New Modes of GPCR Signalling

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Identification a Novel MYO6 Mutation Associated with Autosomal Dominant Non-Syndromic Hearing Impairment in a Large Chinese Family Yulei Li1,2, Zhenping Xu1,2, Xiangyang Zhang1, Juan Li1, Jing Yu Liu1* 1Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, 430074, Wuan, Hubei, P. R. China; 2Department of Life Science and Technique, Xinxiang Medical University, Xinxiang, 453003, China) Objectives: Hearing impairment is a disorder of partial or complete hearing loss, it is caused by organic or functional pathological changes in the human auditory system. Hearing impairment have an estimated incidence rate of approximately 1 in 500 newborns with bilateral congenital sensorineural hearing loss≥40dB in developed countries. And the ratio up to 2.7‰ for the age of 5. In the adolescent, this number rises to 3.5‰. Genetic factor is the most important nosogenesis among all the factors. Most of the inherited cases are non-syndromic, with the only symptom of auditory dysfunction, not accompanied with other malformation or disorder. Most of the non-syndromic hearing impairment (NSHI) is caused by monogenic mutation, and they are genetically heterogeneity. Many autosomal dominant NSHI genes have been identified. Most of these genes have a high expression or specially expressed in the inner ear cells. By the molecular basis of these studies, it gives us a further understands of the physiological mechanism of auditory system and the pathological basis of hearing impairment.Methods: Linkage analysis was carried out by STR Markers flanking all known autosomal dominant NSHI genes and direct DNA sequence for the proband was used to mutation analysis by ABI PRISM 3100 Genetic Analyzer.Results: A large Chinese Han family with an autosomal dominant non-syndromic hearing impairment have been identified and characterized. Linkage analysis of genotyping data from the family showed the DFNA22 locus can not be excluded. There is only one candidate gene MYO6 in this locus which is responsible for NSHI. Mutational analysis showed a novel missense mutation c.599A>G in exon 8 was found in proband, it was co-segregated with the affected individuals in the family and did not exist in the unaffected family members and 100 unrelated normal controls. The mutation results in a substitution of an asparagine residue by a serine residue at codon 200 (p.N200S). The p.N200S occurred in the motor domain near the ATP binding site of myosin VI, and the N200 residue is evolutionally highly conserved from flagellum to human.Conclusion: It is presumed that the mutation p.N200S in the motor domain maybe affect the generation of mechanical force in myosin VI, and lead to the dysfunction of inner ear hair cell, and eventually result in the hearing impairment. Key Words: non-syndromic hearing impairment, mutation analysis, myosin VI, p.N200S, motor domain *Correspondence to: Dr. J. Y. Liu, liujy@mail.hust.edu.cn
MAPK Scaffolding by BIT1 in the Golgi Complex Modulates Stress Resistance Ping Yi1,2,3*, Duc Thang Nguyên4*, Arisa Higa-Nishiyama1,2, Patrick Auguste2,4, Marion Bouchecareilh1, Michel Dominguez5, Regula Bielmann4, Sandrine Palcy2, Jian Feng Liu3 and Eric Chevet1,2,3 ‡ 1Avenir, INSERM U889, Bordeaux, France; 2Université Victor Segalen Bordeaux 2, IFR 66, F-33076, Bordeaux, France; 3Key Laboratory of Molecular Biophysics of Ministry of Education, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China; 4Department of Surgery, McGill University, Montreal, QC, Canada; 5HyperOmics Farma, Montreal, QC, Canada; *These authors contributed equally to this work The endoplasmic reticulum (ER) is an essential organelle whose major functions are to ensure proper secretory protein folding and trafficking. These mechanisms involve the activation of specific ER-resident molecular machines, which might be regulated by their membranous environments. Based on this observation, we aimed to characterize the proteome of ER-membrane microdomains to identify new components of the ER that have a role in secretory pathway-associated functions. Using this approach with dog pancreatic rough microsomes, we found that mitochondrial Bcl-2 inhibitor of transcription (BIT1) localized in the early secretory pathway and accumulated in the Golgi complex. Using both a chimeric protein of the luminal and transmembrane domains of ER-resident TRAPa and the cytosolic domain of BIT1, and silencing of BIT1 expression, we perturbed endogenous BIT1 oligomerization and localization to the Golgi. This led to enhanced ERK signaling from the Golgi complex, which resulted in improved stress resistance. This work provides the first evidence for the existence of ER microdomains that are involved in the regulation of BIT1 structure and trafficking, and identifies BIT1 as a negative regulator of the ERK-MAPK signaling pathway in the Golgi. Key Words: BIT1, MAPK, Secretory pathway, Stress ‡Author for correspondence: Eric Chevet, eric.chevet@u-bordeaux2.fr
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