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The clusterin ( CLU ) rs11136000 CC genotype is a probable risk factor for Alzheimer's disease (AD). CLU , also known as the apolipoprotein J gene, shares certain properties with the apolipoprotein E ( APOE ) gene with a well-established relationship with AD. This study aimed to determine whether the electrophysiological patterns of brain activation during the letter fluency task (LFT) depend on CLU genotypes in adults without dementia. Previous studies have shown that LFT performance involves activation of the frontal cortex. We examined EEG alpha1 and alpha2 band desynchronization in the frontal regions during the LFT in 94 nondemented individuals stratified by CLU (rs11136000) genotype. Starting at 30 years of age, CLU CC carriers exhibited more pronounced task-related alpha2 desynchronization than CLU CT&TT carriers in the absence of any differences in LFT performance. In CLU CC carriers, alpha2 desynchronization was significantly correlated with age. Increased task-related activation in individuals at genetic risk for AD may reflect greater "effort" to perform the task and/or neuronal hyperexcitability. The results show that the CLU genotype is associated with neuronal hyperactivation in the frontal cortex during cognitive tasks performances in nondemented individuals, suggesting systematic vulnerability of LFT related cognitive networks in people carrying unfavorable CLU alleles.

Metabotropic glutamate receptor 1 (mGluR1) plays a crucial role in slow excitatory postsynaptic conductance, synapse formation, synaptic plasticity, and motor control. The GRM1 gene is expressed mainly in the brain, with the highest expression in the cerebellum. Mutations in the GRM1 gene have previously been known to cause autosomal recessive and autosomal dominant spinocerebellar ataxias. In this study, whole-exome sequencing of a patient from a family of Azerbaijani origin with a diagnosis of congenital cerebellar ataxia was performed, and a new homozygous missense mutation in the GRM1 gene was identified. The mutation leads to the homozygous amino acid substitution of p.Thr824Arg in an evolutionarily highly conserved region encoding the transmembrane domain 7, which is critical for ligand binding and modulating of receptor activity. This is the first report in which a mutation has been identified in the last transmembrane domain of the mGluR1, causing a congenital autosomal recessive form of cerebellar ataxia with no obvious intellectual disability. Additionally, we summarized all known presumable pathogenic genetic variants in the GRM1 gene to date. We demonstrated that multiple rare variants in the GRM1 underlie a broad diversity of clinical neurological and behavioral phenotypes depending on the nature and protein topology of the mutation.

Bipedalism, speech, and intellect are the most prominent traits that emerged in the evolution of Homo sapiens . Here, we describe a novel genetic cause of an "involution" phenotype in four patients, who are characterized by quadrupedal locomotion, intellectual impairment, the absence of speech, small stature, and hirsutism, observed in a consanguineous Brazilian family. Using whole-genome sequencing analysis and homozygous genetic mapping, we identified genes bearing homozygous genetic variants and found a homozygous 36.2 kb deletion in the gene of glutamate receptor delta 2 ( GRID2 ) in the patients, resulting in the lack of a coding region from the fifth to the seventh exons. The GRID2 gene is highly expressed in the cerebellum cortex from prenatal development to adulthood, specifically in Purkinje neurons. Deletion in this gene leads to the loss of the alpha chain in the extracellular amino-terminal protein domain (ATD), essential in protein folding and transport from the endoplasmic reticulum (ER) to the cell surface. Then, we studied the evolutionary trajectories of the GRID2 gene. There was no sign of strong selection of the highly conservative GRID2 gene in ancient hominids (Neanderthals and Denisovans) or modern humans; however, according to in silico tests using the Mfold tool, the GRID 2 gene possibly gained human-specific mutations that increased the stability of GRID2 mRNA.

LINE-1 (L1) is a class of autonomous mobile genetic elements that form somatic mosaicisms in various tissues of the organism. The activity of L1 retrotransposons is strictly controlled by many factors in somatic and germ cells at all stages of ontogenesis. Alteration of L1 activity was noted in a number of diseases: in neuropsychiatric and autoimmune diseases, as well as in various forms of cancer. Altered activity of L1 retrotransposons for some pathologies is associated with epigenetic changes and defects in the genes involved in their repression. This review discusses the molecular genetic mechanisms of the retrotransposition and regulation of the activity of L1 elements. The contribution of various factors controlling the expression and distribution of L1 elements in the genome occurs at all stages of the retrotransposition. The regulation of L1 elements at the transcriptional, post-transcriptional and integration into the genome stages is described in detail. Finally, this review also focuses on the evolutionary aspects of L1 accumulation and their interplay with the host regulation system.