Idiopathic scoliosis (IS) is a spine deformity that affects approximately 3% of the population. The underlying causes of IS are not well understood, although there is clear evidence that there is a genetic component to the disease. Genetic mapping studies suggest high genetic heterogeneity, but no IS disease-causing gene has yet been identified. Here, genetic linkage analyses combined with exome sequencing identified a rare missense variant (p.A446T) in the centriolar protein gene
Shunmoogum A. Patten, Patricia Margaritte-Jeannin, Jean-Claude Bernard, Eudeline Alix, Audrey Labalme, Alicia Besson, Simon L. Girard, Khaled Fendri, Nicolas Fraisse, Bernard Biot, Coline Poizat, Amandine Campan-Fournier, Kariman Abelin-Genevois, Vincent Cunin, Charlotte Zaouter, Meijiang Liao, Raphaelle Lamy, Gaetan Lesca, Rita Menassa, Charles Marcaillou, Melanie Letexier, Damien Sanlaville, Jerome Berard, Guy A. Rouleau, Françoise Clerget-Darpoux, Pierre Drapeau, Florina Moldovan, Patrick Edery
Tau is a highly abundant and multifunctional brain protein that accumulates in neurofibrillary tangles (NFTs), most commonly in Alzheimer’s disease (AD) and primary age-related tauopathy. Recently, microRNAs (miRNAs) have been linked to neurodegeneration; however, it is not clear whether miRNA dysregulation contributes to tau neurotoxicity. Here, we determined that the highly conserved brain miRNA miR-219 is downregulated in brain tissue taken at autopsy from patients with AD and from those with severe primary age-related tauopathy. In a
Ismael Santa-Maria, Maria E. Alaniz, Neil Renwick, Carolina Cela, Tudor A. Fulga, David Van Vactor, Thomas Tuschl, Lorraine N. Clark, Michael L. Shelanski, Brian D. McCabe, John F. Crary
Satiety and other core physiological functions are modulated by sensory signals arising from the surface of the gut. Luminal nutrients and bacteria stimulate epithelial biosensors called enteroendocrine cells. Despite being electrically excitable, enteroendocrine cells are generally thought to communicate indirectly with nerves through hormone secretion and not through direct cell-nerve contact. However, we recently uncovered in intestinal enteroendocrine cells a cytoplasmic process that we named neuropod. Here, we determined that neuropods provide a direct connection between enteroendocrine cells and neurons innervating the small intestine and colon. Using cell-specific transgenic mice to study neural circuits, we found that enteroendocrine cells have the necessary elements for neurotransmission, including expression of genes that encode pre-, post-, and transsynaptic proteins. This neuroepithelial circuit was reconstituted in vitro by coculturing single enteroendocrine cells with sensory neurons. We used a monosynaptic rabies virus to define the circuit’s functional connectivity in vivo and determined that delivery of this neurotropic virus into the colon lumen resulted in the infection of mucosal nerves through enteroendocrine cells. This neuroepithelial circuit can serve as both a sensory conduit for food and gut microbes to interact with the nervous system and a portal for viruses to enter the enteric and central nervous systems.
Diego V. Bohórquez, Rafiq A. Shahid, Alan Erdmann, Alex M. Kreger, Yu Wang, Nicole Calakos, Fan Wang, Rodger A. Liddle
Premature ovarian failure (POF) is a genetically and phenotypically heterogeneous disorder that includes individuals with manifestations ranging from primary amenorrhea to loss of menstrual function prior to age 40. POF presents as hypergonadotropic hypogonadism and can be part of a syndrome or occur in isolation. Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and hypergonadotropic hypogonadism. The sisters were born to parents who are first cousins. SNP analysis and whole-exome sequencing revealed the presence of a pathogenic variant of the minichromosome maintenance 8 gene (
Saleh AlAsiri, Sulman Basit, Michelle A. Wood-Trageser, Svetlana A. Yatsenko, Elizabeth P. Jeffries, Urvashi Surti, Deborah M. Ketterer, Sibtain Afzal, Khushnooda Ramzan, Muhammad Faiyaz-Ul Haque, Huaiyang Jiang, Michael A. Trakselis, Aleksandar Rajkovic
Hematopoietic stem cell (HSC) function is regulated by activation of receptor tyrosine kinases (RTKs). Receptor protein tyrosine phosphatases (PTPs) counterbalance RTK signaling; however, the functions of receptor PTPs in HSCs remain incompletely understood. We found that a receptor PTP, PTPσ, was substantially overexpressed in mouse and human HSCs compared with more mature hematopoietic cells. Competitive transplantation of bone marrow cells from PTPσ-deficient mice revealed that the loss of PTPσ substantially increased long-term HSC-repopulating capacity compared with BM cells from control mice. While HSCs from PTPσ-deficient mice had no apparent alterations in cell-cycle status, apoptosis, or homing capacity, these HSCs exhibited increased levels of activated RAC1, a RhoGTPase that regulates HSC engraftment capacity. shRNA-mediated silencing of PTPσ also increased activated RAC1 levels in wild-type HSCs. Functionally, PTPσ-deficient BM cells displayed increased cobblestone area–forming cell (CAFC) capacity and augmented transendothelial migration capacity, which was abrogated by RAC inhibition. Specific selection of human cord blood CD34+CD38–CD45RA–lin– PTPσ– cells substantially increased the repopulating capacity of human HSCs compared with CD34+CD38–CD45RA–lin– cells and CD34+CD38–CD45RA–lin–PTPσ+ cells. Our results demonstrate that PTPσ regulates HSC functional capacity via RAC1 inhibition and suggest that selecting for PTPσ-negative human HSCs may be an effective strategy for enriching human HSCs for transplantation.
Mamle Quarmyne, Phuong L. Doan, Heather A. Himburg, Xiao Yan, Mai Nakamura, Liman Zhao, Nelson J. Chao, John P. Chute
Innate immunity to viral infection involves induction of the type I IFN response; however, dysfunctional regulation of this pathway leads to inappropriate inflammation. Here, we evaluated a nonconsanguineous family of mixed European descent, with 4 members affected by systemic inflammatory and autoimmune conditions, including lupus, with variable clinical expression. We identified a germline dominant gain-of-function mutation in
Nadia Jeremiah, Bénédicte Neven, Matteo Gentili, Isabelle Callebaut, Sophia Maschalidi, Marie-Claude Stolzenberg, Nicolas Goudin, Marie-Louis Frémond, Patrick Nitschke, Thierry J. Molina, Stéphane Blanche, Capucine Picard, Gillian I. Rice, Yanick J. Crow, Nicolas Manel, Alain Fischer, Brigitte Bader-Meunier, Frédéric Rieux-Laucat
Genome-wide association studies have identified a link between genetic variation at the human chromosomal locus 1p13.3 and coronary artery disease. The gene encoding sortilin (
Martin B. Mortensen, Mads Kjolby, Stine Gunnersen, Jakob V. Larsen, Johan Palmfeldt, Erling Falk, Anders Nykjaer, Jacob F. Bentzon
Many patients who undergo general anesthesia and surgery experience cognitive dysfunction, particularly memory deficits that can persist for days to months. The mechanisms underlying this postoperative cognitive dysfunction in the adult brain remain poorly understood. Depression of brain function during anesthesia is attributed primarily to increased activity of γ-aminobutyric acid type A receptors (GABAARs), and it is assumed that once the anesthetic drug is eliminated, the activity of GABAARs rapidly returns to baseline and these receptors no longer impair memory. Here, using a murine model, we found that a single in vivo treatment with the injectable anesthetic etomidate increased a tonic inhibitory current generated by α5 subunit–containing GABAARs (α5GABAARs) and cell-surface expression of α5GABAARs for at least 1 week. The sustained increase in α5GABAAR activity impaired memory performance and synaptic plasticity in the hippocampus. Inhibition of α5GABAARs completely reversed the memory deficits after anesthesia. Similarly, the inhaled anesthetic isoflurane triggered a persistent increase in tonic current and cell-surface expression of α5GABAARs. Thus, α5GABAAR function does not return to baseline after the anesthetic is eliminated, suggesting a mechanism to account for persistent memory deficits after general anesthesia.
Agnieszka A. Zurek, Jieying Yu, Dian-Shi Wang, Sean C. Haffey, Erica M. Bridgwater, Antonello Penna, Irene Lecker, Gang Lei, Tom Chang, Eric W.R. Salter, Beverley A. Orser
Tooth enamel is the hardest substance in the human body and has a unique combination of hardness and fracture toughness that protects teeth from dental caries, the most common chronic disease worldwide. In addition to a high mineral content, tooth enamel comprises organic material that is important for mechanical performance and influences the initiation and progression of caries; however, the protein composition of tooth enamel has not been fully characterized. Here, we determined that epithelial hair keratins, which are crucial for maintaining the integrity of the sheaths that support the hair shaft, are expressed in the enamel organ and are essential organic components of mature enamel. Using genetic and intraoral examination data from 386 children and 706 adults, we found that individuals harboring known hair disorder–associated polymorphisms in the gene encoding keratin 75 (KRT75), KRT75A161T and KRT75E337K, are prone to increased dental caries. Analysis of teeth from individuals carrying the KRT75A161T variant revealed an altered enamel structure and a marked reduction of enamel hardness, suggesting that a functional keratin network is required for the mechanical stability of tooth enamel. Taken together, our results identify a genetic locus that influences enamel structure and establish a connection between hair disorders and susceptibility to dental caries.
Olivier Duverger, Takahiro Ohara, John R. Shaffer, Danielle Donahue, Patricia Zerfas, Andrew Dullnig, Christopher Crecelius, Elia Beniash, Mary L. Marazita, Maria I. Morasso
Allergic contact dermatitis (ACD) is well recognized as an adverse event associated with implantable medical devices that contain allergenic materials like nickel; however, other cutaneous consequences of chronic exposure to allergens in implanted devices are not well understood. Here, we present a clinical case of Marjolin’s ulcer, an invasive squamous cell carcinoma (SCC) that developed in response to chronic ACD caused by an orthopedic implant. We used a standard murine model of contact hypersensitivity to determine whether chronic ACD promotes skin carcinogenesis. Chronic application of 1-fluoro-2,4-dinitrobenzene (DNFB) to carcinogen-treated skin led to the development of papillomas and aggressive SCC. DNFB-driven chronic ACD was marked by type 2 inflammation, which mediated skin carcinogenesis, as mice unable to mount an inflammatory response were less likely to develop skin tumors. Importantly, we found similar tumor-promoting inflammation surrounding the SCC in our patient. Our findings demonstrate that chronic ACD caused by constant exposure to an allergen can promote tumorigenesis at skin sites with preexisting cancer-initiated cells. Moreover, our results suggest that patients with implantable devices placed in close proximity to the skin should be monitored for ACD and highlight the importance of patch testing prior to the placement of such devices.
Shadmehr Demehri, Trevor J. Cunningham, Eva A. Hurst, Andras Schaffer, David M. Sheinbein, Wayne M. Yokoyama
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