It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain–containing protein 9 (
Federica Buonocore, Peter Kühnen, Jenifer P. Suntharalingham, Ignacio Del Valle, Martin Digweed, Harald Stachelscheid, Noushafarin Khajavi, Mohammed Didi, Angela F. Brady, Oliver Blankenstein, Annie M. Procter, Paul Dimitri, Jerry K.H. Wales, Paolo Ghirri, Dieter Knöbl, Brigitte Strahm, Miriam Erlacher, Marcin W. Wlodarski, Wei Chen, George K. Kokai, Glenn Anderson, Deborah Morrogh, Dale A. Moulding, Shane A. McKee, Charlotte M. Niemeyer, Annette Grüters, John C. Achermann
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder that is characterized by extreme variability in symptoms, with females being less severely affected than males and presenting a higher proportion of asymptomatic carriers. The sex-related factors involved in the disease are not known. Here, we have utilized myoblasts isolated from FSHD patients (FSHD myoblasts) to investigate the effect of estrogens on muscle properties. Our results demonstrated that estrogens counteract the differentiation impairment of FSHD myoblasts without affecting cell proliferation or survival. Estrogen effects are mediated by estrogen receptor β (ERβ), which reduces chromatin occupancy and transcriptional activity of double homeobox 4 (DUX4), a protein whose aberrant expression has been implicated in FSHD pathogenesis. During myoblast differentiation, we observed that the levels and activity of DUX4 increased progressively and were associated with its enhanced recruitment in the nucleus. ERβ interfered with this recruitment by relocalizing DUX4 in the cytoplasm. This work identifies estrogens as a potential disease modifier that underlie sex-related differences in FSHD by protecting against myoblast differentiation impairments in this disease.
Emanuela Teveroni, Marsha Pellegrino, Sabrina Sacconi, Patrizia Calandra, Isabella Cascino, Stefano Farioli-Vecchioli, Angela Puma, Matteo Garibaldi, Roberta Morosetti, Giorgio Tasca, Enzo Ricci, Carlo Pietro Trevisan, Giuliana Galluzzi, Alfredo Pontecorvi, Marco Crescenzi, Giancarlo Deidda, Fabiola Moretti
Obesity causes insulin resistance, and PPARγ ligands such as rosiglitazone are insulin sensitizing, yet the mechanisms remain unclear. In C57BL/6 (B6) mice, obesity induced by a high-fat diet (HFD) has major effects on visceral epididymal adipose tissue (eWAT). Here, we report that HFD-induced obesity in B6 mice also altered the activity of gene regulatory elements and genome-wide occupancy of PPARγ. Rosiglitazone treatment restored insulin sensitivity in obese B6 mice, yet, surprisingly, had little effect on gene expression in eWAT. However, in subcutaneous inguinal fat (iWAT), rosiglitazone markedly induced molecular signatures of brown fat, including the key thermogenic gene
Raymond E. Soccio, Zhenghui Li, Eric R. Chen, Yee Hoon Foong, Kiara K. Benson, Joanna R. Dispirito, Shannon E. Mullican, Matthew J. Emmett, Erika R. Briggs, Lindsey C. Peed, Richard K. Dzeng, Carlos J. Medina, Jennifer F. Jolivert, Megan Kissig, Satyajit R. Rajapurkar, Manashree Damle, Hee-Woong Lim, Kyoung-Jae Won, Patrick Seale, David J. Steger, Mitchell A. Lazar
MicroRNAs (miRNAs) are negative modulators of gene expression that fine-tune numerous biological processes. miRNA loss-of-function rarely results in highly penetrant phenotypes, but rather, influences cellular responses to physiologic and pathophysiologic stresses. Here, we have reported that a single member of the evolutionarily conserved miR-7 family, miR-7a2, is essential for normal pituitary development and hypothalamic-pituitary-gonadal (HPG) function in adulthood. Genetic deletion of
Kashan Ahmed, Mary P. LaPierre, Emanuel Gasser, Rémy Denzler, Yinjie Yang, Thomas Rülicke, Jukka Kero, Mathieu Latreille, Markus Stoffel
Primary adrenal insufficiency is life threatening and can present alone or in combination with other comorbidities. Here, we have described a primary adrenal insufficiency syndrome and steroid-resistant nephrotic syndrome caused by loss-of-function mutations in sphingosine-1-phosphate lyase (SGPL1). SGPL1 executes the final decisive step of the sphingolipid breakdown pathway, mediating the irreversible cleavage of the lipid-signaling molecule sphingosine-1-phosphate (S1P). Mutations in other upstream components of the pathway lead to harmful accumulation of lysosomal sphingolipid species, which are associated with a series of conditions known as the sphingolipidoses. In this work, we have identified 4 different homozygous mutations, c.665G>A (p.R222Q), c.1633_1635delTTC (p.F545del), c.261+1G>A (p.S65Rfs*6), and c.7dupA (p.S3Kfs*11), in 5 families with the condition. In total, 8 patients were investigated, some of whom also manifested other features, including ichthyosis, primary hypothyroidism, neurological symptoms, and cryptorchidism.
Rathi Prasad, Irene Hadjidemetriou, Avinaash Maharaj, Eirini Meimaridou, Federica Buonocore, Moin Saleem, Jenny Hurcombe, Agnieszka Bierzynska, Eliana Barbagelata, Ignacio Bergadá, Hamilton Cassinelli, Urmi Das, GOSgene, Ruth Krone, Bulent Hacihamdioglu, Erkan Sari, Ediz Yesilkaya, Helen L. Storr, Maria Clemente, Monica Fernandez-Cancio, Nuria Camats, Nanik Ram, John C. Achermann, Paul P. Van Veldhoven, Leonardo Guasti, Debora Braslavsky, Tulay Guran, Louise A. Metherell
The mechanism by which leptin reverses diabetic ketoacidosis (DKA) is unknown. We examined the acute insulin-independent effects of leptin replacement therapy in a streptozotocin-induced rat model of DKA. Leptin infusion reduced rates of lipolysis, hepatic glucose production (HGP), and hepatic ketogenesis by 50% within 6 hours and were independent of any changes in plasma glucagon concentrations; these effects were abrogated by coinfusion of corticosterone. Treating leptin- and corticosterone-infused rats with an adipose triglyceride lipase inhibitor blocked corticosterone-induced increases in plasma glucose concentrations and rates of HGP and ketogenesis. Similarly, adrenalectomized type 1 diabetic (T1D) rats exhibited decreased rates of lipolysis, HGP, and ketogenesis; these effects were reversed by corticosterone infusion. Leptin-induced decreases in lipolysis, HGP, and ketogenesis in DKA were also nullified by relatively small increases (15 to 70 pM) in plasma insulin concentrations. In contrast, the chronic glucose-lowering effect of leptin in a STZ-induced mouse model of poorly controlled T1D was associated with decreased food intake, reduced plasma glucagon and corticosterone concentrations, and decreased ectopic lipid (triacylglycerol/diacylglycerol) content in liver and muscle. Collectively, these studies demonstrate marked differences in the acute insulin-independent effects by which leptin reverses fasting hyperglycemia and ketoacidosis in a rodent model of DKA versus the chronic pleotropic effects by which leptin reverses hyperglycemia in a non-DKA rodent model of T1D.
Rachel J. Perry, Liang Peng, Abudukadier Abulizi, Lynn Kennedy, Gary W. Cline, Gerald I. Shulman
Type 2 diabetes is thought to involve a compromised β cell differentiation state, but the mechanisms underlying this dysfunction remain unclear. Here, we report a key role for the TF PAX6 in the maintenance of adult β cell identity and function. PAX6 was downregulated in β cells of diabetic
Avital Swisa, Dana Avrahami, Noa Eden, Jia Zhang, Eseye Feleke, Tehila Dahan, Yamit Cohen-Tayar, Miri Stolovich-Rain, Klaus H. Kaestner, Benjamin Glaser, Ruth Ashery-Padan, Yuval Dor
Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene
Lisa C. Burnett, Charles A. LeDuc, Carlos R. Sulsona, Daniel Paull, Richard Rausch, Sanaa Eddiry, Jayne F. Martin Carli, Michael V. Morabito, Alicja A. Skowronski, Gabriela Hubner, Matthew Zimmer, Liheng Wang, Robert Day, Brynn Levy, Ilene Fennoy, Beatrice Dubern, Christine Poitou, Karine Clement, Merlin G. Butler, Michael Rosenbaum, Jean Pierre Salles, Maithe Tauber, Daniel J. Driscoll, Dieter Egli, Rudolph L. Leibel
Small nucleolar RNAs (snoRNAs) are non-coding RNAs that form ribonucleoproteins to guide covalent modifications of ribosomal and small nuclear RNAs in the nucleus. Recent studies have also uncovered additional non-canonical roles for snoRNAs. However, the physiological contributions of these small RNAs are largely unknown. Here, we selectively deleted four snoRNAs encoded within the introns of the ribosomal protein L13a (
Jiyeon Lee, Alexis N. Harris, Christopher L. Holley, Jana Mahadevan, Kelly D. Pyles, Zeno Lavagnino, David E. Scherrer, Hideji Fujiwara, Rohini Sidhu, Jessie Zhang, Stanley Ching-Cheng Huang, David W. Piston, Maria S. Remedi, Fumihiko Urano, Daniel S. Ory, Jean E. Schaffer
Obese, insulin-resistant states are characterized by a paradoxical pathogenic condition in which the liver appears to be selectively insulin resistant. Specifically, insulin fails to suppress glucose production, yet successfully stimulates de novo lipogenesis. The mechanisms underlying this dysregulation remain controversial. Here, we hypothesized that carbohydrate-responsive element-binding protein (ChREBP), a transcriptional activator of glycolytic and lipogenic genes, plays a central role in this paradox. Administration of fructose increased hepatic hexose-phosphate levels, activated ChREBP, and caused glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis in mice. Activation of ChREBP was required for the increased expression of glycolytic and lipogenic genes as well as glucose-6-phosphatase (
Mi-Sung Kim, Sarah A. Krawczyk, Ludivine Doridot, Alan J. Fowler, Jennifer X. Wang, Sunia A. Trauger, Hye-Lim Noh, Hee Joon Kang, John K. Meissen, Matthew Blatnik, Jason K. Kim, Michelle Lai, Mark A. Herman