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Characterization of a new mutation with loss of function in the KMT2D gene in mice

Grant number: 16/23659-6
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): April 01, 2017
Effective date (End): May 31, 2020
Field of knowledge:Agronomical Sciences - Veterinary Medicine - Animal Pathology
Principal Investigator:Claudia Madalena Cabrera Mori
Grantee:Pedro Kenzo Yamamoto
Host Institution: Faculdade de Medicina Veterinária e Zootecnia (FMVZ). Universidade de São Paulo (USP). São Paulo , SP, Brazil


The recessive mutant mouse named bate palmas (bapa) - claps in Portuguese, which presents balance impairment and incoordination, was originated from an ENU (N-Ethyl-N-nitrosourea) mutagenesis program. The lysine (K) -specific methyltransferase 2D gene (KMT2D), located on chromosome 15, was identified as a candidate gene by exome sequencing. The mutation was confirmed by Sanger DNA sequencing. Mutations with loss of function in the KMT2D gene located on chromosome 12 or in the KDM6A gene located on chromosome X in humans are responsible for the Kabuki syndrome, which is a rare autosomal dominant disorder also known as Niikawa-Koruki syndrome. The phenotype is variable, but most patients have a peculiar face, skeletal anomalies, dermatoglyphic abnormalities, mild to moderate mental retardation and postnatal growth deficiency. Thus, the characterization of the mutant mouse phenotype through behavioral analysis, evaluation of cell proliferation in vivo and radiographic examinations may aid in the functional validation of the bapa mutation. Mice of both sexes, from four to twelve-week-old, 42 bapa and 42 BALB/c as the control group will be analysed. The phenotypic characterization of the mutant mouse will be performed by evaluation of behavioral motion parameters, psychomotor, physiological and connected to the nervous system by direct observation of the animals. Initially, tests will be conducted in the open field and ordered by parameter evaluated in the following sequence: 1) general activity and sensory system 2) psychomotor tests; 3) evaluation of the central and autonomic nervous system, tremors, convulsions, tail standing sedation, anesthesia, ataxia, ptosis, lacrimation, urination and defecation. In addition, other tests will be performed, such as: the behavior at elevated plus maze, motor coordination on high beam, and the behavioral response in the tail suspension test and forced swimming test. In order to verify skeletal anomalies, the mutants will be X-rayed and compared to their controls. The cell proliferation in vivo test with BrdU (5-bromo-2'-deoxyuridine) will be used to check for possible impairment in neurogenesis of the mutant mice. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
YAMAMOTO, PEDRO K.; DE SOUZA, TIAGO A.; ANTIORIO, ANA T. F. B.; ZANATTO, DENNIS A.; GARCIA-GOMES, MARIANA DE SOUZA A.; ALEXANDRE-RIBEIRO, SANDRA R.; OLIVEIRA, NICASSIA DE SOUZA; MENCK, CARLOS F. M.; BERNARDI, MARIA M.; MASSIRONI, SILVIA M. G.; et al. Genetic and behavioral characterization of a Kmt2d mouse mutant, a new model for Kabuki Syndrome. GENES BRAIN AND BEHAVIOR, v. 18, n. 8, . (17/21103-3, 16/23659-6, 12/25387-2)

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