title: Identification of mutations through dominant screening for obesity using C57BL/6 substrains.
abstract: The discovery of leptin substantiated the usefulness of a forward genetic approach in elucidating the molecular network regulating energy metabolism. However, no successful dominant screening for obesity has been reported, which may be due to the influence of quantitative trait loci between the screening and counter strains and the low fertility of obese mice. Here, we performed a dominant screening for obesity using C57BL/6 substrains, C57BL/6J and C57BL/6N, with the routine use of in vitro fertilization. The screening of more than 5000 mutagenized mice established two obese pedigrees in which single nucleotide substitutions in Mc4r and Sim1 genes were identified through whole-exome sequencing. The mutation in the Mc4r gene produces a premature stop codon, and the mutant SIM1 protein lacks transcriptional activity, showing that the haploinsufficiency of SIM1 and MC4R results in obesity. We further examined the hypothalamic neuropeptide expressions in the mutant pedigrees and mice with diet-induced obesity, which showed that each obesity mouse model has distinct neuropeptide expression profiles. This forward genetic screening scheme is useful and applicable to any research field in which mouse models work.
authors: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors: Mohammad Sarowar
authors: MS
authors: Hossain
authors: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors: Fuyuki
authors: F
authors: Asano
authors: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors: Tomoyuki
authors: T
authors: Fujiyama
authors: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors: Chika
authors: C
authors: Miyoshi
authors: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors: Makito
authors: M
authors: Sato
authors: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors: Aya
authors: A
authors: Ikkyu
authors: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors: Satomi
authors: S
authors: Kanno
authors: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors: Noriko
authors: N
authors: Hotta
authors: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors: Miyo
authors: M
authors: Kakizaki
authors: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.|Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, 1-1-1 Tennodai, Tsukuba Ibaraki, 305-8575, Japan.
authors: Takato
authors: T
authors: Honda
authors: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.|Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, 1-1-1 Tennodai, Tsukuba Ibaraki, 305-8575, Japan.
authors: Staci J
authors: SJ
authors: Kim
authors: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors: Haruna
authors: H
authors: Komiya
authors: Technology and Development Team for Mouse Phenotype Analysis, RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan.
authors: Ikuo
authors: I
authors: Miura
authors: Technology and Development Team for Mouse Phenotype Analysis, RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan.
authors: Tomohiro
authors: T
authors: Suzuki
authors: Technology and Development Team for Mouse Phenotype Analysis, RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan.
authors: Kimio
authors: K
authors: Kobayashi
authors: Technology and Development Team for Mouse Phenotype Analysis, RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan.
authors: Hideki
authors: H
authors: Kaneda
authors: Department of Neuroscience, University of Texas Southwestern Medical Center at Dallas, Texas 75390, USA.|The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors: Vivek
authors: V
authors: Kumar
authors: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.|Department of Neuroscience, University of Texas Southwestern Medical Center at Dallas, Texas 75390, USA.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Taxas, 75390, USA.
authors: Joseph S
authors: JS
authors: Takahashi
authors: Technology and Development Team for Mouse Phenotype Analysis, RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan.
authors: Shigeharu
authors: S
authors: Wakana
authors: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.|Department of Anatomy, Toho University Faculty of Medicine, Tokyo 143-8540, Japan.
authors: Hiromasa
authors: H
authors: Funato
authors: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Taxas, 75390, USA.|Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Texas 75390, USA.
authors: Masashi
authors: M
authors: Yanagisawa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics; D002874:Chromosome Mapping; D004032:Diet; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D007031:Hypothalamus / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics; D000073359:Exome Sequencing
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D008156:Luciferases; D009479:Neuropeptides; D044105:Receptor, Melanocortin, Type 4; D012097:Repressor Proteins; C101750:Sim1 protein, mouse