title: Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes.
abstract: BACKGROUND
  Senescence-accelerated mice (SAM) are a series of mouse strains originally derived from unexpected crosses between AKR/J and unknown mice, from which phenotypically distinct senescence-prone (SAMP) and -resistant (SAMR) inbred strains were subsequently established. Although SAMP strains have been widely used for aging research focusing on their short life spans and various age-related phenotypes, such as immune dysfunction, osteoporosis, and brain atrophy, the responsible gene mutations have not yet been fully elucidated.
  
  
  RESULTS
  To identify mutations specific to SAMP strains, we performed whole exome sequencing of 6 SAMP and 3 SAMR strains. This analysis revealed 32,019 to 38,925 single-nucleotide variants in the coding region of each SAM strain. We detected Ogg1 p.R304W and Mbd4 p.D129N deleterious mutations in all 6 of the SAMP strains but not in the SAMR or AKR/J strains. Moreover, we extracted 31 SAMP-specific novel deleterious mutations. In all SAMP strains except SAMP8, we detected a p.R473W missense mutation in the Ldb3 gene, which has been associated with myofibrillar myopathy. In 3 SAMP strains (SAMP3, SAMP10, and SAMP11), we identified a p.R167C missense mutation in the Prx gene, in which mutations causing hereditary motor and sensory neuropathy (Dejerine-Sottas syndrome) have been identified. In SAMP6 we detected a p.S540fs frame-shift mutation in the Il4ra gene, a mutation potentially causative of ulcerative colitis and osteoporosis.
  
  
  CONCLUSIONS
  Our data indicate that different combinations of mutations in disease-causing genes may be responsible for the various phenotypes of SAMP strains.
authors.affiliation: Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Tokyo, Itabashi, Japan. mtanaka@tmig.or.jp
authors.forename: Kumpei
authors.initials: K
authors.lastname: Tanisawa
authors.forename: Eri
authors.initials: E
authors.lastname: Mikami
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Fuku
authors.forename: Yoko
authors.initials: Y
authors.lastname: Honda
authors.forename: Shuji
authors.initials: S
authors.lastname: Honda
authors.forename: Ikuro
authors.initials: I
authors.lastname: Ohsawa
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ito
authors.forename: Shogo
authors.initials: S
authors.lastname: Endo
authors.forename: Kunio
authors.initials: K
authors.lastname: Ihara
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kishimoto
authors.forename: Akihito
authors.initials: A
authors.lastname: Ishigami
authors.forename: Naoki
authors.initials: N
authors.lastname: Maruyama
authors.forename: Motoji
authors.initials: M
authors.lastname: Sawabe
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Iseki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Sanae
authors.initials: S
authors.lastname: Hasegawa-Ishii
authors.forename: Shiro
authors.initials: S
authors.lastname: Takei
authors.forename: Atsuyoshi
authors.initials: A
authors.lastname: Shimada
authors.forename: Masanori
authors.initials: M
authors.lastname: Hosokawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Mori
authors.forename: Keiichi
authors.initials: K
authors.lastname: Higuchi
authors.forename: Toshio
authors.initials: T
authors.lastname: Takeda
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Higuchi
authors.forename: Masashi
authors.initials: M
authors.lastname: Tanaka
mesh_terms: D000375:Aging / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004194:Disease / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005091:Exons / Q000235:genetics; D023281:Genomics; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D017421:Sequence Analysis; D013045:Species Specificity
chemical_list: D008565:Membrane Proteins; C086745:periaxin