An ENU-induced splice site mutation of mouse Col1a1 causing recessive osteogenesis imperfecta and revealing a novel splicing rescue.
An ENU-induced splice site mutation of mouse Col1a1 causing recessive osteogenesis imperfecta and revealing a novel splicing rescue.
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DOI：
10.1038/s41598-017-10343-9
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发表时间：
2017-09-15
影响因子：
4.6
通讯作者：
Beutler B
中科院分区：
文献类型：
--
作者：
Tabeta K;Du X;Arimatsu K;Yokoji M;Takahashi N;Amizuka N;Hasegawa T;Crozat K;Maekawa T;Miyauchi S;Matsuda Y;Ida T;Kaku M;Hoebe K;Ohno K;Yoshie H;Yamazaki K;Moresco EMY;Beutler B
GU-AG共有序列在真核生物中前mRNA剪接的大多数情况下用于内含子识别。剪接点的突变通常导致成熟mRNA中的外显子跳跃、短缺失或插入，这是遗传疾病的一种常见分子机制。使用N-乙基-N-亚硝基脲，产生了一种新的隐性突变，名为海豹，与脆弱的骨骼和骨折（脊柱和四肢）的易感性有关。编码Ⅰ型胶原α1链的Col 1a 1基因内含子36第二位的单核苷酸颠换（T → A）是导致表型的原因。与野生型转录本相比，Col 1a 1海豹mRNA的表达水平大大降低，导致海豹纯合子小鼠胫骨中胶原纤维减少和异常。出乎意料的是，尽管存在供体剪接位点突变，Col 1a 1 seal mRNA的剪接仍遵循正常模式，这可能是由于内含子25中存在的推定内含子剪接增强子的作用，该内含子25似乎与内含子36的剪接供体位点冗余地起作用。海豹鼠代表了人类成骨细胞的一种模型，并揭示了一种以前未知的剪接“拯救”机制。
GU-AG consensus sequences are used for intron recognition in the majority of cases of pre-mRNA splicing in eukaryotes. Mutations at splice junctions often cause exon skipping, short deletions, or insertions in the mature mRNA, underlying one common molecular mechanism of genetic diseases. Using N-ethyl-N-nitrosourea, a novel recessive mutation named seal was produced, associated with fragile bones and susceptibility to fractures (spine and limbs). A single nucleotide transversion (T → A) at the second position of intron 36 of the Col1a1 gene, encoding the type I collagen, α1 chain, was responsible for the phenotype. Col1a1 seal mRNA expression occurred at greatly reduced levels compared to the wild-type transcript, resulting in reduced and aberrant collagen fibers in tibiae of seal homozygous mice. Unexpectedly, splicing of Col1a1 seal mRNA followed the normal pattern despite the presence of the donor splice site mutation, likely due to the action of a putative intronic splicing enhancer present in intron 25, which appeared to function redundantly with the splice donor site of intron 36. Seal mice represent a model of human osteogenesis imperfecta, and reveal a previously unknown mechanism for splicing “rescue.”
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DOI：
10.1002/ajmg.c.30072
发表时间：
2005-11-15
影响因子：
3.1
作者：
Rauch, F;Glorieux, FH
通讯作者：
Glorieux, FH
DOI：
10.1179/096805103225001459
发表时间：
2003-01-01
期刊：
JOURNAL OF ENDOTOXIN RESEARCH
影响因子：
--
作者：
Hoebe, K;Du, X;Beutler, B
通讯作者：
Beutler, B
影响因子：
4.2
作者：
McBride, DJ;Shapiro, JR;Dunn, MG
通讯作者：
Dunn, MG
影响因子：
4.1
作者：
BATEMAN, JF;CHAN, D;COLE, WG
通讯作者：
COLE, WG
影响因子：
2.9
作者：
PROCKOP, DJ;UDENFRIEND, S
通讯作者：
UDENFRIEND, S