Open Access Research article

Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes

Kumpei Tanisawa12, Eri Mikami123, Noriyuki Fuku1, Yoko Honda1, Shuji Honda1, Ikuro Ohsawa4, Masafumi Ito5, Shogo Endo6, Kunio Ihara7, Kinji Ohno8, Yuki Kishimoto9, Akihito Ishigami9, Naoki Maruyama9, Motoji Sawabe10, Hiroyoshi Iseki11, Yasushi Okazaki11, Sanae Hasegawa-Ishii12, Shiro Takei12, Atsuyoshi Shimada12, Masanori Hosokawa12, Masayuki Mori13, Keiichi Higuchi13, Toshio Takeda14, Mitsuru Higuchi15 and Masashi Tanaka1*

Author Affiliations

1 Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Tokyo, Itabashi, 173-0015, Japan

2 Graduate School of Sport Sciences, Waseda University, Tokorozawa, 359-1192, Japan

3 Japan Society for the Promotion of Science, Tokyo, 102-8472, Japan

4 Department of Biological Process of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan

5 Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan

6 Aging Regulation Research Team, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan

7 Center for Gene Research, Nagoya University, Nagoya, 464-8602, Japan

8 Department of Neurogenetics and Bioinformatics, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan

9 Department of Aging Regulation, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan

10 Department of Pathology and Bioresource Center for Geriatric Research, Tokyo Metropolitan Institute of Gerontology, Tokyo, 1730015, Japan

11 Research Center for Genomic Medicine, Saitama Medical University, Hidaka, 350-1241, Japan

12 Department of Pathology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, 480-0392, Japan

13 Department of Aging Biology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto, 390-8621, Japan

14 The Council for SAM Research, Kyoto, 604-8856, Japan

15 Faculty of Sport Sciences, Waseda University, Tokorozawa, 359-1192, Japan

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BMC Genomics 2013, 14:248  doi:10.1186/1471-2164-14-248

Published: 15 April 2013

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.

Keywords:
Exome sequencing; Senescence-accelerated mice; Aging