DMD基因新发错义突变致Becker型肌营养不良症一家系临床表型及基因突变分析
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摘要
目的总结DMD基因新发错义突变导致的Becker型肌营养不良症一家系临床表型及基因突变特点。方法与结果采用第二代测序技术对1例25岁男性Becker型肌营养不良症患者进行基因检测,Sanger测序进一步验证患者之母和妹DMD基因c.4449T> G(p.Asn1483Lys)位点,并结合患者及其家族成员的临床资料进行分析。结果显示,患者及其两位舅父具有相同的临床表型,双小腿肌肉呈假性肥大,双下肢近端肌萎缩和肌无力,血清肌酸激酶水平升高。患者基因检测DMD基因外显子34c.4449T> G(p.Asn1483Lys)为错义突变,经检索为新发突变,其母和妹为携带者,结合患者两位舅父临床表现,确诊为Becker型肌营养不良症,该家系为Becker型肌营养不良症家系且存在该基因突变位点的共分离现象。结论 DMD基因外显子34 c.4449T> G(p.Asn1483Lys)为新发错义突变,丰富了DMD基因突变谱,为该家系遗传咨询和产前诊断提供了有价值的信息。
Objective To summarize the phenotype and genotype of a family of Becker muscular dystrophy(BMD) caused by a novel missense mutation of DMD gene. Methods and Results Clinical data of one BMD proband and the family members were collected. Next-generation sequencing technology was used to detect possible gene mutation in the proband, a 25-year-old male BMD patient. Sanger sequencing technology was used to further detect possible mutation of c.4449 T > G(p.Asn1483 Lys) locus of DMD gene in the proband's mother and younger sister. The analysis was carried out combined with clinical data of the proband and other family members. Results showed the patient had the same phenotype as his two uncles(mother's brothers), who presented pseudohypertrophy of calf muscles, atrophy and weakness of proximal lower extremities and elevated serum creatine kinase(CK). Gene mutation analysis demonstrated a novel missense mutation c.4449 T > G(p.Asn1483 Lys) in exon 34 of DMD gene in the proband. The proband's mother and younger sister were carriers of mutated gene. Combined with the clinical manifestations of proband's uncles, the patient was clearly diagnosed as BMD, and the family was clearly diagnosed as BMD pedigree. Besides, there was a common separation phenomenon in the family.Conclusions The study described a novel missense mutation in exon 34 c.4449 T >G(p.Asn1483 Lys) of DMD gene which caused BMD. This enriches the mutation map of DMD gene, and also provides valuable information for genetic counseling and prenatal diagnosis.
Objective To summarize the phenotype and genotype of a family of Becker muscular dystrophy(BMD) caused by a novel missense mutation of DMD gene. Methods and Results Clinical data of one BMD proband and the family members were collected. Next-generation sequencing technology was used to detect possible gene mutation in the proband, a 25-year-old male BMD patient. Sanger sequencing technology was used to further detect possible mutation of c.4449 T > G(p.Asn1483 Lys) locus of DMD gene in the proband's mother and younger sister. The analysis was carried out combined with clinical data of the proband and other family members. Results showed the patient had the same phenotype as his two uncles(mother's brothers), who presented pseudohypertrophy of calf muscles, atrophy and weakness of proximal lower extremities and elevated serum creatine kinase(CK). Gene mutation analysis demonstrated a novel missense mutation c.4449 T > G(p.Asn1483 Lys) in exon 34 of DMD gene in the proband. The proband's mother and younger sister were carriers of mutated gene. Combined with the clinical manifestations of proband's uncles, the patient was clearly diagnosed as BMD, and the family was clearly diagnosed as BMD pedigree. Besides, there was a common separation phenomenon in the family.Conclusions The study described a novel missense mutation in exon 34 c.4449 T >G(p.Asn1483 Lys) of DMD gene which caused BMD. This enriches the mutation map of DMD gene, and also provides valuable information for genetic counseling and prenatal diagnosis.
引文
[1]Bushby KM,Thambyayah M,Gardner-Medwin D.Prevalence and incidence of Becker muscular dystrophy[J].Lancet,1991,337:1022-1024.
[2]Bushby K,Finkel R,Birnkrant DJ,Case LE,Clemens PR,Cripe L,Kaul A,Kinnett K,McDonald C,Pandya S,Poysky J,Shapiro F,Tomezsko J,Constantin C;DMD Care Considerations Working Group.Diagnosis and management of Duchenne muscular dystrophy,part 1:diagnosis,and pharmacological and psychosocial managemen[tJ].Lancet Neurol,2010,9:77-93.
[3]Zhang C.Interpretation of"Chinese guidelines for diagnosis and treatment of pseudohypertrophy muscular dystrophy"[J].Zhongguo Xian Dai Shen Jing Ji Bing Za Zhi,2018,18:475-479.[张成.《中国假肥大型肌营养不良症诊治指南》解读[J].中国现代神经疾病杂志,2018,18:475-479.]
[4]Koenig M,Hoffman EP,Bertelson CJ,Monaco AP,Feener C,Kunkel LM.Complete cloning of the Duchenne muscular dystrophy(DMD)cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals[J].Cell,1987,50:509-517.
[5]Hoffman EP,Brown RJ,Kunkel LM.Dystrophin:the protein product of the Duchenne muscular dystrophy locus[J].Cell,1987,51:919-928.
[6]Aartsma-Rus A,Ginjaar IB,Bushby K.The importance of genetic diagnosis for Duchenne muscular dystrophy[J].J Med Genet,2016,53:145-151.
[7]Kondo-Iida E.Commentary on'Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center'[J].J Hum Genet,2010,55:555-556.
[8]Bladen CL,Salgado D,Monges S,Foncuberta ME,Kekou K,Kosma K,Dawkins H,Lamont L,Roy AJ,Chamova T,Guergueltcheva V,Chan S,Korngut L,Campbell C,Dai Y,Wang J,Bari?ic N,Brabec P,Lahdetie J,Walter MC,SchreiberKatz O,Karcagi V,Garami M,Viswanathan V,Bayat F,Buccella F,Kimura E,Koeks Z,van den Bergen JC,Rodrigues M,Roxburgh R,Lusakowska A,Kostera-Pruszczyk A,Zimowski J,Santos R,Neagu E,Artemieva S,Rasic VM,Vojinovic D,Posada M,Bloetzer C,Jeannet PY,Joncourt F,Díaz-Manera J,Gallardo E,Karaduman AA,Topaloglu H,El Sherif R,Stringer A,Shatillo AV,Martin AS,Peay HL,Bellgard MI,Kirschner J,Flanigan KM,Straub V,Bushby K,Verschuuren J,Aartsma- Rus A,Béroud C,Lochmüller H.The TREAT-NMD DMDGlobal Database:analysis of more than 7,000 Duchenne muscular dystrophy mutations[J].Hum Mutat,2015,36:395-402.
[9]Okubo M,Goto K,Komaki H,Nakamura H,Mori-Yoshimura M,Hayashi YK,Mitsuhashi S,Noguchi S,Kimura E,Nishino I.Comprehensive analysis for genetic diagnosis of Dystrophinopathies in Japan[J].Orphanet J Rare Dis,2017,12:149.
[10]Juan-Mateu J,Gonzalez-Quereda L,Rodriguez MJ,Baena M,Verdura E,Nascimento A,Ortez C,Baiget M,Gallano P.DMDmutations in 576 dystrophinopathy families:a step forward in genotype-phenotype correlations[J].PLoS One,2015,10:E0135189.
[11]Yuan R,Yi J,Xie Z,Zheng Y,Han M,Hou Y,Wang Z,Yuan Y.Genotype-phenotype correlation in Becker muscular dystrophy in Chinese patients[J].J Hum Genet,2018,63:1041-1048.
[12]Bai Y,Li S,Zong YN,Li XL,Zhao ZH,Kong XD.Mutation screening of 433 families with Duchenne/Becker muscular dystrophy[J].Zhonghua Yi Xue Za Zhi,2016,96:1261-1269.[白莹,李双,宗亚楠,李晓丽,赵振华,孔祥东.杜氏/贝氏肌营养不良症433个家系的基因突变分析[J].中华医学杂志,2016,96:1261-1269.]
[13]Cao JQ,Yang J,Li YQ,Feng SW,Chen F,Zheng H,Liang YY,Zhao BJ,Zhang X,Zhang HL,Zhu YL,Zhang C.Clinical study of DMD gene point mutation causing Becker muscular dystrophy[J].Zhongguo Xian Dai Shen Jing Ji Bing Za Zhi,2015,15:442-447[.操基清,杨娟,李亚勤,冯善伟,陈菲,郑卉,梁颖茵,赵保健,张旭,张惠丽,朱瑜龄,张成.DMD基因点突变致Becker型肌营养不良症临床研究[J].中国现代神经疾病杂志,2015,15:442-447.]
[14]Richards S,Aziz N,Bale S,Bick D,Das S,Gastier-Foster J,Grody WW,Hegde M,Lyon E,Spector E,Voelkerding K,Rehm HL;ACMG Laboratory Quality Assurance Committee.Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J].Genet Med,2015,17:405-424.
[15]Monaco AP,Bertelson CJ,Liechti-Gallati S,Moser H,Kunkel LM.An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus[J].Genomics,1988,2:90-95.
[16]Guglieri M,Bushby K,McDermott MP,Hart KA,Tawil R,Martens WB,Herr BE,McColl E,Wilkinson J,Kirschner J,King WM,Eagle M,Brown MW,Willis T,Hirtz D,Shieh PB,Straub V,Childs AM,Ciafaloni E,Butterfield RJ,Horrocks I,Spinty S,Flanigan KM,Kuntz NL,Baranello G,Roper H,Morrison L,Mah JK,Manzur AY,McDonald CM,Schara U,von der Hagen M,Barohn RJ,Campbell C,Darras BT,Finkel RS,Vita G,Hughes I,Mongini T,Pegoraro E,Wicklund M,Wilichowski E,Bryan Burnette W,Howard JF,McMillan HJ,Thangarajh M,Griggs RC.Developing standardized corticosteroid treatment for Duchenne muscular dystrophy[J].Contemp Clin Trials,2017,58:34-39.
[17]Henricson EK,Abresch RT,Cnaan A,Hu F,Duong T,Arrieta A,Han J,Escolar DM,Florence JM,Clemens PR,Hoffman EP,McDonald CM;CINRG Investigators.The cooperative international neuromuscular research group Duchenne natural history study:glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures[J].Muscle Nerve,2013,48:55-67.
[18]Zhang C,Li H.Research advance and application prospect of therapeutic strategies for Duchenne muscular dystrophy[J].Zhongguo Xian Dai Shen Jing Ji Bing Za Zhi,2018,18:480-493.[张成,李欢.Duchenne型肌营养不良症治疗研究进展及应用前景[J].中国现代神经疾病杂志,2018,18:480-493.]
[19]Crabtree NJ,Adams JE,Padidela R,Shaw NJ,H?gler W,Roper H,Hughes I,Daniel A,Mughal MZ.Growth,bone health&ambulatory status of boys with DMD treated with daily vs.intermittent oral glucocorticoid regimen[J].Bone,2018,116:181-186.
[20]Zhang C,Lin JF.The research status and problems of Duchenne muscular dystrophy in China[J].Zhongguo Xian Dai Shen Jing Ji Bing Za Zhi,2018,18:470-474[.张成,林金福.我国Duchenne型肌营养不良症研究现状及存在问题[J].中国现代神经疾病杂志,2018,18:470-474.]
[21]Aslesh T,Maruyama R,Yokota T.Skipping multiple exons to treat DMD:promises and challenges[J].Biomedicines,2018,6:E1.
[22]Nelson CE,Wu Y,Gemberling MP,Oliver ML,Waller MA,Bohning JD,Robinson-Hamm JN,Bulaklak K,Castellanos Rivera RM,Collier JH,Asokan A,Gersbach CA.Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy[J].Nat Med,2019,25:427-432.
[23]Beksac MS,Tanacan A,Aydin Hakli D,Orgul G,Soyak B,Balci Hayta B,Dincer P,Topaloglu H.Gestational outcomes of pregnant women who have had invasive prenatal testing for the prenatal diagnosis of Duchenne muscular dystrophy[J].JPregnancy,2018:ID9718316.
[24]Xu Y,Li Y,Song T,Guo F,Zheng J,Xu H,Yan F,Cheng L,Li C,Chen B,Zhang J.A retrospective analysis of 237 Chinese families with Duchenne muscular dystrophy history and strategies of prenatal diagnosis[J].J Clin Lab Anal,2018,32:E22445.
[2]Bushby K,Finkel R,Birnkrant DJ,Case LE,Clemens PR,Cripe L,Kaul A,Kinnett K,McDonald C,Pandya S,Poysky J,Shapiro F,Tomezsko J,Constantin C;DMD Care Considerations Working Group.Diagnosis and management of Duchenne muscular dystrophy,part 1:diagnosis,and pharmacological and psychosocial managemen[tJ].Lancet Neurol,2010,9:77-93.
[3]Zhang C.Interpretation of"Chinese guidelines for diagnosis and treatment of pseudohypertrophy muscular dystrophy"[J].Zhongguo Xian Dai Shen Jing Ji Bing Za Zhi,2018,18:475-479.[张成.《中国假肥大型肌营养不良症诊治指南》解读[J].中国现代神经疾病杂志,2018,18:475-479.]
[4]Koenig M,Hoffman EP,Bertelson CJ,Monaco AP,Feener C,Kunkel LM.Complete cloning of the Duchenne muscular dystrophy(DMD)cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals[J].Cell,1987,50:509-517.
[5]Hoffman EP,Brown RJ,Kunkel LM.Dystrophin:the protein product of the Duchenne muscular dystrophy locus[J].Cell,1987,51:919-928.
[6]Aartsma-Rus A,Ginjaar IB,Bushby K.The importance of genetic diagnosis for Duchenne muscular dystrophy[J].J Med Genet,2016,53:145-151.
[7]Kondo-Iida E.Commentary on'Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center'[J].J Hum Genet,2010,55:555-556.
[8]Bladen CL,Salgado D,Monges S,Foncuberta ME,Kekou K,Kosma K,Dawkins H,Lamont L,Roy AJ,Chamova T,Guergueltcheva V,Chan S,Korngut L,Campbell C,Dai Y,Wang J,Bari?ic N,Brabec P,Lahdetie J,Walter MC,SchreiberKatz O,Karcagi V,Garami M,Viswanathan V,Bayat F,Buccella F,Kimura E,Koeks Z,van den Bergen JC,Rodrigues M,Roxburgh R,Lusakowska A,Kostera-Pruszczyk A,Zimowski J,Santos R,Neagu E,Artemieva S,Rasic VM,Vojinovic D,Posada M,Bloetzer C,Jeannet PY,Joncourt F,Díaz-Manera J,Gallardo E,Karaduman AA,Topaloglu H,El Sherif R,Stringer A,Shatillo AV,Martin AS,Peay HL,Bellgard MI,Kirschner J,Flanigan KM,Straub V,Bushby K,Verschuuren J,Aartsma- Rus A,Béroud C,Lochmüller H.The TREAT-NMD DMDGlobal Database:analysis of more than 7,000 Duchenne muscular dystrophy mutations[J].Hum Mutat,2015,36:395-402.
[9]Okubo M,Goto K,Komaki H,Nakamura H,Mori-Yoshimura M,Hayashi YK,Mitsuhashi S,Noguchi S,Kimura E,Nishino I.Comprehensive analysis for genetic diagnosis of Dystrophinopathies in Japan[J].Orphanet J Rare Dis,2017,12:149.
[10]Juan-Mateu J,Gonzalez-Quereda L,Rodriguez MJ,Baena M,Verdura E,Nascimento A,Ortez C,Baiget M,Gallano P.DMDmutations in 576 dystrophinopathy families:a step forward in genotype-phenotype correlations[J].PLoS One,2015,10:E0135189.
[11]Yuan R,Yi J,Xie Z,Zheng Y,Han M,Hou Y,Wang Z,Yuan Y.Genotype-phenotype correlation in Becker muscular dystrophy in Chinese patients[J].J Hum Genet,2018,63:1041-1048.
[12]Bai Y,Li S,Zong YN,Li XL,Zhao ZH,Kong XD.Mutation screening of 433 families with Duchenne/Becker muscular dystrophy[J].Zhonghua Yi Xue Za Zhi,2016,96:1261-1269.[白莹,李双,宗亚楠,李晓丽,赵振华,孔祥东.杜氏/贝氏肌营养不良症433个家系的基因突变分析[J].中华医学杂志,2016,96:1261-1269.]
[13]Cao JQ,Yang J,Li YQ,Feng SW,Chen F,Zheng H,Liang YY,Zhao BJ,Zhang X,Zhang HL,Zhu YL,Zhang C.Clinical study of DMD gene point mutation causing Becker muscular dystrophy[J].Zhongguo Xian Dai Shen Jing Ji Bing Za Zhi,2015,15:442-447[.操基清,杨娟,李亚勤,冯善伟,陈菲,郑卉,梁颖茵,赵保健,张旭,张惠丽,朱瑜龄,张成.DMD基因点突变致Becker型肌营养不良症临床研究[J].中国现代神经疾病杂志,2015,15:442-447.]
[14]Richards S,Aziz N,Bale S,Bick D,Das S,Gastier-Foster J,Grody WW,Hegde M,Lyon E,Spector E,Voelkerding K,Rehm HL;ACMG Laboratory Quality Assurance Committee.Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J].Genet Med,2015,17:405-424.
[15]Monaco AP,Bertelson CJ,Liechti-Gallati S,Moser H,Kunkel LM.An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus[J].Genomics,1988,2:90-95.
[16]Guglieri M,Bushby K,McDermott MP,Hart KA,Tawil R,Martens WB,Herr BE,McColl E,Wilkinson J,Kirschner J,King WM,Eagle M,Brown MW,Willis T,Hirtz D,Shieh PB,Straub V,Childs AM,Ciafaloni E,Butterfield RJ,Horrocks I,Spinty S,Flanigan KM,Kuntz NL,Baranello G,Roper H,Morrison L,Mah JK,Manzur AY,McDonald CM,Schara U,von der Hagen M,Barohn RJ,Campbell C,Darras BT,Finkel RS,Vita G,Hughes I,Mongini T,Pegoraro E,Wicklund M,Wilichowski E,Bryan Burnette W,Howard JF,McMillan HJ,Thangarajh M,Griggs RC.Developing standardized corticosteroid treatment for Duchenne muscular dystrophy[J].Contemp Clin Trials,2017,58:34-39.
[17]Henricson EK,Abresch RT,Cnaan A,Hu F,Duong T,Arrieta A,Han J,Escolar DM,Florence JM,Clemens PR,Hoffman EP,McDonald CM;CINRG Investigators.The cooperative international neuromuscular research group Duchenne natural history study:glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures[J].Muscle Nerve,2013,48:55-67.
[18]Zhang C,Li H.Research advance and application prospect of therapeutic strategies for Duchenne muscular dystrophy[J].Zhongguo Xian Dai Shen Jing Ji Bing Za Zhi,2018,18:480-493.[张成,李欢.Duchenne型肌营养不良症治疗研究进展及应用前景[J].中国现代神经疾病杂志,2018,18:480-493.]
[19]Crabtree NJ,Adams JE,Padidela R,Shaw NJ,H?gler W,Roper H,Hughes I,Daniel A,Mughal MZ.Growth,bone health&ambulatory status of boys with DMD treated with daily vs.intermittent oral glucocorticoid regimen[J].Bone,2018,116:181-186.
[20]Zhang C,Lin JF.The research status and problems of Duchenne muscular dystrophy in China[J].Zhongguo Xian Dai Shen Jing Ji Bing Za Zhi,2018,18:470-474[.张成,林金福.我国Duchenne型肌营养不良症研究现状及存在问题[J].中国现代神经疾病杂志,2018,18:470-474.]
[21]Aslesh T,Maruyama R,Yokota T.Skipping multiple exons to treat DMD:promises and challenges[J].Biomedicines,2018,6:E1.
[22]Nelson CE,Wu Y,Gemberling MP,Oliver ML,Waller MA,Bohning JD,Robinson-Hamm JN,Bulaklak K,Castellanos Rivera RM,Collier JH,Asokan A,Gersbach CA.Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy[J].Nat Med,2019,25:427-432.
[23]Beksac MS,Tanacan A,Aydin Hakli D,Orgul G,Soyak B,Balci Hayta B,Dincer P,Topaloglu H.Gestational outcomes of pregnant women who have had invasive prenatal testing for the prenatal diagnosis of Duchenne muscular dystrophy[J].JPregnancy,2018:ID9718316.
[24]Xu Y,Li Y,Song T,Guo F,Zheng J,Xu H,Yan F,Cheng L,Li C,Chen B,Zhang J.A retrospective analysis of 237 Chinese families with Duchenne muscular dystrophy history and strategies of prenatal diagnosis[J].J Clin Lab Anal,2018,32:E22445.
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