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Human Genetics and Clinical Genetics

Research Topics

Cryptic Rearrangements of the Pseudo-Autosomal Region 1

Cryptic rearrangements of the genome are structural aberrations of chromosomes (deletions, duplications, translocations) that are not detectable by classical cytogenetic methods (cytogenetic banding), meaning they have less than 3 - 5 Mb in length. They can be revealed by molecular genetic methods such as array-CGH (microarrays) or MLPA (multiplex ligation-dependent amplification). Cryptic abberations may be the cause of complex disorders including mental retardation and body and facial malformations or dysmorphies. Mostly these are so-called "microdeletion syndromes” where several neighboring genes are heterozygously lost and the absence of each of them is then responsible for part of a pathological phenotype (so-called contiguous gene syndromes). However, the consequence can also be the hemizygous loss of only one gene or its part.

In our lab, we mainly focus on rearrangements of the pseudo-autosomal region 1 (PAR1 region of sex chromosomes), especially the SHOX gene region which encodes an important transcription factor regulating the growth of long bones, and whose aberrations are the cause of some types of bone dysplasia. As a result of loss of one allele of the SHOX gene, Léri-Weill syndrome (dyschondrosteosis) occurs, whereas loss of both alleles leads to Langer syndrome. Mutations of the SHOX gene are also found in a small fraction of patients with an idiopathic small stature. In coding and non-coding regions of the gene and its adjacent regulatory sequences, there are a number of point and structural mutations that may have a pathogenic effect, but can also be a normal part of the variability of the human genome. While the clinical significance of most deletions and point mutations is known, a very different situation exists in case of duplications. Duplications are found significantly more rarely than deletions and there is a lot of controversy about their clinical significance, which is one of the reasons for our recent research focus on duplication in the SHOX gene, especially in both its known and hypothetical regulatory regions.

This research is carried out in cooperation with Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague.

 

Genetics of Circadian Rhythms

Each person has "biological clocks" which mediate biorhythms and thus periodically change internal metabolic processes within a certain time period (day, year, etc.). Biorhythms with period of approximately 24 hours (circa-dial, "approximately daily") alternate in particular periods of activity and rest, and their synchronization takes place in response to a change of light and darkness (day and night). It can be said that on average, the activity period corresponds to the bright day and the rest period to the night - however, in particular settings, these rhythms can be characterized by a high degree of individual variability. There are people with so-called extreme chronotypes, i.e. people who have a significant period of activity in the early morning hours (“early birds”), or late in the evening ("night owls"). On the molecular level, circadian rhythms are caused by periodic changes in gene transcription and enzymatic activity - loops in which so-called "clock genes" are significantly involved. Polymorphisms of these genes can therefore play a role in setting the individual rhythms.

In our research, we focus on people with extreme chronotypes (both early and late types), and we perform genotyping of four polymorphisms in four clock genes (CLOCK, BMAL1, PER2, PER3) that are suspected of playing significant role in individual biorhythms. We then look for a connection between the genotype and the chronotype (determined according to the standardized MEQ score) and between genotype and physical and cognitive performance in the preferred ("early birds" early in the morning and “night owls” late in the evening) and unpreferred ("early birds" late in the evening and "night owls" early in the morning) time periods of the day.

Research in still at the level of pilot studies and is carried out in cooperation with Department of Physiology, Faculty of Science, Charles University and National Institute of Mental Health.

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