TY - JOUR
T1 - Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes
AU - Tanisawa, Kumpei
AU - Mikami, Eri
AU - Fuku, Noriyuki
AU - Honda, Yoko
AU - Honda, Shuji
AU - Ohsawa, Ikuro
AU - Ito, Masafumi
AU - Endo, Shogo
AU - Ihara, Kunio
AU - Ohno, Kinji
AU - Kishimoto, Yuki
AU - Ishigami, Akihito
AU - Maruyama, Naoki
AU - Sawabe, Motoji
AU - Iseki, Hiroyoshi
AU - Okazaki, Yasushi
AU - Hasegawa-Ishii, Sanae
AU - Takei, Shiro
AU - Shimada, Atsuyoshi
AU - Hosokawa, Masanori
AU - Mori, Masayuki
AU - Higuchi, Keiichi
AU - Takeda, Toshio
AU - Higuchi, Mitsuru
AU - Tanaka, Masashi
N1 - Funding Information:
This work was supported in part by Grants-in-Aid for Scientific Research A-22240072, B-21390459, C-21590411 to MT) and a Grant-in-Aid for the Global COE (Sport Sciences for the Promotion of Active Life to Waseda University) from the Ministry of Education, Culture, Sports, Science, and Technology (to MT); by Grants-in-Aid for Young Scientists (A-21680050 and B-18700541 to NF) and a Grant-in-Aid for Exploratory Research (20650113 to NF) from the Ministry of Education, Culture, Sports, Science, and Technology; by grants for scientific research from The Takeda Science Foundation (to MT) and from The Uehara Memorial Foundation (to NF).
PY - 2013/4/15
Y1 - 2013/4/15
N2 - 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.
AB - 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.
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U2 - 10.1186/1471-2164-14-248
DO - 10.1186/1471-2164-14-248
M3 - Article
C2 - 23586671
AN - SCOPUS:84876143284
SN - 1471-2164
VL - 14
JO - BMC genomics
JF - BMC genomics
IS - 1
M1 - 248
ER -