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

Kumpei Tanisawa, Eri Mikami, Noriyuki Fuku, Yoko Honda, Shuji Honda, Ikuro Ohsawa, Masafumi Ito, Shogo Endo, Kunio Ihara, Kinji Ohno, Yuki Kishimoto, Akihito Ishigami, Naoki Maruyama, Motoji Sawabe, Hiroyoshi Iseki, Yasushi Okazaki, Sanae Hasegawa-Ishii, Shiro Takei, Atsuyoshi Shimada, Masanori Hosokawa & 5 others Masayuki Mori, Keiichi Higuchi, Toshio Takeda, Mitsuru Higuchi, Masashi Tanaka

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Article number248
JournalBMC Genomics
Volume14
Issue number1
DOIs
Publication statusPublished - 2013 Apr 15

Fingerprint

Exome
Mutation
Genes
Hereditary Sensory and Motor Neuropathy
Missense Mutation
Osteoporosis
4-(4-sulfophenylazo)-2-mercuriphenol
Phenotype
Frameshift Mutation
Ulcerative Colitis
Atrophy
Nucleotides

Keywords

  • Aging
  • Exome sequencing
  • Senescence-accelerated mice

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

Cite this

Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes. / Tanisawa, Kumpei; Mikami, Eri; Fuku, Noriyuki; Honda, Yoko; Honda, Shuji; Ohsawa, Ikuro; Ito, Masafumi; Endo, Shogo; Ihara, Kunio; Ohno, Kinji; Kishimoto, Yuki; Ishigami, Akihito; Maruyama, Naoki; Sawabe, Motoji; Iseki, Hiroyoshi; Okazaki, Yasushi; Hasegawa-Ishii, Sanae; Takei, Shiro; Shimada, Atsuyoshi; Hosokawa, Masanori; Mori, Masayuki; Higuchi, Keiichi; Takeda, Toshio; Higuchi, Mitsuru; Tanaka, Masashi.

In: BMC Genomics, Vol. 14, No. 1, 248, 15.04.2013.

Research output: Contribution to journalArticle

Tanisawa, K, Mikami, E, Fuku, N, Honda, Y, Honda, S, Ohsawa, I, Ito, M, Endo, S, Ihara, K, Ohno, K, Kishimoto, Y, Ishigami, A, Maruyama, N, Sawabe, M, Iseki, H, Okazaki, Y, Hasegawa-Ishii, S, Takei, S, Shimada, A, Hosokawa, M, Mori, M, Higuchi, K, Takeda, T, Higuchi, M & Tanaka, M 2013, 'Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes', BMC Genomics, vol. 14, no. 1, 248. https://doi.org/10.1186/1471-2164-14-248
Tanisawa, Kumpei ; Mikami, Eri ; Fuku, Noriyuki ; Honda, Yoko ; Honda, Shuji ; Ohsawa, Ikuro ; Ito, Masafumi ; Endo, Shogo ; Ihara, Kunio ; Ohno, Kinji ; Kishimoto, Yuki ; Ishigami, Akihito ; Maruyama, Naoki ; Sawabe, Motoji ; Iseki, Hiroyoshi ; Okazaki, Yasushi ; Hasegawa-Ishii, Sanae ; Takei, Shiro ; Shimada, Atsuyoshi ; Hosokawa, Masanori ; Mori, Masayuki ; Higuchi, Keiichi ; Takeda, Toshio ; Higuchi, Mitsuru ; Tanaka, Masashi. / Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes. In: BMC Genomics. 2013 ; Vol. 14, No. 1.
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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

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.

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KW - Aging

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