Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features

Sim1 haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain. In humans, abnormalities in chromosome 6q16, a region that includes SIM1, were reported in obese children with a Prader-Willi–like syndrome; however, SIM1 involvement in obesity has never been conclusively demonstrated. Here, SIM1 was sequenced in 44 children with Prader-Willi–like syndrome features, 198 children with severe early-onset obesity, 568 morbidly obese adults, and 383 controls. We identified 4 rare variants (p.I128T, p.Q152E, p.R581G, and p.T714A) in 4 children with Prader-Willi–like syndrome features (including severe obesity) and 4 other rare variants (p.T46R, p.E62K, p.H323Y, and p.D740H) in 7 morbidly obese adults. By assessing the carriers’ relatives, we found a significant contribution of SIM1 rare variants to intra-family risk for obesity. We then assessed functional effects of the 8 substitutions on SIM1 transcriptional activities in stable cell lines using luciferase gene reporter assays. Three mutations showed strong loss-of-function effects (p.T46R, p.H323Y, and p.T714A) and were associated with high intra-family risk for obesity, while the variants with mild or no effects on SIM1 activity were not associated with obesity within families. Our genetic and functional studies demonstrate a firm link between SIM1 loss of function and severe obesity associated with, or independent of, Prader-Willi–like features.Amélie Bonnefond, Anne Raimondo, Fanny Stutzmann, Maya Ghoussaini, Shwetha Ramachandrappa, David C. Bersten, Emmanuelle Durand, Vincent Vatin, Beverley Balkau, Olivier Lantieri, Violeta Raverdy, François Pattou, Wim Van Hul, Luc Van Gaal, Daniel J. Peet, Jacques Weill, Jennifer L. Miller, Fritz Horber, Anthony P. Goldstone, Daniel J. Driscoll, John B. Bruning, David Meyre, Murray L. Whitelaw and Philippe Frogue

Modulated structure of Ba6ZnIr4O15; a comparison with Ba6CuIr4O15 and SrMn1−xCoxO3−y

The new phase Ba6CuIr4O15 has been shown by powder X-ray diffraction to be a member of the perovskite-related structural family A3n+3A'nBn+3O6n+9 with n=1; space group R32, a=10.1196(3), c=13.4097(4) Å. The trigonal-prismatic A' sites and the octahedral B sites are both occupied by a disordered distribution of Ir and Cu. A combination of electron microscopy and X-ray diffraction has shown that Ba6ZnIr4O15 has a related incommensurate structure with a≈10.1, c≈4.4 Å and a modulation vector q=a*+0.35c*. Alternatively, Ba6ZnIr4O15 can be considered as a composite of trigonal (cell 1) and rhombohedral (cell 2) substructures with a1=a2=10.1228(9) c1=4.4099(6), c2=2.6982(2) Å. It is shown that the same structural formalism can be used to describe the incommensurate hexagonal phase of SrMn1−xCoxO3−y

Use of the 3D radon transform to examine the properties of oceanic Rossby waves

One of the most successful applications of satellite-borne radar altimeter data over the oceans in recent years has been the extraction of information about long-wavelength baroclinic Rossby (or planetary) waves, which play a significant role in ocean circulation and climate dynamics. These waves cross ocean basins from east to west at speeds of few centimetres per second at mid-latitudes. The cross-basin propagation time may therefore be several months or even years and an accurate estimation of the speed of the waves is important. We review the methods for obtaining information on Rossby wave velocity from altimetry data, particularly the two-dimensional Radon transform. Unfortunately the use of longitude-time plots, although it allows the estimation of the zonal phase speeds, does not give any information on the speed vector when the propagation of the waves is not purely zonal (east-west). We show how the two-dimensional Radon Transform can be generalised to three dimensions, enabling not only the true propagation velocity component to be determined, but also the direction of the waves and thus any deviation from the pure-westward case. As examples of the application of this extended technique, we show maps of direction, speed and energy of Rossby waves in the North Atlantic Ocean

Radiographic features of osteogenesis imperfecta

BACKGROUND: Osteogenesis imperfecta (OI), commonly called “brittle bone disease”, is a genetic disorder characterised by increased bone fragility and decreased bone density due to quantitative and/or qualitative abnormalities of type I collagen. Different types of OI exist, from mild to severe; they may lead to death, multiple bone fractures, skeletal deformity and short stature. METHODS: Severe cases are usually diagnosed before birth and may incite the parents to choose therapeutic abortion, whereas milder cases are much more difficult to diagnose and may be sometimes confused with non-accidental injury (NAI) (“child abuse”) in young children. Whatever the degree of severity, conventional radiography still remains the mainstay in diagnosing OI. RESULTS: The prognosis of this disorder has changed in the last few years thanks to biphosphonate therapy. CONCLUSION: The aim of this pictorial review is to illustrate the radiographic manifestations of OI, including in children receiving biphosphonates, and to outline specific patterns that help differentiate OI from NAI when necessary. KEY POINTS: • The main radiographic features of OI are osteopenia, bone fractures and bone deformities. • Some radiographic features depend on the type of OI or may be encountered with biphosphonates

Molecular analysis of thyroglobulin mutations found in patients with goiter and hypothyroidism

Thyroid dyshormonogenesis due to thyroglobulin (TG) gene mutations have an estimated incidence of approximately 1 in 100,000 newborns. The clinical spectrum ranges from euthyroid to mild or severe hypothyroidism. Up to now, one hundred seventeen deleterious mutations in the TG gene have been identified and characterized. The purpose of the present study was to identify and characterize new mutations in the TG gene. We report eight patients from seven unrelated families with goiter, hypothyroidism and low levels of serum TG. All patients underwent clinical, biochemical and image evaluation. Sequencing of DNA, genotyping, as well as bioinformatics analysis were performed. Molecular analyses revealed three novel inactivating TG mutations: c.5560G>T [p.E1835*], c.7084G>C [p.A2343P] and c.7093T>C [p.W2346R], and four previously reported mutations: c.378C>A [p.Y107*], c.886C>T [p.R277*], c.1351C>T [p.R432*] and c.7007G>A [p.R2317Q]. Two patients carried homozygous mutations (p.R277*/p.R277*, p.W2346R/p.W2346R), four were compound heterozygous mutations (p.Y107*/p.R277* (two unrelated patients), p.R432*/p.A2343P, p.Y107*/p.R2317Q) and two siblings from another family had a single p.E1835* mutated allele. Additionally, we include the analysis of 48 patients from 31 unrelated families with TG mutations identified in our present and previous studies. Our observation shows that mutations in both TG alleles were found in 27 families (9 as homozygote and 18 as heterozygote compound), whereas in the remaining four families only one mutated allele was detected. The majority of the detected mutations occur in exons 4, 7, 38 and 40. 28 different mutations were identified, 33 of the 96 TG alleles encoded the change p.R277*. In conclusion, our results confirm the genetic heterogeneity of TG defects and the pathophysiological importance of the predicted TG misfolding and therefore thyroid hormone formation as a consequence of truncated TG proteins and/or missense mutations located within its ACHE-like domain.This study was funded by grants from the FONCyT-ANPCyT-MINCyT (PICT 2014-1193 to CMR, PICT 2012-1090 and PICT 2015–1811 to HMT), CONICET (PIP 2015-11220150100499 to CMR) and Universidad de Buenos Aires (UBACyT 2016-20020150100099BA to CMR)

Allelic Variation Contributes to Bacterial Host Specificity

Understanding the molecular parameters that regulate cross-species transmission and host adaptation of potential pathogens is crucial to control emerging infectious disease. Although microbial pathotype diversity is conventionally associated with gene gain or loss, the role of pathoadaptive nonsynonymous single-nucleotide polymorphisms (nsSNPs) has not been systematically evaluated. Here, our genome-wide analysis of core genes within Salmonella enterica serovar Typhimurium genomes reveals a high degree of allelic variation in surface-exposed molecules, including adhesins that promote host colonization. Subsequent multinomial logistic regression, MultiPhen and Random Forest analyses of known/suspected adhesins from 580 independent Typhimurium isolates identifies distinct host-specific nsSNP signatures. Moreover, population and functional analyses of host-associated nsSNPs for FimH, the type 1 fimbrial adhesin, highlights the role of key allelic residues in host-specific adherence in vitro. Together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts

Screening of MAMLD1 Mutations in 70 Children with 46,XY DSD: Identification and Functional Analysis of Two New Mutations

More than 50% of children with severe 46,XY disorders of sex development (DSD) do not have a definitive etiological diagnosis. Besides gonadal dysgenesis, defects in androgen biosynthesis, and abnormalities in androgen sensitivity, the Mastermind-like domain containing 1 (MAMLD1) gene, which was identified as critical for the development of male genitalia, may be implicated. The present study investigated whether MAMLD1 is implicated in cases of severe 46,XY DSD and whether routine sequencing of MAMLD1 should be performed in these patients