Two Hypomorphic Alleles of Mouse Ass1 as a New Animal Model of Citrullinemia Type I and Other Hyperammonemic Syndromes
| Autor: | Vicente C. Quintanilla, Cecilia R Giulivi, Donna F. Kusewitt, Jimi L. Brandon, Fernando Benavides, Jean Jaubert, Kirstin F. Barnhart, Irma B. Gimenez-Conti, Nancy W. Otto, Catherine Ross-Inta, John DiGiovanni, Claudio J. Conti, Carlos J. Perez, Jean-Louis Guénet, Isabelle Aubin |
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| Přispěvatelé: | The University of Texas M.D. Anderson Cancer Center [Houston], Graduate School of Biomedical Sciences [Houston], The University of Texas Health Science Center at Houston (UTHealth)-The University of Texas M.D. Anderson Cancer Center [Houston], Génétique de la souris - Mouse Genetics, Institut Pasteur [Paris] (IP), Michale E. Keeling Center for Comparative Medicine and Research [Bastrop, Texas], School of Veterinary Medicine [Univ California Davis] (VetMed - UC Davis), University of California [Davis] (UC Davis), University of California (UC)-University of California (UC), Génétique fonctionnelle de la Souris, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Supported by National Institutes of Health grant CA90922 (C.J.C.), Department of Health and Human Services/National Cancer Institute grants P30 CA016672 (F.B. and D.F. K.) and P30 ES007784 (I.G.C.), and funding from Autism Speaks (C.G.)., We thank the Research Animal Support Facility-Smithville for their assistance with the maintenance of the mouse strains. We also thank Kevin Lin for statistical analyses, the Histology and Tissue Processing Facility Core for the IHC, and the Molecular Biology Facility Core for DNA sequencing., We are grateful to Brenda Webb (Michale E. Keeling Center) for her excellent technical skills with blood sampling. We thank Qin Sun (BCM Medical Genetics Laboratories) for the plasma amino acid analysis and ASS liver activity assays., Institut Pasteur [Paris], School of Veterinary Medicine [UC Davis], University of California-University of California, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2010 |
| Předmět: |
Male
MESH: Disease Models Animal Cerebellum MESH: Mice Mutant Strains Developmental Disabilities Argininosuccinate synthase MESH: Sodium Benzoate / pharmacology MESH: Mice Knockout Immunoenzyme Techniques Mice 0302 clinical medicine Cell Movement Sodium Benzoate Hyperammonemia MESH: Animals MESH: Syndrome MESH: Cell Movement Growth Disorders Mice Knockout Citrullinemia 0303 health sciences biology MESH: Developmental Disabilities / etiology Syndrome MESH: Arginine / pharmacology MESH: Mutation Missense / genetics MESH: Hyperammonemia / etiology Phenotype MESH: Citrullinemia / etiology 3. Good health medicine.anatomical_structure Urea cycle MESH: Argininosuccinate Synthase / physiology Female medicine.symptom medicine.medical_specialty Ataxia Urea cycle disorder Blotting Western Mutation Missense Argininosuccinate Synthase MESH: Developmental Disabilities / drug therapy Arginine Nitric Oxide MESH: Hyperammonemia / drug therapy MESH: Phenotype Pathology and Forensic Medicine 03 medical and health sciences MESH: Mice Inbred C57BL Internal medicine MESH: Growth Disorders / etiology medicine Animals Humans MESH: Blotting Western MESH: Growth Disorders / drug therapy Allele MESH: Immunoenzyme Techniques MESH: Mice Alleles 030304 developmental biology MESH: Humans MESH: Alleles medicine.disease MESH: Cerebellum / abnormalities Mice Mutant Strains MESH: Male Mice Inbred C57BL Disease Models Animal [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics Endocrinology biology.protein MESH: Nitric Oxide / metabolism MESH: Female MESH: Citrullinemia / drug therapy 030217 neurology & neurosurgery Regular Articles |
| Zdroj: | American Journal of Pathology American Journal of Pathology, 2010, 177 (4), pp.1958-1968. ⟨10.2353/ajpath.2010.100118⟩ American Journal of Pathology, American Society for Investigative Pathology, 2010, 177 (4), pp.1958-1968. ⟨10.2353/ajpath.2010.100118⟩ |
| ISSN: | 0002-9440 1525-2191 |
| Popis: | International audience; Citrullinemia type I (CTLN1, OMIM# 215700) is an inherited urea cycle disorder that is caused by an argininosuccinate synthetase (ASS) enzyme deficiency. In this report, we describe two spontaneous hypomorphic alleles of the mouse Ass1 gene that serve as an animal model of CTLN1. These two independent mouse mutant alleles, also described in patients affected with CTLN1, interact to produce a range of phenotypes. While some mutant mice died within the first week after birth, others survived but showed severe retardation during postnatal development as well as alopecia, lethargy, and ataxia. Notable pathological findings were similar to findings in human CTLN1 patients and included citrullinemia and hyperammonemia along with delayed cerebellar development, epidermal hyperkeratosis, and follicular dystrophy. Standard treatments for CTLN1 were effective in rescuing the phenotype of these mutant mice. Based on our studies, we propose that defective cerebellar granule cell migration secondary to disorganization of Bergmann glial cell fibers cause cerebellar developmental delay in the hyperammonemic and citrullinemic brain, pointing to a possible role for nitric oxide in these processes. These mouse mutations constitute a suitable model for both mechanistic and preclinical studies of CTLN1 and other hyperammonemic encephalopathies and, at the same time, underscore the importance of complementing knockout mutations with hypomorphic mutations for the generation of animal models of human genetic diseases. |
| Databáze: | OpenAIRE |
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