Biomedical subjects

Marcel Smits

Publications and source records attributed to Marcel Smits.

5 recordsLinked to original sources

PubMed2006

A silent polymorphism in the PER1 gene associates with extreme diurnal preference in humans.

The three PERIOD proteins form a major negative feedback component of the molecular mechanism governing the periodicity of the vertebrate circadian clock. Genetic variations within the human PER2 and PER3 genes have been linked with diurnal preference and disorders of sleep timing. We screened the coding region of PER1, as well as the 5'- and 3'-untranslated regions and the promoter region, for polymorphisms. The T2434C polymorphism in exon 18, a synonymous substitution, associated with extreme diurnal preference. The C allele was more frequent in subjects with extreme morning preference (frequency=0.24) than in subjects with extreme evening preference (frequency=0.12). No significant association was observed between either allele and delayed sleep phase syndrome. This polymorphism may have a direct effect on RNA translatability, or be in linkage disequilibrium with another polymorphism which affects PER1 expression at the DNA, RNA, or protein level. This is the first reported association between a PER1 polymorphism and extreme diurnal preference. Functionally important polymorphisms in PER1 are rare, which may indicate that it is subject to more stringent selection pressure than the other PER genes.

3' Untranslated Regions↗

PubMed2006

Dim light melatonin onset (DLMO): a tool for the analysis of circadian phase in human sleep and chronobiological disorders.

The circadian rhythm of melatonin in saliva or plasma, or of the melatonin metabolite 6-sulphatoxymelatonin (aMT6S) in urine, is a defining feature of suprachiasmatic nucleus (SCN) function, the endogenous oscillatory pacemaker. A substantial number of studies have shown that, within this rhythmic profile, the onset of melatonin secretion under dim light conditions (the dim light melatonin onset or DLMO) is the single most accurate marker for assessing the circadian pacemaker. Additionally, melatonin onset has been used clinically to evaluate problems related to the onset or offset of sleep. DLMO is useful for determining whether an individual is entrained (synchronized) to a 24-h light/dark (LD) cycle or is in a free-running state. DLMO is also useful for assessing phase delays or advances of rhythms in entrained individuals. Additionally, it has become an important tool for psychiatric diagnosis, its use being recommended for phase typing in patients suffering from sleep and mood disorders. More recently, DLMO has also been used to assess the chronobiological features of seasonal affective disorder (SAD). DLMO marker is also useful for identifying optimal application times for therapies such as bright light or exogenous melatonin treatment.

Animals↗

PubMed2006

Melatonin in mood disorders.

The cyclic nature of depressive illness, the diurnal variations in its symptomatology and the existence of disturbed sleep-wake and core body temperature rhythms, all suggest that dysfunction of the circadian time keeping system may underlie the pathophysiology of depression. As a rhythm-regulating factor, the study of melatonin in various depressive illnesses has gained attention. Melatonin can be both a 'state marker' and a 'trait marker' of mood disorders. Measurement of melatonin either in saliva or plasma, or of its main metabolite 6-sulfatoxymelatonin in urine, have documented significant alterations in melatonin secretion in depressive patients during the acute phase of illness. Not only the levels but also the timing of melatonin secretion is altered in bipolar affective disorder and in patients with seasonal affective disorder (SAD). A phase delay of melatonin secretion takes place in SAD, as well as changes in the onset, duration and offset of melatonin secretion. Bright light treatment, that suppresses melatonin production, is effective in treating bipolar affective disorder and SAD, winter type. This review discusses the role of melatonin in the pathophysiology of bipolar disorder and SAD.

Antidepressive Agents↗

PubMed2005

A single-nucleotide polymorphism in the 5'-untranslated region of the hPER2 gene is associated with diurnal preference.

The PERIOD2 (PER2) gene is a key component of the molecular mechanism that generates circadian rhythms in mammals. A missense mutation in the human PER2 gene has previously been linked to advanced sleep phase syndrome (ASPS). We have investigated three other single-nucleotide polymorphisms in the hPER2 gene, one downstream of the transcription start site (C-1228T), one in exon 2 in the 5'-untranslated region (5'-UTR) (C111G), and one missense mutation (G3853A) causing a glycine to glutamine substitution in the predicted protein. Subjects selected from a group of 484 volunteers for extreme morning or evening preference, or intermediate diurnal preference were genotyped with regard to the three polymorphisms (n=35 for each group). Whereas allele frequencies for the other two polymorphisms did not differ significantly between any of the groups, the 111G allele frequency was significantly higher in subjects with extreme morning preference (0.14) than in subjects with extreme evening preference (0.03) (Fisher's exact test, two-sided P value=0.031, odds ratio=5.67). No significant difference in 111G allele frequency was observed between either of these groups and subjects with intermediate diurnal preference. Computer prediction indicated that the C111G polymorphism, which occurs 12 bases upstream from the translation start codon, might alter the secondary structure of the transcript. The PER2 111G allele associates with morning preference and is a potential candidate allele for ASPS.

5' Untranslated Regions↗

PubMed2003

A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference.

STUDY OBJECTIVES: To investigate the link between extreme diurnal preference, delayed sleep phase syndrome, and a length polymorphism in Per3. DESIGN: Subjects were genotyped using polymerase chain reaction. PATIENTS OR PARTICIPANTS: Subjects with defined diurnal preference as determined by the Horne-Ostberg questionnaire and patients with delayed sleep phase syndrome. MEASUREMENTS AND RESULTS: The Per3 polymorphism correlated significantly with extreme diurnal preference, the longer allele associating with morningness and the shorter allele with eveningness. The shorter allele was strongly associated with the delayed sleep phase syndrome patients, 75% of whom were homozygous. CONCLUSION: The length of the Per3 repeat region identifies a potential genetic marker for extreme diurnal preference.

Adolescent↗