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The pathogenic mechanism of syndactyly type V identified in aHoxd13Q50R knock-in mice

Bone Research 2024年第2期12卷 349-360页

作者： han Wang Xiumin Chen Xiaolu Meng Yixuan Cao shirui han Keqiang Liu Ximeng Zhao Xiuli Zhao Xue Zhang McKusick-Zhang Center for Genetic Medicine State Key Laboratory of Complex Severe and Rare DiseasesDepartment of Medical GeneticsInstitute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijing 100005China Department of Orthopedics State Key Laboratory of Complex Severe and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China

Syndactyly type V (SDTY5) is an autosomal dominant extremity malformation characterized by fusion of the fourth and fifthmetacarpals. In the previous publication, we first identified a heterozygous missense mutation Q50R in homeobox domain (HD) ofHOXD13 in a large Chinese family with SDTY5. In order to substantiate the pathogenicity of the variant and elucidate the underlyingpathogenic mechanism causing limb malformation, transcription-activator-like effector nucleases (TALEN) was employed togenerate a Hoxd13Q50R mutant mouse. The mutant mice exhibited obvious limb malformations including slight brachydactyly andpartial syndactyly between digits 2-4 in the heterozygotes, and severe syndactyly, brachydactyly and polydactyly in *** on BMP2 and SHH/GREM1/AER-FGF epithelial mesenchymal (e-m) feedback, a crucial signal pathway for limbdevelopment, we found the ectopically expressed Shh, Grem1 and Fgf8 and down-regulated Bmp2 in the embryonic limb bud atE10.5 to E12.5. A transcriptome sequencing analysis was conducted on limb buds (LBs) at E11.5, revealing 31 genes that exhibitednotable disparities in mRNA level between the Hoxd13Q50R homozygotes and the wild-type. These genes are known to be involvedin various processes such as limb development, cell proliferation, migration, and apoptosis. Our findings indicate that the ectopicexpression of Shh and Fgf8, in conjunction with the down-regulation of Bmp2, results in a failure of patterning along both theanterior-posterior and proximal-distal axes, as well as a decrease in interdigital programmed cell death (PCD). This cascadeultimately leads to the development of syndactyly and brachydactyly in heterozygous mice, and severe limb malformations inhomozygous mice. These findings suggest that abnormal expression of SHH, FGF8, and BMP2 induced by HOXD13Q50R may beresponsible for the manifestation of human SDTY5.

关键词： BMP2 mechanism finding

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Panoramic variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants in TMEM141,DDHD2,and LHFPL5

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Frontiers of Medicine 2024年第1期18卷 81-97页

作者： Liwei Sun Xueting Yang Amjad Khan Xue Yu han Zhang shirui han Xiaerbati Habulieti Yang Sun Rongrong Wang Xue Zhang McKusick-Zhang Center for Genetic Medicine State Key Laboratory for Complex Severe and Rare DiseasesInstitute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijing100005China Chongqing Key Laboratory of Human Embryo Engineering Center for Reproductive MedicineNational Key Clinical Speciality Construction Project(Obstetrics and Gynecology)Chongqing Health Center for Women and ChildrenChongqing400013China Chongqing Clinical Research Center for Reproductive Medicine Women and Children’s Hospital of Chongqing Medical UniversityChongqing400013China Faculty of Biological Sciences Department of ZoologyUniversity of Lakki MarwatKhyber Pakhtunkhwa28420Pakistan Institute for Medical Genetics and Applied Genomics University of TübingenTübingen72076Germany Alexander von Humboldt fellowship Foundation Berlin10117Germany Department of Pediatrics The First Affiliated Hospital of Guangxi Medical UniversityNanning530000China Department of Laboratory Medicine State Key Laboratory for Complex Severe and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Science and Peking Union Medical CollegeBeijing100730China

Highly clinical and genetic heterogeneity of neurodevelopmental disorders presents a major challenge in clinical genetics and *** variation analysis is imperative to analyze the disease phenotypes resulting from multilocus genomic ***,a Pakistani family with parental consanguinity was presented,characterized with severe intellectual disability(ID),spastic paraplegia,and *** mapping,integrated single nucleotide polymorphism(SNP)array,whole-exome sequencing,and whole-genome sequencing were performed,and homozygous variants in TMEM141(c.270G>A,***90^(*)),DDHD2(c.411+767_c.1249-327del),and LHFPL5(c.250delC,***84^(*))were identified.A Tmem141^(***90^(*)/***90^(*))mouse model was *** studies showed impairments in learning ability and motor *** slice electrophysiology and Golgi staining demonstrated deficient synaptic plasticity in hippocampal neurons and abnormal dendritic branching in cerebellar Purkinje *** electron microscopy showed abnormal mitochondrial ***,studies on a human in vitro neuronal model(SH-SY5Y cells)with stable shRNA-mediated knockdown of TMEM141 showed deleterious effect on bioenergetic function,possibly explaining the pathogenesis of replicated phenotypes in the cross-species mouse ***,panoramic variation analysis revealed that multilocus genomic variations of TMEM141,DDHD2,and LHFPL5 together caused variable phenotypes in ***,the biallelic loss-of-function variants of TMEM141 were responsible for syndromic ID.

关键词： neurodevelopmental disorder autosomal recessive intellectual disability consanguinity spastic paraplegia hearing loss TMEM141

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Molecular analysis of 12 Pakistani families with non-syndromic or syndromic hearing loss

Molecular analysis of 12 Pakistani families with non-syndrom...

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中华医学会第十五次全国医学遗传学学术会议暨中国医师协会医学遗传医师分会第一届全国学术会议暨2016年浙江省医学遗传学年会

作者： Wang Rongrong han shirui Khan Amjad Zhang Xue Institute of Basic Medical Sciences Chinese Academy of Medical Sciences School of Basic Medicine Peking Union Medical College China Medical University

Objective To investigate the causative genetic mutations in 12 Pakistani families with non-syndro mic or syndromic hearing loss Method Mutations in the commonest causative gene GJB2 were pre-excluded by Sanger sequen cing. Then, targeted next-generation sequencing or whole-exome sequencing was carried out to analyze the genomic DNA samples from the 11 prob ands with hearing loss. Sanger sequencing was performed to verify all identi?ed variants. Result We found pathogenic or likely to be pathogenic mutations in all 12 families, including six k nown mutations in GJB2, SLC26 A4, LHFPL5, or USH2 A and eight novel mutations in ESPN, MY O7 A, LRTOMT, PCDH15, USH2 A or EPS8 L2. Notably, four compound heterozygous mutations i n the MYO7 A and USH2 A genes were detected in two consanguineous families, respectively. In addition, the novel frameshift mutation in EPS8 L2 was first documented in Pakistan. Conclusion Our study has increased the spectrum of mutations associated with hearing loss in t he Pakistani population. In addition, our study highlights the possibility of rare occurrences of com pound heterozygous mutations in consanguineous families.

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Novel-compound heterozygous mutations in the TTI2 gene cause syndromic-intellectual disability in a Chinese family

Novel-compound heterozygous mutations in the TTI2 gene cause...

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中华医学会第十五次全国医学遗传学学术会议暨中国医师协会医学遗传医师分会第一届全国学术会议暨2016年浙江省医学遗传学年会

作者： han shirui Wang Rongrong Liu Hongyan Zhang Xue The Research Center for Medical Genomics Key Laboratory of Medical Cell Biology Chinese Ministry of Ed ucation College of Basic Medical Science China Medical University Department of Medical Genetics and National Key Laboratory of Medical Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences School of Basic Medicine Peking Union Medical College People's Hospital of Zhengzhou University Henan Provincial People's Hospital

Objective Background Tel2-interacting proteins 2(TTI2)interact with Tel2-interacting proteins 1(TTI1) and telomere maintenance 2(TELO2) to form the Triple T complex, which acts as a co-ch aperone of phosphoinositide-3-kinase-related protein kinase. Two missense mutations in TTI2 ha ve been reported to be associate with non-syndromic or syndromic intellectual disability. Objectives To identify the causitive mutation in a Chinese family with syndromic intellectual disab ility. Method Methods Here,we describe a Chinese family with a recessive inheritance pattern of intell ectual disability characterized by cognitive impairment, microcephaly, aggressive, behavioral trou bles and skeletal anomalies. We performed whole-exomes sequencing on two-affected patients. Candidate variants were validated by Sanger sequencing. Quantitative real-time PCR was emplo yed to evaluate the effect of the frameshift mutation on gene expression. Cellular localization of t wo TTI2 isoforms were examined using immunostaing. Result Results We identified compound heterozygous-mutations(c.94244 del TCTins CTGTGC TTCCATTCCTTCCTCCTAG[p.C314 Cfs*9]and c.1100 C>T [p.P367 L]) in TTI2. Maternal novel fra meshift mutation resulted in premature termination codon and nonsense-mediate m RNA decay. P aternal reported c.1100 C>T mutation changed the highly conserved proline to leucine that locate d in the DUF2454 domain, and maybe disrupt essential for stability and function of the Triple T complex. Additionally,we found a TTI2 short isoform, which is wildly expressed and located both in cytoplasm and nucleus. Conclusion Conclusion These results suggest that compound heterozygous mutations in TTI2 might cause syndromic intellectual disability in our family. Our case expands the genetic causes o f intellectual disability in Chinese population.

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乌金疏石液的制备及临床观察

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中国药师 2006年第8期9卷 714-715页

作者：韩石蕊濮阳市人民医院河南濮阳457000

目的:研究乌金疏石液的制备工艺与质量控制标准,并观察其临床疗效。方法:采用薄层色谱鉴别进行质量控制,以排石饮液为对照进行临床疗效观察。结果:乌金疏石液治疗泌尿系结石的总有效率为86．7％,对照组总有效率为57．5％,治疗组明显优... 详细信息

目的:研究乌金疏石液的制备工艺与质量控制标准,并观察其临床疗效。方法:采用薄层色谱鉴别进行质量控制,以排石饮液为对照进行临床疗效观察。结果:乌金疏石液治疗泌尿系结石的总有效率为86．7％,对照组总有效率为57．5％,治疗组明显优于对照组(P<0．01)。绪论:乌金疏石液制备简单,质量可控,临床疗效较好。

关键词：乌金疏石液制备质量控制临床观察

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芪参益气滴丸治疗肝纤维化疗效研究

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陕西中医 2018年第4期39卷 473-475页

作者：韩石蕊河南省濮阳市人民医院药剂科濮阳457000

目的:观察分析芪参益气滴丸治疗肝纤维化的临床疗效及对TIMP-1、MMP-1的影响。方法:将106例肝纤维化患者随机分为对照组和观察组,每组53例,对照组给予常规方案治疗,观察组在对照组的治疗方案基础上给予芪参益气滴丸治疗,6个月为1个疗程... 详细信息

目的:观察分析芪参益气滴丸治疗肝纤维化的临床疗效及对TIMP-1、MMP-1的影响。方法:将106例肝纤维化患者随机分为对照组和观察组,每组53例,对照组给予常规方案治疗,观察组在对照组的治疗方案基础上给予芪参益气滴丸治疗,6个月为1个疗程。分别对两组患者临床治疗有效率、肝纤维化指标、FibroScan值及治疗前后TIMP-1和MMP-1等因子水平进行评定,并记录不良反应。结果:观察组总有效率(77.4%)明显高于对照组(50.9%)。观察组治疗后肝纤维化指标水平较对照组明显好转(P<0.05)。两组患者治疗后FibroScan值、金属蛋白酶组织抑制因子-1(TIMP-1)水平较治疗前明显下降(P<0.05),且观察组水平低于对照组(P<0.05);基质金属蛋白酶-1(MMP-1)水平与治疗前相比明显升高(P<0.05),且观察组水平高于对照组(P<0.05)。对照组和观察组均未见不良反应。结论:芪参益气滴丸治疗肝纤维化疗效显著,安全可靠,且可显著下调患者FibroScan值以及改善患者血清TIMP-1、MMP-1水平,值得临床使用。

关键词：肝纤维化/中西医结合疗法芪参益气滴丸

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复方异丙嗪甘草口服溶液的制备及临床应用

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中国药师 2009年第5期12卷 604-606页

作者：程洪兵韩石蕊濮阳市人民医院河南濮阳457000

目的:研制一种儿科常用止咳化痰药复方异丙嗪甘草口服溶液,并考察临床疗效。方法:建立复方异丙嗪甘草口服溶液的制备及质量控制方法;并与急支糖浆作对照,进行临床疗效观察。结果:该制剂质量稳定,治疗组总有效率为84.2%,对照组总有效率为... 详细信息

目的:研制一种儿科常用止咳化痰药复方异丙嗪甘草口服溶液,并考察临床疗效。方法:建立复方异丙嗪甘草口服溶液的制备及质量控制方法;并与急支糖浆作对照,进行临床疗效观察。结果:该制剂质量稳定,治疗组总有效率为84.2%,对照组总有效率为45.1%,治疗组疗效明显优于对照组(P<0.05)。结论:复方异丙嗪甘草口服溶液制备方法简单,质量控制方法可靠,临床疗效满意。

关键词：复方异丙嗪甘草口服溶液制备临床应用

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肛肠袋泡剂质量标准研究

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中国药业 2014年第23期23卷 45-46页

作者：程洪兵韩石蕊赵永旗邵海荣河南省濮阳市人民医院河南濮阳457000

目的建立肛肠袋泡剂的质量控制标准。方法采用高效液相色谱（HPLC）法测定了处方中主药黄柏内盐酸小檗碱的含量。结果盐酸小檗碱进样质量浓度在30.0-150.0μg/mL范围内与峰面积线性关系良好（r=0.999 6）,平均回收率为97.40%,RSD为1.27%... 详细信息

目的建立肛肠袋泡剂的质量控制标准。方法采用高效液相色谱（HPLC）法测定了处方中主药黄柏内盐酸小檗碱的含量。结果盐酸小檗碱进样质量浓度在30.0-150.0μg/mL范围内与峰面积线性关系良好（r=0.999 6）,平均回收率为97.40%,RSD为1.27%（n=6）。结论该方法可有效控制肛肠袋泡剂的质量。

关键词：高效液相色谱法盐酸小檗碱质量标准

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HPLC法测定冬菊利咽合剂中绿原酸的含量

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中国药师 2009年第9期12卷 1214-1215页

作者：程洪兵韩石蕊赵永旗邵海荣濮阳市人民医院河南濮阳457000

目的:建立冬菊利咽合剂中绿原酸含量测定的高效液相色谱方法。方法:采用色谱柱为Kromasil C_(18)柱(250mm×4.6mm,5μm),以乙腈-0.4%磷酸溶液(10:90)为流动相,流速为1.0ml·min^(-1),检测波长为327nm进行检测。结果:绿原酸在16.64～37.4... 详细信息

目的:建立冬菊利咽合剂中绿原酸含量测定的高效液相色谱方法。方法:采用色谱柱为Kromasil C_(18)柱(250mm×4.6mm,5μm),以乙腈-0.4%磷酸溶液(10:90)为流动相,流速为1.0ml·min^(-1),检测波长为327nm进行检测。结果:绿原酸在16.64～37.44μg·ml^(-1)范围内线性关系良好(r=0.999 8),平均回收率为99.2%,RSD为0.94%(n=6)。结论:该方法操作简便、准确、精密度高,可用于控制冬菊利咽合剂的质量。

关键词：高效液相色谱法冬菊利咽合剂绿原酸

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HPLC测定旱莲胶囊中补骨脂素和异补骨脂素的含量

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中国药师 2008年第2期11卷 184-185页

作者：韩石蕊程洪兵赵永旗邵海荣濮阳市人民医院河南濮阳457000

目的:建立测定旱莲胶囊中补骨脂素和异补骨脂素含量的高效液相色谱方法。方法:色谱柱为Thermo C_(18)柱(250 mm×4.6 mm,5μm),流动相为甲醇-水(50:50),流速为0.6 ml·min^(-1),检测波长为295 nm。结果:补骨脂素的线性范围为0.2～0.6μg... 详细信息

目的:建立测定旱莲胶囊中补骨脂素和异补骨脂素含量的高效液相色谱方法。方法:色谱柱为Thermo C_(18)柱(250 mm×4.6 mm,5μm),流动相为甲醇-水(50:50),流速为0.6 ml·min^(-1),检测波长为295 nm。结果:补骨脂素的线性范围为0.2～0.6μg,r=0.999 8(n=5),平均回收率为99.2%,RSD为1.01%;异补骨脂素的线性范围为0.2～0.6μg,r=0.999 9(n =5),平均回收率为100.3%,RSD为2.22%。结论:该方法操作简便,准确,精密度高,可用于控制旱莲胶囊的质量。

关键词：高效液相色谱法旱莲胶囊补骨脂素异补骨脂素

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