- 作者: Tsung-Chieh Chen, Jiun-Shian Wu, Wei-Pang Chang, Ping-Ning Hsu, Sung-Tsang Hsieh, Bai-Chuang Shyu
- 作者服務機構: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China
- 中文摘要: --
- 英文摘要:
Background: N-ethyl-N-nitrosourea mutagenesis was used to induce a point mutation in C57BL/6J mice. A set of pain-related phenotype screening was performed in 915 G3 mice. Here we report the detection of a heritable recessive mutant in meiotic recombinant N1F1 mice that caused an abnormal pain sensitivity phenotype with spontaneous skin inflammation in the paws and ears.
Methods: We investigated the abnormal sensory process, neuronal peptides, and behavioral response after the induction of autoinflammatory disease. SNP markers and sequencing polymerase chain reaction products were used to identify the mutation site.
Results: All affected mice developed paw inflammation at 4-8 weeks. Histological examinations revealed hyperplasia of the epidermis in the inflamed paws and increased macrophage expression in the spleen and paw tissues. The thresholds for the mechanical and thermal nociceptive responses were reduced in the affected mice. Locomotor activity was decreased in affected mice with inflamed hind paws and this reduction was due to the avoidance of the contact of affected paw with the floor. The motor strength and daily activities in the home cage of the affected mice did not show any significant changes. Although c-Fos immunoreactivity was normal in the dorsal horn of affected mice, CGRP immunoreactivity significantly increased in the deep layer of the dorsal horn. The number of microglia was increased in spinal cord, hippocampus and cerebral cortex in affected mice and the proliferation of microglia maintained for couple of months. 285 single nucleotide polymorphism markers were used to reveal the affected gene locus, which was found on the distal part of chromosome 18. A point mutation was detected at A to G in exon 8 of the pstpip2 gene, resulting in a conserved tyrosine residue at amino acid 180 replaced by cysteine (Y180 C).
Conclusions: The data provide definitive evidence that a mutation in pstpip2 causes autoinflammatory disease in an N-ethyl-N-nitrosourea mutagenesis mouse model. Thus, our pstpip2 mutant mice provide a new model for investigating the potential mechanisms of inflammatory pain. - 中文關鍵字: --
- 英文關鍵字: N-ethyl-N-nitrosourea, Autoinflammation, pstpip2, Single-nucleotide polymorphism, Nociception, Inflammatory pain