Germline DDX41 mutations cause ineffective hematopoiesis and myelodysplasia

DDX41 mutations are the most common germline alterations in adult myelodysplastic syndromes (MDSs). The majority of affected individuals harbor germline monoallelic frameshift DDX41 mutations and subsequently acquire somatic mutations in their other DDX41 allele, typically missense R525H. Hematopoietic progenitor cells (HPCs) with biallelic frameshift and R525H mutations undergo cell cycle arrest and apoptosis, causing bone marrow failure in mice. Mechanistically, DDX41 is essential for small nucleolar RNA (snoRNA) processing, ribosome assembly, and protein synthesis. Although monoallelic DDX41 mutations do not affect hematopoiesis in young mice, a subset of aged mice develops features of MDS. Biallelic mutations in DDX41 are observed at a low frequency in non-dominant hematopoietic stem cell clones in bone marrow (BM) from individuals with MDS. Mice chimeric for monoallelic DDX41 mutant BM cells and a minor population of biallelic mutant BM cells develop hematopoietic defects at a younger age, suggesting that biallelic DDX41 mutant cells are disease modifying in the context of monoallelic DDX41 mutant BM

The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases

The Ca2+-sensing receptor (CaSR) is a dimeric family C G protein-coupled receptor that is expressed in calcitropic tissues such as the parathyroid glands and the kidneys and signals via G proteins and β-arrestin. The CaSR has a pivotal role in bone and mineral metabolism, as it regulates parathyroid hormone secretion, urinary Ca2+ excretion, skeletal development and lactation. The importance of the CaSR for these calcitropic processes is highlighted by loss-of-function and gain-of-function CaSR mutations that cause familial hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, respectively, and also by the fact that alterations in parathyroid CaSR expression contribute to the pathogenesis of primary and secondary hyperparathyroidism. Moreover, the CaSR is an established therapeutic target for hyperparathyroid disorders. The CaSR is also expressed in organs not involved in Ca2+ homeostasis: it has noncalcitropic roles in lung and neuronal development, vascular tone, gastrointestinal nutrient sensing, wound healing and secretion of insulin and enteroendocrine hormones. Furthermore, the abnormal expression or function of the CaSR is implicated in cardiovascular and neurological diseases, as well as in asthma, and the CaSR is reported to protect against colorectal cancer and neuroblastoma but increase the malignant potential of prostate and breast cancers

Population-scale sequencing reveals genetic differentiation due to local adaptation in Atlantic herring

The Atlantic herring (Clupea harengus), one of the most abundant marine fishes in the world, has historically been a critical food source in Northern Europe. It is one of the few marine species that can reproduce throughout the brackish salinity gradient of the Baltic Sea. Previous studies based on few genetic markers have revealed a conspicuous lack of genetic differentiation between geographic regions, consistent with huge population sizes and minute genetic drift. Here, we present a cost-effective genome-wide study in a species that lacks a genome sequence. We first assembled a muscle transcriptome and then aligned genomic reads to the transcripts, creating an “exome assembly,” capturing both exons and flanking sequences. We then resequenced pools of fish from a wide geographic range, including the Northeast Atlantic, as well as different regions in the Baltic Sea, aligned the reads to the exome assembly, and identified 440,817 SNPs. The great majority of SNPs showed no appreciable differences in allele frequency among populations; however, several thousand SNPs showed striking differences, some approaching fixation for different alleles. The contrast between low genetic differentiation at most loci and striking differences at others implies that the latter category primarily reflects natural selection. A simulation study confirmed that the distribution of the fixation index F(ST) deviated significantly from expectation for selectively neutral loci. This study provides insights concerning the population structure of an important marine fish and establishes the Atlantic herring as a model for population genetic studies of adaptation and natural selection

Long-Term Weight-Loss in Gastric Bypass Patients Carrying Melanocortin 4 Receptor Variants

<div><p>Background</p><p>The melanocortin 4 receptor (MC4R) critically regulates feeding and satiety. Rare variants in <i>MC4R</i> are predominantly found in obese individuals. Though some rare variants in <i>MC4R</i> discovered in patients have defects in localization, ligand binding and signaling to cAMP, many have no recognized defects.</p><p>Subjects/Methods</p><p>In our cohort of 1433 obese subjects that underwent Roux-en-Y Gastric Bypass (RYGB) surgery, we found fifteen variants of <i>MC4R</i>. We matched rare variant carriers to patients with the <i>MC4R</i> reference alleles for gender, age, starting BMI and T2D to determine the variant effect on weight-loss post-RYGB. <i>In vitro</i>, we determined expression of mutant receptors by ELISA and western blot, and cAMP production by microscopy.</p><p>Results</p><p>While carrying a rare <i>MC4R</i> allele is associated with obesity, carriers of rare variants exhibited comparable weight-loss after RYGB to non-carriers. However, subjects carrying three of these variants, <i>V95I</i>, <i>I137T</i> or <i>L250Q</i>, lost less weight after surgery. <i>In vitro</i>, the R305Q mutation caused a defect in cell surface expression while only the I137T and C326R mutations showed impaired cAMP signaling. Despite these apparent differences, there was no correlation between <i>in vitro</i> signaling and pre- or post-surgery clinical phenotype.</p><p>Conclusions</p><p>These data suggest that subtle differences in receptor signaling conferred by rare <i>MC4R</i> variants combined with additional factors predispose carriers to obesity. In the absence of complete <i>MC4R</i> deficiency, these differences can be overcome by the powerful weight-reducing effects of bariatric surgery. In a complex disorder such as obesity, genetic variants that cause subtle defects that have cumulative effects can be overcome after appropriate clinical intervention.</p></div

BMIs of patients with rare variants only found in obese populations.

<p>The pre-surgery BMIs of patients with rare variants were matched with non-carrier patients of the same gender, T2D status, insulin medication status and similar age (within 5 years) (black symbols). The variant carrier's age, sex and T2D status is also listed (○). *The starting BMI range for the matched patient was extended to ±2.</p

Clinical variables for Roux-en Y gastric bypass patients with rare <i>MC4R</i> variants.

<p>Non-carrier patients are separated into non-diabetics, type 2 diabetics (T2D) and T2Ds taking insulin. Pre-surgery BMIs and blood pressure are reported as three month averages. No data were collected after surgery for the S4F (denoted ¶).</p><p>*The total number of patients differ in the six month remission data because those patients that did not have enough follow-up data collected were excluded from analysis (T2D-25 patients, T2D insulin dependent-9 patients).</p