目的对我国一个先天性特发性眼球震颤(congenital idiopathic nystagmus,CIN)家系进行基因突变筛查。方法在获取知情同意后,对该家系成员进行病史采集及眼科检查。采集该CIN家系成员及200名正常对照者的外周静脉血各5 m L,并提取基因组...目的对我国一个先天性特发性眼球震颤(congenital idiopathic nystagmus,CIN)家系进行基因突变筛查。方法在获取知情同意后,对该家系成员进行病史采集及眼科检查。采集该CIN家系成员及200名正常对照者的外周静脉血各5 m L,并提取基因组DNA。对FRMD7基因进行引物的设计与合成,使用聚合酶链式反应技术对FRMD7基因的所有编码区序列进行扩增,扩增产物直接测序,寻找突变位点。结果在该CIN家系发现FRMD7基因上c.1003C>T突变,该突变为无义突变(p.R335X)。家系中5例患者均为男性且为该突变的纯合子,3位女性携带者为该突变的杂合子,其余成员和200名正常对照者均未发现此突变。结论该CIN家系致病突变为FRMD7基因上c.1003C>T p.R335X突变。展开更多
FRMD6,a member of the 4.1 ezrin-radixin-moesin domain-containing protein family,has been reported to inhibit tumor progression in multiple cancers.Here,we demonstrate the involvement of FRMD6 in lung cancer progressio...FRMD6,a member of the 4.1 ezrin-radixin-moesin domain-containing protein family,has been reported to inhibit tumor progression in multiple cancers.Here,we demonstrate the involvement of FRMD6 in lung cancer progression.We find that FRMD6 is overexpressed in lung cancer tissues relative to in normal lung tissues.In addition,the enhanced expression of FRMD6 is associated with poor outcomes in patients with lung squamous cell carcinoma(n=75,P=0.0054)and lung adenocarcinoma(n=94,P=0.0330).Cell migration and proliferation in vitro and tumor formation in vivo are promoted by FRMD6 but are suppressed by the depletion of FRMD6.Mechanistically,FRMD6 interacts and colocalizes with mTOR and S6K,which are the key molecules of the mTOR signaling pathway.FRMD6 markedly enhances the interaction between mTOR and S6K,subsequently increasing the levels of endogenous pS6K and downstream pS6 in lung cancer cells.Furthermore,knocking out FRMD6 inhibits the activation of the mTOR signaling pathway in Frmd6^(−/−)gene KO MEFs and mice.Altogether,our results show that FRMD6 contributes to lung cancer progression by activating the mTOR signaling pathway.展开更多
目的研究一个先天性特发性眼球震颤家系的致病基因。方法选取X染色体上微卫星标记物，通过PCR扩增后，进行基因组扫描。应用GeneMapper软件进行PCR扩增产物片段大小和单倍型分析，Linkage5．1软件进行两点汉连锁值（Log of odds，LOD）...目的研究一个先天性特发性眼球震颤家系的致病基因。方法选取X染色体上微卫星标记物，通过PCR扩增后，进行基因组扫描。应用GeneMapper软件进行PCR扩增产物片段大小和单倍型分析，Linkage5．1软件进行两点汉连锁值（Log of odds，LOD）计算，通过基因序列分析发现致病基因突变。结果经两点法计算，在DXS1047可获最大LOD值为8．55；基因序列分析发现FRMD7基因第9外显子存在G990T的杂合性基因突变。结论FRMD7基因突变是导致该家系出现疾病的主要原因。展开更多
Objective:To screen mutations in FERM domain-containing protein 7(FRMD7) gene in two Chinese families with X-linked idiopathic congenital nystagmus(XLICN).Methods:Common ophthalmic data and peripheral blood of two Chi...Objective:To screen mutations in FERM domain-containing protein 7(FRMD7) gene in two Chinese families with X-linked idiopathic congenital nystagmus(XLICN).Methods:Common ophthalmic data and peripheral blood of two Chinese XLICN families(families A and B) were collected after informed consent.Genomic DNA was prepared from the peripheral blood of members of the two families and from 100 normal controls.Mutations in the FRMD7 gene were determined by directly sequencing polymerase chain reaction(PCR) products.Results:We identified a novel mutation c.980_983delATTA compound with c.986C>A mutation in the 11th exon of FRMD7 in family B,and a previously reported splicing mutation c.782G>C(p.R261G) in family A.The mutations were detected in patients and female carriers,while they were absent in other relatives or in the 100 normal controls.Conclusions:Our results expand the spectrum of FRMD7 mutations in association with XLICN,and further confirm that the mutations of FRMD7 are the underlying molecular mechanism for XLICN.展开更多
Infant nystagmus sydrome presents as involuntary eye movement disorder and can affect seriously ocular function. We performed a retrospective study of clinical data and FRMD7 genetic test results in 12 cases of infant...Infant nystagmus sydrome presents as involuntary eye movement disorder and can affect seriously ocular function. We performed a retrospective study of clinical data and FRMD7 genetic test results in 12 cases of infantile nystagmus syndrome to correlate waveform, stereopsis, and visual acuity. The patients(age 6.40±2.67 years) had FRMD7 mutations as follows: missense in eight cases, shear in two cases, frameshift in one case, and non-frameshift in one case. Horizontal jerk waveform was observed in six cases, versus horizontal pendulum in five cases and dual jerk in one case. The uncorrected visual acuity(24 eyes) was 0.21±0.12,compared with a corrected visual acuity(24 eyes) of 0.32±0.14. All patients had simultaneous perception, versus fusion function in 10 cases(83.33%) and stereoscopic vision in seven cases(58.33%) using the synoptophore. Eleven cases(91.67%) detected the stereo fly, compared with five cases(41.67%) for stereoscopic circles and seven cases(58.33%) for stereoscopic animals by Titmus test. Stereoscopic vision using the synoptophore did not correlate with the frequency, amplitude, or intensity of nystagmus or with corrected binocular visual acuity. The infantile nystagmus syndrome with FRMD7 mutations in our cases was caused primarily de novo and missense mutations. Visual acuity and binocular visual function were significant impaired, and the waveform was generally horizontal jerk. Also, an infrared videonystagmogram can record the frequency, amplitude, and intensity of nystagmus accurately.展开更多
The Hippo pathway is evolutionarily conserved from Drosophila to mammals. FRMD6 is one crucial up- stream component of the Hippo pathway while its function and regulatory mechanism are largely elusive. We decided to p...The Hippo pathway is evolutionarily conserved from Drosophila to mammals. FRMD6 is one crucial up- stream component of the Hippo pathway while its function and regulatory mechanism are largely elusive. We decided to purify the protein complex of FRMD6 to further explore its regulatory mechanism. We established the MCF7 breast cancer cells that stably expressed FRMD6 by retroviruses infection. And we purified the FRMD6-interacting protein complex for further analysis by high performance liquid chromatography-mass spectrometry/mass spectrometry（HPLC- MS/MS）. Interestingly, we observed that the major binding partner of FRMD6 is 14-3-3 family of proteins. The interac- tion between FRMD6 and 14-3-3 proteins was detected by co-immunoprecipitation（CO-IP）. The disruption of their interaction resulted in the nuclear localization of FRMD6. Importantly, the T28A mutant of FRMD6 showed stronger tumor suppressor function than wild type（WT） FRMD6. Our results indicate that 14-3-3 proteins tightly regulate the subcellular localization of FRMD6 so as to endow FRMD6 with the tumor suppressor function on breast cancer.展开更多
基金supported by grants from the National Natural Science Foundation of China(Nos.82172972,81972609,81472734,31170711,81773199,81730071,81972616,81230051,and 81670626)the Beijing Natural Science Foundation(Nos.202084,7171005,7120002,and 7202080).
文摘FRMD6,a member of the 4.1 ezrin-radixin-moesin domain-containing protein family,has been reported to inhibit tumor progression in multiple cancers.Here,we demonstrate the involvement of FRMD6 in lung cancer progression.We find that FRMD6 is overexpressed in lung cancer tissues relative to in normal lung tissues.In addition,the enhanced expression of FRMD6 is associated with poor outcomes in patients with lung squamous cell carcinoma(n=75,P=0.0054)and lung adenocarcinoma(n=94,P=0.0330).Cell migration and proliferation in vitro and tumor formation in vivo are promoted by FRMD6 but are suppressed by the depletion of FRMD6.Mechanistically,FRMD6 interacts and colocalizes with mTOR and S6K,which are the key molecules of the mTOR signaling pathway.FRMD6 markedly enhances the interaction between mTOR and S6K,subsequently increasing the levels of endogenous pS6K and downstream pS6 in lung cancer cells.Furthermore,knocking out FRMD6 inhibits the activation of the mTOR signaling pathway in Frmd6^(−/−)gene KO MEFs and mice.Altogether,our results show that FRMD6 contributes to lung cancer progression by activating the mTOR signaling pathway.
文摘目的研究一个先天性特发性眼球震颤家系的致病基因。方法选取X染色体上微卫星标记物，通过PCR扩增后，进行基因组扫描。应用GeneMapper软件进行PCR扩增产物片段大小和单倍型分析，Linkage5．1软件进行两点汉连锁值（Log of odds，LOD）计算，通过基因序列分析发现致病基因突变。结果经两点法计算，在DXS1047可获最大LOD值为8．55；基因序列分析发现FRMD7基因第9外显子存在G990T的杂合性基因突变。结论FRMD7基因突变是导致该家系出现疾病的主要原因。
基金Project supported by the Zhejiang Provincial Science Fund of Health Bureau of China (No. 2012KYA102)the Fundamental Research Funds for the Central Universities (No. 2011FZA7014)+1 种基金the Zhejiang Key Innovation Team Project of China (No. 2009R50039)the Zhejiang Key Laboratory Fund of China (No. 2011E10006)
文摘Objective:To screen mutations in FERM domain-containing protein 7(FRMD7) gene in two Chinese families with X-linked idiopathic congenital nystagmus(XLICN).Methods:Common ophthalmic data and peripheral blood of two Chinese XLICN families(families A and B) were collected after informed consent.Genomic DNA was prepared from the peripheral blood of members of the two families and from 100 normal controls.Mutations in the FRMD7 gene were determined by directly sequencing polymerase chain reaction(PCR) products.Results:We identified a novel mutation c.980_983delATTA compound with c.986C>A mutation in the 11th exon of FRMD7 in family B,and a previously reported splicing mutation c.782G>C(p.R261G) in family A.The mutations were detected in patients and female carriers,while they were absent in other relatives or in the 100 normal controls.Conclusions:Our results expand the spectrum of FRMD7 mutations in association with XLICN,and further confirm that the mutations of FRMD7 are the underlying molecular mechanism for XLICN.
基金supported by the capital special features of the Beijing municipal science and technology commission(Z151100004015072)
文摘Infant nystagmus sydrome presents as involuntary eye movement disorder and can affect seriously ocular function. We performed a retrospective study of clinical data and FRMD7 genetic test results in 12 cases of infantile nystagmus syndrome to correlate waveform, stereopsis, and visual acuity. The patients(age 6.40±2.67 years) had FRMD7 mutations as follows: missense in eight cases, shear in two cases, frameshift in one case, and non-frameshift in one case. Horizontal jerk waveform was observed in six cases, versus horizontal pendulum in five cases and dual jerk in one case. The uncorrected visual acuity(24 eyes) was 0.21±0.12,compared with a corrected visual acuity(24 eyes) of 0.32±0.14. All patients had simultaneous perception, versus fusion function in 10 cases(83.33%) and stereoscopic vision in seven cases(58.33%) using the synoptophore. Eleven cases(91.67%) detected the stereo fly, compared with five cases(41.67%) for stereoscopic circles and seven cases(58.33%) for stereoscopic animals by Titmus test. Stereoscopic vision using the synoptophore did not correlate with the frequency, amplitude, or intensity of nystagmus or with corrected binocular visual acuity. The infantile nystagmus syndrome with FRMD7 mutations in our cases was caused primarily de novo and missense mutations. Visual acuity and binocular visual function were significant impaired, and the waveform was generally horizontal jerk. Also, an infrared videonystagmogram can record the frequency, amplitude, and intensity of nystagmus accurately.
基金Supported by the National Natural Science Foundation of China（No.30973274） and the Doctoral Fund of Youth Scholars of Ministry of Education of China（No.20090061120073）
文摘The Hippo pathway is evolutionarily conserved from Drosophila to mammals. FRMD6 is one crucial up- stream component of the Hippo pathway while its function and regulatory mechanism are largely elusive. We decided to purify the protein complex of FRMD6 to further explore its regulatory mechanism. We established the MCF7 breast cancer cells that stably expressed FRMD6 by retroviruses infection. And we purified the FRMD6-interacting protein complex for further analysis by high performance liquid chromatography-mass spectrometry/mass spectrometry（HPLC- MS/MS）. Interestingly, we observed that the major binding partner of FRMD6 is 14-3-3 family of proteins. The interac- tion between FRMD6 and 14-3-3 proteins was detected by co-immunoprecipitation（CO-IP）. The disruption of their interaction resulted in the nuclear localization of FRMD6. Importantly, the T28A mutant of FRMD6 showed stronger tumor suppressor function than wild type（WT） FRMD6. Our results indicate that 14-3-3 proteins tightly regulate the subcellular localization of FRMD6 so as to endow FRMD6 with the tumor suppressor function on breast cancer.
