Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes.
Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes.
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DOI：
10.1186/1471-2164-14-248
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发表时间：
2013-04-15
期刊：
影响因子：
4.4
通讯作者：
Tanaka M
中科院分区：
文献类型：
--
作者：
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
加速衰老小鼠（SAM）是一系列小鼠品系，最初来源于AKR/J与未知小鼠之间的意外杂交，随后从其建立表型不同的易衰老（SAMP）和抗衰老（SAMR）近交系。虽然SAMP菌株已被广泛用于衰老研究，重点是其寿命短和各种年龄相关的表型，如免疫功能障碍，骨质疏松症和脑萎缩，但负责的基因突变尚未完全阐明。为了鉴定SAMP菌株的特异性突变，我们对6个SAMP和3个SAMR菌株进行了全外显子组测序。该分析揭示了每个SAM菌株编码区中的32，019至38，925个单核苷酸变体。我们在所有6个SAMP菌株中检测到Ogg 1 p.R304W和Mbd 4 p.D129N有害突变，但在SAMR或AKR/J菌株中未检测到。此外，我们提取了31个SAMP特异性新的有害突变。在除SAMP 8外的所有SAMP菌株中，我们检测到Ldb 3基因中的p.R473W错义突变，该突变与肌原纤维性肌病相关。在3个SAMP菌株（SAMP 3、SAMP 10和SAMP 11）中，我们鉴定了Prx基因中的p.R167C错义突变，该突变导致遗传性运动和感觉神经病（Dejerine-Sottas综合征）。在SAMP 6中，我们检测到Il 4 ra基因中的p.S540fs移码突变，该突变可能导致溃疡性结肠炎和骨质疏松症。我们的数据表明，致病基因的突变的不同组合可能是负责SAMP菌株的各种表型。
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. 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. 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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影响因子：
11.4
作者：
Cheung, Eric C. C.;Joza, Nicholas;Slack, Ruth S.
通讯作者：
Slack, Ruth S.
影响因子：
16.2
作者：
GILLESPIE, CS;SHERMAN, DL;BROPHY, PJ
通讯作者：
BROPHY, PJ
影响因子：
3.5
作者：
Guilbot, A;Williams, A;Claustres, M
通讯作者：
Claustres, M
影响因子：
12.3
作者：
Fairfield H;Gilbert GJ;Barter M;Corrigan RR;Curtain M;Ding Y;D'Ascenzo M;Gerhardt DJ;He C;Huang W;Richmond T;Rowe L;Probst FJ;Bergstrom DE;Murray SA;Bult C;Richardson J;Kile BT;Gut I;Hager J;Sigurdsson S;Mauceli E;Di Palma F;Lindblad-Toh K;Cunningham ML;Cox TC;Justice MJ;Spector MS;Lowe SW;Albert T;Donahue LR;Jeddeloh J;Shendure J;Reinholdt LG
通讯作者：
Reinholdt LG
影响因子：
3.7
作者：
Feng, Bing-Jian;Tavtigian, Sean V.;Goldgar, David E.
通讯作者：
Goldgar, David E.