MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus.

Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms "mental retardation". To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus.

Creaming in black tea.

Tea cream is the precipitate formed as tea cools. Its formation has been studied by X-ray scattering, and it is shown that a higher tea concentration leads to earlier onset of creaming and larger particles and that addition of theaflavin and calcium promotes creaming. Association constants between the major components of black tea have been obtained using NMR and show that calcium and glucose enhance the self-association of caffeine, polyphenols, and theaflavin but have little effect on hetero-association. Glycosylation of a polyphenol reduced self-association and reduced binding to caffeine. We conclude that theaflavin is important for the initiation of creaming, forming nanoclusters of typically 3 nm diameter, whereas caffeine acts more to fill in the gaps within the clusters and thus adds to the bulk of tea cream without being necessary for its initiation. Tea creaming may be reduced by increasing the solubility of the polyphenols (i.e., by glycosylation) or by removing calcium. Tea cream; theaflavin; caffeine; small-angle X-ray scattering; NMR; colloid.

Polyphenol/peptide binding and precipitation.

Polyphenols are largely responsible for the astringency and "mouthfeel" of tea and wine by their interactions with basic salivary proline-rich proteins. Astringency arises from precipitation of polyphenol/peptide complexes, which is an important protective mechanism in animals that consume polyphenols. This paper presents biophysical studies of the interactions between chemically defined polyphenols and peptides. It is shown that intermolecular binding is dominated by stacking of polyphenolic rings onto planar hydrophobic surfaces and is strengthened by multiple cooperative binding of polyphenolic rings. Affinities weaken at higher temperatures and are unaffected by pH between pH 3.8 and 6.0. Measurements of self-diffusion rates for peptides with increasing concentrations of polyphenol demonstrate that peptides become increasingly coated with polyphenol. When the coating is sufficiently extensive to provide cooperative polyphenol bridges, the peptide dimerizes and precipitates. Light scattering measurements and electron microscopy indicate that the insoluble particles fall into two discrete size classes of ca. 80 and 500 nm diameter. The larger particles are favored at higher temperature and pH, suggesting that the particles are in a colloidal state, with the smaller particles being stabilized by charge repulsion between particles, and that precipitation of the complexes may be a phase separation process.