氨基糖苷类抗生素致聋一家系线粒体DNA突变研究
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摘要
目的应用遗传性耳聋基因芯片检测母系遗传药物性耳聋家系成员线粒体DNA常见突变类型及频率,筛查聋哑学校学生和门诊耳聋患者中的药物性敏感个体,预测氨基糖苷类抗生素耳毒性损害风险,给予宣教,降低耳聋的发病率。
方法收集一母系遗传药物性耳聋家系成员、太原聋哑学校在校学生及门诊散发的非综合征性耳聋患者共计82人的外周静脉血5ml,用酚／氯仿法提取DNA；经PCR扩增和杂交后,用耳聋基因芯片检测国人中常见的药物相关性耳聋基因的2个热点突变,包括线粒体DNA12S rRNA(A1555G,C1494T)。
结果在82例样本中,成功提取DNA 81例,其中包括12例家系成员、61例聋哑学校学生及8例门诊患者,共检测出线粒体DNA A1555G突变7例,全部来自药物性耳聋家系,未检测出线粒体DNA C1494T突变阳性。
结论线粒体DNA A1555G点突变是导致该家系致聋的主要因素之一,且携带该突变的患者多分布在母系遗传特点的耳聋家系。家系成员的耳聋程度从正常到极重度不等,临床表现为感音性耳聋,遗传方式符合线粒体遗传。
Objective Application of the DNA microarray which is able to perform mutation detection of 2 hot-spot mutations in one most common mitochondrial DNA gene simultaneously, including mitochondrial 12S rRNA(A1555G,C1494T),to detect the patients who were the family members of a pedigree with a maternally inherited aminoglycoside antibiotic-induced deafness,deaf students,and clinical patients.Screening and testing for this mutation are effective methods to prevent ototoxicity in A1555G carriers and their maternal family members.
Methods Eigty-two non-syndromic hearing loss individuals were included in this study. Blood samples were obtained from 12 family members in a pedigree with a maternally inherited aminoglycoside antibiotic-induced deafness,and 70 sporadic non-syndromic deafness coming from Taiyuan School for the Deaf and our hospital. We collected peripheral blood 5ml and extracted DNA from the isolated leukocytes with phenol/chloroform method,then the mitochondrial DNA target fragments were amplified by polymerase chain reaction (PCR). Their genomic DNA samples were detected with the DNA microarray which is able to perform mutation detection of 2 hot-spot mutations in one most common pathologic mitochondrial DNA gene including mitochondrial 12SrRNA(A1555G,C1494T) simultaneously.
Results In the 82 cases of samples,we extracted DNA 81cases successfully,including 12 cases of family members,61 cases of deaf school students and 8 clinical patients. The homoplasmic A1555G mutation was found in 7 individuals of 81 patients,and all the positive patients were coning from the drug-induced deafness pedigree. The C1494Tmutation did not appear in all cases.
Conclusion Our results suggested that the mitochondrial DNA 1555G mutation may be one of major factors resulted in aminoglycoside antibiotic-induced deafness in this pedigree, and the 1555G carriers were mainly distributed in the pedigree with maternally inherited deafness.Additionally,this mutation can result in various grades of deafness.The deafness grades ranged from normal to profound. We identified the hereditary model of the pedigree was non-syndromic sensoneural hearing loss mitochondrial inheritance.
方法收集一母系遗传药物性耳聋家系成员、太原聋哑学校在校学生及门诊散发的非综合征性耳聋患者共计82人的外周静脉血5ml,用酚／氯仿法提取DNA；经PCR扩增和杂交后,用耳聋基因芯片检测国人中常见的药物相关性耳聋基因的2个热点突变,包括线粒体DNA12S rRNA(A1555G,C1494T)。
结果在82例样本中,成功提取DNA 81例,其中包括12例家系成员、61例聋哑学校学生及8例门诊患者,共检测出线粒体DNA A1555G突变7例,全部来自药物性耳聋家系,未检测出线粒体DNA C1494T突变阳性。
结论线粒体DNA A1555G点突变是导致该家系致聋的主要因素之一,且携带该突变的患者多分布在母系遗传特点的耳聋家系。家系成员的耳聋程度从正常到极重度不等,临床表现为感音性耳聋,遗传方式符合线粒体遗传。
Objective Application of the DNA microarray which is able to perform mutation detection of 2 hot-spot mutations in one most common mitochondrial DNA gene simultaneously, including mitochondrial 12S rRNA(A1555G,C1494T),to detect the patients who were the family members of a pedigree with a maternally inherited aminoglycoside antibiotic-induced deafness,deaf students,and clinical patients.Screening and testing for this mutation are effective methods to prevent ototoxicity in A1555G carriers and their maternal family members.
Methods Eigty-two non-syndromic hearing loss individuals were included in this study. Blood samples were obtained from 12 family members in a pedigree with a maternally inherited aminoglycoside antibiotic-induced deafness,and 70 sporadic non-syndromic deafness coming from Taiyuan School for the Deaf and our hospital. We collected peripheral blood 5ml and extracted DNA from the isolated leukocytes with phenol/chloroform method,then the mitochondrial DNA target fragments were amplified by polymerase chain reaction (PCR). Their genomic DNA samples were detected with the DNA microarray which is able to perform mutation detection of 2 hot-spot mutations in one most common pathologic mitochondrial DNA gene including mitochondrial 12SrRNA(A1555G,C1494T) simultaneously.
Results In the 82 cases of samples,we extracted DNA 81cases successfully,including 12 cases of family members,61 cases of deaf school students and 8 clinical patients. The homoplasmic A1555G mutation was found in 7 individuals of 81 patients,and all the positive patients were coning from the drug-induced deafness pedigree. The C1494Tmutation did not appear in all cases.
Conclusion Our results suggested that the mitochondrial DNA 1555G mutation may be one of major factors resulted in aminoglycoside antibiotic-induced deafness in this pedigree, and the 1555G carriers were mainly distributed in the pedigree with maternally inherited deafness.Additionally,this mutation can result in various grades of deafness.The deafness grades ranged from normal to profound. We identified the hereditary model of the pedigree was non-syndromic sensoneural hearing loss mitochondrial inheritance.
引文
[1]邱维勤,胡诞宁,吴保同,等.氨基糖苷抗生素致聋的遗传流行病学研究.上海铁道大学学报(医版),1997,11(3)：188-191.
[2]Li Z, Li R, Chen J, et al. Mutational analysis of the mitochondrial 12S rRNA gene in Chinese pediatric subjects with aminoglycoside-induced and non-syndromic hearing loss. Hum Genet, 2005,117(1):9-15.
[3]袁慧军,姜泅长,杨伟炎.线粒体DNA A1555G突变与遗传性耳聋.国外医学耳鼻咽喉科册.1997,21：322-326.
[4]Dai P,Yu F, Han B, et al. The prevalence of the 235delC GJB2 mutation in a Chinese deaf population. Genetics in Medicine,2007,9(5):283-289.
[5]戴朴,刘新,于飞,等.18个省市聋校学生非综合征性聋病分子流行病学研究(Ⅰ)-GJB2235delC和线粒体DNA12SrRNAA1555G突变筛查报告.中华耳科学杂志,2006,4：1-5.
[6]袁慧军,姜泗长,杨伟炎,等.氨基糖苷类抗生素致聋家系线粒体DNA1555G点突变分析.中华耳鼻咽喉科杂志,1998,33(2)：67-70.
[7]潘虹,柯肖枚,戚豫,等.非综合征家族性耳聋线粒体DNA1555A-G点突变分析.实用儿科临床杂志,1999,14(2)：67-68.
[8]李为民,韩东一,袁慧军,等.遗传性耳聋29家系线粒体基因突变检测与系谱分析.临床耳鼻咽喉科杂志,2001,15(增刊)：53-58.
[9]牟奕,单祥年,严明,等.一个母系遗传非综合征耳聋大家系mtDNA序列分析.遗传2001,23(5)：401-405.
[10]戴朴,袁慧军,曹菊阳,等.线粒体基因A1555G突变检测试剂盒在药物性耳聋分子诊断中的应用.中国听力语言康复科学2004,(6)：21-23.
[11]Scott DA, Kraft ML, et al.Connexin mutation and hearing loss.Nature,1998,391(6662):32.
[12]王国建,戴朴,韩东一,等.基因芯片技术在非综合征性耳聋快速基因诊断中的应用研究.中华耳科学杂志,2008,6(1)：61-66.
[13]Zhao H,Li R,Wang Q,et al.Maternally inherited aminoglycoside-induced and non-syndromic deafness associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family.Am J Hum Genet,2004,74(1):139-152.
[14]Zhao H,Young WY,Yan Q,et al.Functional charaterization of the mitochondrial 12S rRNA C1494T mutation associated with aminoglycoside induced and non-syndromic hearing loss.Nuclein Acids Res,2005,33(3):1132-1139.
[15]Guan MX, Young WY, Zhao LD,et al.88 Variants in mitochondrial tRNAs may influence the phenotypic manifestation of deafness-associated 12S rRNA A1555G and C1494T mutations in Chinese families with hearing loss.Mitochondrion,2007,7(6):430-437.
[16]Zhao L,Young WY,Li R,et al.Clinical evaluation and sequence analysis of the complete mitochondrial genome of three Chinese patients with hearing impairment associated with the 12S rRNA T1095C mutation.Biochem Biochem Biophys Res Commun,2004,325(4):1503-1508.
[17]Kabayashi K,Oguchi T,Asamura K,et al.Genetic features,clinical phenotypes,and prevalence of sensorineural hearing loss associated with the 961delC mitochondrial mutation.Auris Nasus Larynx,2005,32(2):119-124.
[18]刘新,戴朴,黄德亮,等.线粒体DNA A1555G突变大规模筛查及其预防意义探讨.中华医学杂志,2006,86：1318-1322.
[19]Prezant TR,Agapian JV,Bohlman MC,et al.Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nature Genetic,1993,4 (3):289-294.
[20]张丽珊,张志平,周晓雷.三例氨基糖苷类抗生素致聋患者的线粒体DNA序列分析.遗传,1996,18(6)：3-5.
[21]Fischel-Ghodsian N. Mitochondrial mutations and hearing loss:paradigm for mitochondrial genetics. Am J Hum Genet,1998,62(1):15-19.
[22]Pandya A, Xia XJ, Erdenetungalag R, et al. Heterogenous point mutations in the mitochondrial tRNA Ser(UCN) precursor coexisting with the A1555G mutation in deaf students from Mongolia. Am J Hum Genet,1999,65(6):1803-1806.
[23]Li R, Xing G, Yan M, et al. Cosegregation of C-insertion at position 961 with the A1555G mutation of the mitochondrial 12S rRNA gene in a large Chinese family with maternally inherited hearing loss. Am J Med Genet A,2004,124A(2):113-117.
[24]Yoshida M, Shintani T, Hirao M, et al. Aminoglycoside induced hearing loss in a patient with the 961 mutation in mitochondrial DNA. ORL J Otorhinolaryngol Relat Spec, 2002,64(3):219-222.
[25]Tang X, Li Y, Zhu Y, et al.Very low penetrance of hearing loss in seven Han Chinese pedigrees carrying the deafness associated 12S rRNA A1555G mutation.Gene,2007,393(1-2):11-19.
[1]袁慧军,姜泗长,杨伟炎.线粒体DNA A1555G突变与遗传性耳聋.国外医学耳鼻咽喉科册.1997,21：322-326.
[2]Hashimoto S,Robert S,et al.Computer-aided three-dimensional reconstruction and morpho-metry of the outer hair cells of the guinea pig cochlea. Acta Otolaryngology.1988,105:64-74.
[3]Anderson S,Bankier AT,et al.Sequence and organization of the human mitochondrial genome. Nature,1981,90 (5806):457-465.
[4]Prezant TR, Agapian JV, Bohlman MC. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nature Genetic,1993,4(3):289-294.
[5]Hutchin T,Haworth I,Higashi K,et al.A molecular basis for human hypersensitivity to aminoglycoside antibiotics nucleic acids research,1993,21(18):4174-4179.
[6]Shin-ichi Usami,Satoko Abe,Miya Kasai,et al.Genetic and clinical features of sensorineural hearing loss associated with the 1555 mitochondrial mutation.Laryngoscope,1997,107(4):483-490.
[7]袁慧军,姜泗长,杨伟炎,等.氨基糖苷类抗生素致聋家系线粒体点突变分析.中华耳鼻咽喉杂志,1998,33：67-70.
[8]Fischel-Ghodsian N. Mitochondrial mutation and hearing loss:paradigm for mitochondrial genetics.Am J Hum Genet,1998,62(1):15-19.
[9]赵立东,王秋菊,郭维维,管敏鑫,韩东一,杨伟炎.与线粒体DNA A1555G突变有关的非综合征性耳聋.中华耳科学杂志,2004,2：136-141.
[10]Hu DN,Qui WQ,Wu BT,et al.Genetic aspects of antibiotic induced deafness:mitochondrial inheritance.J Med Genet.1991,28(2):79-83.
[11]Fishel-Ghodsian N,Prezant TR,Chaltraw W,et al. Mitochondrial gene mutation is a significant predisposing factor aminoglycoside ototoxicity.Am J Otolaryngol,1997,18(3):173-178.
[12]Schach J,Weiner N.Aminoglycoside-induced hearing loss:a molecular hypothesis.ORL,1986 ,48(2):116-123.
[13]Lim DJ.A review:effects of nosie and ototoxic drugs at the cellular level in the cochlea.Am J Otolaryngol,1986,7:73-99.
[14]Kroese ABA,Das A,Hudspeth AJ.Blockage of the transduction channels of hair cells in the bullfrog's sacculus by aminoglycoside antibiotic.Hear Res.1989,37:203-217.
[15]Williams SE,Zenner HP,Schancht J.Three molecular steps of aminoglycoside ototoxicity demonstrated in the outer hair cells.Hear,Res.1987,30(1):11-18.
[16]Guan MX,Fischel-GhodsianN,Attardi G.Biochemical evidence for nuclear gene involvement in phenotype of nonsyndromic deafness associated with mitochondrial 12S rRNA mutation.Hum Mol Genet,1996,5:963-971.
[17]Guan MX,Fischel-Ghodsian N,Attardi G.Biochemical basis for the inherited susceptibility to aminoglycoside ototoxicity.Hum Mol Genet.2000,9:1781-1793.
[18]Harasaki K,Rando RR.Specific binding of aminoglycoside to a human rRNA construct based on a DNA polymorphism.Biochemistry,1997,36:12323-12328.
[19]Hutchin T,Haworth I,Higashi K.et al.A molecular basis for human hypersensitivity to amino-glycoside antibiotic.Nucleic Acids Res,1993,21 (18):4174-4179.
[20]Prezant TR, Agapian JV, Bohlman MC. Mitochondrial ribosomal RNA mutation associated with both antibiotic induced and nonsyndromic deafness.Nat Genet,1993,4:289-294.
[21]Tang HY, Hutcheson E, Neill S, et al. Genetic susceptibility to aminoglycoside ototoxicity: how many are at risk?.Genet Med,2002,4:336-345.
[22]Fischel-Ghodsian N,Prezant TR,Bu X,et al.Mitochondrial ribosoma RNA gene mutation in a patient with sporadic aminoglycoside ototoxicity.Am J Otolaryngol,1993,14:399-403.
[23]邱维勤,胡诞宁,吴保同,等.氨基糖苷抗生素致聋的遗传流行病学究.上海铁道大学学报(医学版),1997,11(3)：188-191.
[24]Li Z, Li R, Chen J, et al. Mutational analysis of the mitochondrial12S rRNA gene in Chinese pediatric subjects with aminoglycoside-induced and non-syndromic hearing loss. Hum Genet, 2005,117(1):9-15.
[25]刘新,戴朴,黄德亮,等.线粒体DNAA1555G突变大规模筛查及其预防意义探讨.中华医学杂志,2006,86：1318-1322.
[26]戴朴,杨伟炎,韩东一,等Prev-DAF试剂盒分析线粒体基因1555A-G突变.中华耳科学杂志,2004,2：37-41.
[2]Li Z, Li R, Chen J, et al. Mutational analysis of the mitochondrial 12S rRNA gene in Chinese pediatric subjects with aminoglycoside-induced and non-syndromic hearing loss. Hum Genet, 2005,117(1):9-15.
[3]袁慧军,姜泅长,杨伟炎.线粒体DNA A1555G突变与遗传性耳聋.国外医学耳鼻咽喉科册.1997,21：322-326.
[4]Dai P,Yu F, Han B, et al. The prevalence of the 235delC GJB2 mutation in a Chinese deaf population. Genetics in Medicine,2007,9(5):283-289.
[5]戴朴,刘新,于飞,等.18个省市聋校学生非综合征性聋病分子流行病学研究(Ⅰ)-GJB2235delC和线粒体DNA12SrRNAA1555G突变筛查报告.中华耳科学杂志,2006,4：1-5.
[6]袁慧军,姜泗长,杨伟炎,等.氨基糖苷类抗生素致聋家系线粒体DNA1555G点突变分析.中华耳鼻咽喉科杂志,1998,33(2)：67-70.
[7]潘虹,柯肖枚,戚豫,等.非综合征家族性耳聋线粒体DNA1555A-G点突变分析.实用儿科临床杂志,1999,14(2)：67-68.
[8]李为民,韩东一,袁慧军,等.遗传性耳聋29家系线粒体基因突变检测与系谱分析.临床耳鼻咽喉科杂志,2001,15(增刊)：53-58.
[9]牟奕,单祥年,严明,等.一个母系遗传非综合征耳聋大家系mtDNA序列分析.遗传2001,23(5)：401-405.
[10]戴朴,袁慧军,曹菊阳,等.线粒体基因A1555G突变检测试剂盒在药物性耳聋分子诊断中的应用.中国听力语言康复科学2004,(6)：21-23.
[11]Scott DA, Kraft ML, et al.Connexin mutation and hearing loss.Nature,1998,391(6662):32.
[12]王国建,戴朴,韩东一,等.基因芯片技术在非综合征性耳聋快速基因诊断中的应用研究.中华耳科学杂志,2008,6(1)：61-66.
[13]Zhao H,Li R,Wang Q,et al.Maternally inherited aminoglycoside-induced and non-syndromic deafness associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family.Am J Hum Genet,2004,74(1):139-152.
[14]Zhao H,Young WY,Yan Q,et al.Functional charaterization of the mitochondrial 12S rRNA C1494T mutation associated with aminoglycoside induced and non-syndromic hearing loss.Nuclein Acids Res,2005,33(3):1132-1139.
[15]Guan MX, Young WY, Zhao LD,et al.88 Variants in mitochondrial tRNAs may influence the phenotypic manifestation of deafness-associated 12S rRNA A1555G and C1494T mutations in Chinese families with hearing loss.Mitochondrion,2007,7(6):430-437.
[16]Zhao L,Young WY,Li R,et al.Clinical evaluation and sequence analysis of the complete mitochondrial genome of three Chinese patients with hearing impairment associated with the 12S rRNA T1095C mutation.Biochem Biochem Biophys Res Commun,2004,325(4):1503-1508.
[17]Kabayashi K,Oguchi T,Asamura K,et al.Genetic features,clinical phenotypes,and prevalence of sensorineural hearing loss associated with the 961delC mitochondrial mutation.Auris Nasus Larynx,2005,32(2):119-124.
[18]刘新,戴朴,黄德亮,等.线粒体DNA A1555G突变大规模筛查及其预防意义探讨.中华医学杂志,2006,86：1318-1322.
[19]Prezant TR,Agapian JV,Bohlman MC,et al.Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nature Genetic,1993,4 (3):289-294.
[20]张丽珊,张志平,周晓雷.三例氨基糖苷类抗生素致聋患者的线粒体DNA序列分析.遗传,1996,18(6)：3-5.
[21]Fischel-Ghodsian N. Mitochondrial mutations and hearing loss:paradigm for mitochondrial genetics. Am J Hum Genet,1998,62(1):15-19.
[22]Pandya A, Xia XJ, Erdenetungalag R, et al. Heterogenous point mutations in the mitochondrial tRNA Ser(UCN) precursor coexisting with the A1555G mutation in deaf students from Mongolia. Am J Hum Genet,1999,65(6):1803-1806.
[23]Li R, Xing G, Yan M, et al. Cosegregation of C-insertion at position 961 with the A1555G mutation of the mitochondrial 12S rRNA gene in a large Chinese family with maternally inherited hearing loss. Am J Med Genet A,2004,124A(2):113-117.
[24]Yoshida M, Shintani T, Hirao M, et al. Aminoglycoside induced hearing loss in a patient with the 961 mutation in mitochondrial DNA. ORL J Otorhinolaryngol Relat Spec, 2002,64(3):219-222.
[25]Tang X, Li Y, Zhu Y, et al.Very low penetrance of hearing loss in seven Han Chinese pedigrees carrying the deafness associated 12S rRNA A1555G mutation.Gene,2007,393(1-2):11-19.
[1]袁慧军,姜泗长,杨伟炎.线粒体DNA A1555G突变与遗传性耳聋.国外医学耳鼻咽喉科册.1997,21：322-326.
[2]Hashimoto S,Robert S,et al.Computer-aided three-dimensional reconstruction and morpho-metry of the outer hair cells of the guinea pig cochlea. Acta Otolaryngology.1988,105:64-74.
[3]Anderson S,Bankier AT,et al.Sequence and organization of the human mitochondrial genome. Nature,1981,90 (5806):457-465.
[4]Prezant TR, Agapian JV, Bohlman MC. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nature Genetic,1993,4(3):289-294.
[5]Hutchin T,Haworth I,Higashi K,et al.A molecular basis for human hypersensitivity to aminoglycoside antibiotics nucleic acids research,1993,21(18):4174-4179.
[6]Shin-ichi Usami,Satoko Abe,Miya Kasai,et al.Genetic and clinical features of sensorineural hearing loss associated with the 1555 mitochondrial mutation.Laryngoscope,1997,107(4):483-490.
[7]袁慧军,姜泗长,杨伟炎,等.氨基糖苷类抗生素致聋家系线粒体点突变分析.中华耳鼻咽喉杂志,1998,33：67-70.
[8]Fischel-Ghodsian N. Mitochondrial mutation and hearing loss:paradigm for mitochondrial genetics.Am J Hum Genet,1998,62(1):15-19.
[9]赵立东,王秋菊,郭维维,管敏鑫,韩东一,杨伟炎.与线粒体DNA A1555G突变有关的非综合征性耳聋.中华耳科学杂志,2004,2：136-141.
[10]Hu DN,Qui WQ,Wu BT,et al.Genetic aspects of antibiotic induced deafness:mitochondrial inheritance.J Med Genet.1991,28(2):79-83.
[11]Fishel-Ghodsian N,Prezant TR,Chaltraw W,et al. Mitochondrial gene mutation is a significant predisposing factor aminoglycoside ototoxicity.Am J Otolaryngol,1997,18(3):173-178.
[12]Schach J,Weiner N.Aminoglycoside-induced hearing loss:a molecular hypothesis.ORL,1986 ,48(2):116-123.
[13]Lim DJ.A review:effects of nosie and ototoxic drugs at the cellular level in the cochlea.Am J Otolaryngol,1986,7:73-99.
[14]Kroese ABA,Das A,Hudspeth AJ.Blockage of the transduction channels of hair cells in the bullfrog's sacculus by aminoglycoside antibiotic.Hear Res.1989,37:203-217.
[15]Williams SE,Zenner HP,Schancht J.Three molecular steps of aminoglycoside ototoxicity demonstrated in the outer hair cells.Hear,Res.1987,30(1):11-18.
[16]Guan MX,Fischel-GhodsianN,Attardi G.Biochemical evidence for nuclear gene involvement in phenotype of nonsyndromic deafness associated with mitochondrial 12S rRNA mutation.Hum Mol Genet,1996,5:963-971.
[17]Guan MX,Fischel-Ghodsian N,Attardi G.Biochemical basis for the inherited susceptibility to aminoglycoside ototoxicity.Hum Mol Genet.2000,9:1781-1793.
[18]Harasaki K,Rando RR.Specific binding of aminoglycoside to a human rRNA construct based on a DNA polymorphism.Biochemistry,1997,36:12323-12328.
[19]Hutchin T,Haworth I,Higashi K.et al.A molecular basis for human hypersensitivity to amino-glycoside antibiotic.Nucleic Acids Res,1993,21 (18):4174-4179.
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