[Exome sequencing revealed Allan-Herndon-Dudley syndrome underlying multiple disabilities]. / Monivammaisuuden taustalla Allan-Herndon-Dudleyn oireyhtymä.

Normal function of the thyroid gland is the cornerstone of a child's mental development and physical growth. We describe a Finnish family, in which the diagnosis of three brothers became clear after investigations that lasted for more than 30 years. Two of the sons have already died. DNA analysis of the third one, a 16-year-old boy, revealed in exome sequencing of the complete X chromosome a mutation in the SLC16A2 gene, i.e. MCT8, coding for a thyroid hormone transport protein. Allan-Herndon-Dudley syndrome was thus shown to be the cause of multiple disabilities.

Music-listening regulates human microRNA expression.

Music-listening and performance have been shown to affect human gene expression. In order to further elucidate the biological basis of the effects of music on the human body, we studied the effects of music-listening on gene regulation by sequencing microRNAs of the listeners (Music Group) and their controls (Control Group) without music exposure. We identified upregulation of six microRNAs (hsa-miR-132-3p, hsa-miR-361-5p, hsa-miR-421, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-25-3p) and downregulation of two microRNAs (hsa-miR-378a-3p, hsa-miR-16-2-3p) in Music Group with high musical aptitude. Some upregulated microRNAs were reported to be responsive to neuronal activity (miR-132, miR-23a, miR-23b) and modulators of neuronal plasticity, CNS myelination, and cognitive functions like long-term potentiation and memory. miR-132 plays a critical role in regulating TAU protein levels and is important for preventing tau protein aggregation that causes Alzheimer's disease. miR-132 and DICER, upregulated after music-listening, protect dopaminergic neurons and are important for retaining striatal dopamine levels. Some of the transcriptional regulators (FOS, CREB1, JUN, EGR1, and BDNF) of the upregulated microRNAs were immediate early genes and top candidates associated with musical traits. BDNF and SNCA, co-expressed and upregulated in music-listening and music-performance, are both are activated by GATA2, which is associated with musical aptitude. Several miRNAs were associated with song-learning, singing, and seasonal plasticity networks in songbirds. We did not detect any significant changes in microRNA expressions associated with music education or low musical aptitude. Our data thereby show the importance of inherent musical aptitude for music appreciation and for eliciting the human microRNA response to music-listening.

Music-performance regulates microRNAs in professional musicians.

Musical training and performance require precise integration of multisensory and motor centres of the human brain and can be regarded as an epigenetic modifier of brain functions. Numerous studies have identified structural and functional differences between the brains of musicians and non-musicians and superior cognitive functions in musicians. Recently, music-listening and performance has also been shown to affect the regulation of several genes, many of which were identified in songbird singing. MicroRNAs affect gene regulation and studying their expression may give new insights into the epigenetic effect of music. Here, we studied the effect of 2 hours of classical music-performance on the peripheral blood microRNA expressions in professional musicians with respect to a control activity without music for the same duration. As detecting transcriptomic changes in the functional human brain remains a challenge for geneticists, we used peripheral blood to study music-performance induced microRNA changes and interpreted the results in terms of potential effects on brain function, based on the current knowledge about the microRNA function in blood and brain. We identified significant (FDR <0.05) up-regulation of five microRNAs; hsa-miR-3909, hsa-miR-30d-5p, hsa-miR-92a-3p, hsa-miR-222-3p and hsa-miR-30a-5p; and down-regulation of two microRNAs; hsa-miR-6803-3p and hsa-miR-1249-3p. hsa-miR-222-3p and hsa-miR-92a-3p putatively target FOXP2, which was found down-regulated by microRNA regulation in songbird singing. miR-30d and miR-222 corroborate microRNA response observed in zebra finch song-listening/learning. miR-222 is induced by ERK cascade, which is important for memory formation, motor neuron functions and neuronal plasticity. miR-222 is also activated by FOSL1, an immediate early gene from the FOS family of transcriptional regulators which are activated by auditory-motor stimuli. miR-222 and miR-92 promote neurite outgrowth by negatively regulating the neuronal growth inhibitor, PTEN, and by activating CREB expression and phosphorylation. The up-regulation of microRNAs previously found to be regulators of auditory and nervous system functions (miR-30d, miR-92a and miR-222) is indicative of the sensory perception processes associated with music-performance. Akt signalling pathway which has roles in cell survival, cell differentiation, activation of CREB signalling and dopamine transmission was one of the functions regulated by the up-regulated microRNAs; in accordance with functions identified from songbird learning. The up-regulated microRNAs were also found to be regulators of apoptosis, suggesting repression of apoptotic mechanisms in connection with music-performance. Furthermore, comparative analyses of the target genes of differentially expressed microRNAs with that of the song-responsive microRNAs in songbirds suggest convergent regulatory mechanisms underlying auditory perception.

The effect of listening to music on human transcriptome.

Although brain imaging studies have demonstrated that listening to music alters human brain structure and function, the molecular mechanisms mediating those effects remain unknown. With the advent of genomics and bioinformatics approaches, these effects of music can now be studied in a more detailed fashion. To verify whether listening to classical music has any effect on human transcriptome, we performed genome-wide transcriptional profiling from the peripheral blood of participants after listening to classical music (n = 48), and after a control study without music exposure (n = 15). As musical experience is known to influence the responses to music, we compared the transcriptional responses of musically experienced and inexperienced participants separately with those of the controls. Comparisons were made based on two subphenotypes of musical experience: musical aptitude and music education. In musically experiencd participants, we observed the differential expression of 45 genes (27 up- and 18 down-regulated) and 97 genes (75 up- and 22 down-regulated) respectively based on subphenotype comparisons (rank product non-parametric statistics, pfp 0.05, >1.2-fold change over time across conditions). Gene ontological overrepresentation analysis (hypergeometric test, FDR < 0.05) revealed that the up-regulated genes are primarily known to be involved in the secretion and transport of dopamine, neuron projection, protein sumoylation, long-term potentiation and dephosphorylation. Down-regulated genes are known to be involved in ATP synthase-coupled proton transport, cytolysis, and positive regulation of caspase, peptidase and endopeptidase activities. One of the most up-regulated genes, alpha-synuclein (SNCA), is located in the best linkage region of musical aptitude on chromosome 4q22.1 and is regulated by GATA2, which is known to be associated with musical aptitude. Several genes reported to regulate song perception and production in songbirds displayed altered activities, suggesting a possible evolutionary conservation of sound perception between species. We observed no significant findings in musically inexperienced participants.

The effect of music performance on the transcriptome of professional musicians.

Music performance by professional musicians involves a wide-spectrum of cognitive and multi-sensory motor skills, whose biological basis is unknown. Several neuroscientific studies have demonstrated that the brains of professional musicians and non-musicians differ structurally and functionally and that musical training enhances cognition. However, the molecules and molecular mechanisms involved in music performance remain largely unexplored. Here, we investigated the effect of music performance on the genome-wide peripheral blood transcriptome of professional musicians by analyzing the transcriptional responses after a 2-hr concert performance and after a 'music-free' control session. The up-regulated genes were found to affect dopaminergic neurotransmission, motor behavior, neuronal plasticity, and neurocognitive functions including learning and memory. Particularly, candidate genes such as SNCA, FOS and DUSP1 that are involved in song perception and production in songbirds, were identified, suggesting an evolutionary conservation in biological processes related to sound perception/production. Additionally, modulation of genes related to calcium ion homeostasis, iron ion homeostasis, glutathione metabolism, and several neuropsychiatric and neurodegenerative diseases implied that music performance may affect the biological pathways that are otherwise essential for the proper maintenance of neuronal function and survival. For the first time, this study provides evidence for the candidate genes and molecular mechanisms underlying music performance.

X-exome sequencing in Finnish families with intellectual disability--four novel mutations and two novel syndromic phenotypes.

BACKGROUND: X-linked intellectual disability (XLID) is a group of genetically heterogeneous disorders characterized by substantial impairment in cognitive abilities, social and behavioral adaptive skills. Next generation sequencing technologies have become a powerful approach for identifying molecular gene mutations relevant for diagnosis. METHODS & OBJECTIVES: Enrichment of X-chromosome specific exons and massively parallel sequencing was performed for identifying the causative mutations in 14 Finnish families, each of them having several males affected with intellectual disability of unknown cause. RESULTS: We found four novel mutations in known XLID genes. Two mutations; one previously reported missense mutation (c.1111C > T), and one novel frameshift mutation (c. 990_991insGCTGC) were identified in SLC16A2, a gene that has been linked to Allan-Herndon-Dudley syndrome (AHDS). One novel missense mutation (c.1888G > C) was found in GRIA3 and two novel splice donor site mutations (c.357 + 1G > C and c.985 + 1G > C) were identified in the DLG3 gene. One missense mutation (c.1321C > T) was identified in the candidate gene ZMYM3 in three affected males with a previously unrecognized syndrome characterized by unique facial features, aortic stenosis and hypospadia was detected. All of the identified mutations segregated in the corresponding families and were absent in > 100 Finnish controls and in the publicly available databases. In addition, a previously reported benign variant (c.877G > A) in SYP was identified in a large family with nine affected males in three generations, who have a syndromic phenotype. CONCLUSIONS: All of the mutations found in this study are being reported for the first time in Finnish families with several affected male patients whose etiological diagnoses have remained unknown to us, in some families, for more than 30 years. This study illustrates the impact of X-exome sequencing to identify rare gene mutations and the challenges of interpreting the results. Further functional studies are required to confirm the cause of the syndromic phenotypes associated with ZMYM3 and SYP in this study.

Evaluation of non-invasive prenatal RHD genotyping of the fetus.

OBJECTIVE: To evaluate a non-invasive molecular test using free circulating fetal DNA in maternal plasma to predict the fetal RHD type. DESIGN: A prospective cohort study. PARTICIPANTS AND SETTING: Venous blood samples were collected from 140 Rhesus (Rh) D-negative women booked for antenatal care in two tertiary maternity hospitals in Sydney and Brisbane between November 2006 and April 2008. Cell-free DNA, including free maternal and fetal DNA, was extracted from maternal plasma in the tertiary Australian Red Cross Blood Service laboratory, and three exon regions of the RHD gene were amplified. MAIN OUTCOME MEASURES: Comparison of the predicted fetal RHD status and the infant's RhD serotype. Secondary analysis involved using SRY and RASSF1A assays as internal controls to confirm the presence of fetal DNA in RHD-negative samples. RESULTS: Of 140 samples tested, results for RHD status were assigned for 135, and all 135 predictions were correct. A result was not assigned in five cases: three did not meet strict threshold criteria for classification, and two were due to RHD variants. Fetal SRY status was correctly predicted in 137 of 140 cases. In 16 samples typed both RHD- and SRY-negative, a positive RASSF1A result verified the presence of fetal DNA. CONCLUSIONS: Non-invasive testing of multiple exons provides a robust method of assessing fetal RHD status, and provides a safer alternative to amniocentesis for the management of RhD-negative pregnant women who are isoimmunised.