioinformatics functional assessment suggested that RFTN1 may participate in smoking behavior through modulating immune responses or interactions with the glucocorticoid receptor alpha and the androgen receptor. Together, our results may help understand the mechanisms underlying smoking behavior in the Chinese Han population.

Immunohistochemical Study of Psoriasis-related Gene Expression in Imiquimod-induced Psoriasis-like Mouse Model / 대한피부과학회지

BACKGROUND: Psoriasis is a chronic inflammatory skin disease with an incidence of 0.5~3% of the worldwide population. The pathogenesis of psoriasis is related to dysregulated keratinocyte function and immune reactions. Notably, genetic factors are considered important etiological contributors. Globally, several researchers have recently performed genome-wide association studies (GWAS) to identify the genes related with psoriasis. OBJECTIVE: We aimed to investigate the expression pattern of 2 candidate genes that were identified by GWAS. These include interleukin 28 receptor alpha (IL28RA) and CUB and Sushi multiple domains 1 (CSMD1). METHODS: We applied imiquimod cream to develop a psoriasis-like mouse model and obtained skin tissue. We performed immunohistochemistry to detect the expression of IL-28A and CSMD1. RESULTS: IL28RA expression increased at an early time point such as 1 day after the topical application of 5% imiquimod cream. However, its expression returned to baseline levels 2 weeks after the topical application of imiquimod cream. CSMD1 expression also increased after the topical application of imiquimod, with increased expression particularly observed in the upper epidermal layer. Notably, CSMD1 expression decreased 7 days after imiquimod cream application. CONCLUSION: These results suggest that IL28RA and CSMD1 may play key roles in the pathogenesis of psoriasis.