一个掌跖角化-牙周破坏综合征患者家系组织蛋白酶C基因突变分析
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摘要
目的对一个掌跖角化-牙周破坏综合征(PLS)患者及其家系组织蛋白酶C基因(CTSC)突变位点进行分析,探讨PLS的分子致病机制。方法提取1例PLS先证者及其直系血亲(父母、弟弟)的基因组DNA,应用聚合酶链反应和DNA直接测序技术分析先证者及其直系血亲CTSC基因的突变情况。结果 PLS先证者CTSC基因存在复合型杂合突变。先证者位于外显子6的第800位碱基发生了一个杂合错义突变,该碱基对中的碱基T被C取代(c.800T>C),其编码的氨基酸由亮氨酸改变为脯氨酸(p.L267P);位于外显子7的第1015位碱基发生了一个杂合错义突变,该碱基对中的碱基C被T取代(c.1015C>T),其编码的氨基酸由精氨酸改变为半胱氨酸(p.R339C)。其中,c.800T>C来自母亲,c.1015C>T来自父亲,弟弟的CTSC基因未见突变。结论 PLS的临床表征与CTSC基因突变有关。
Objective This study aimed to investigate the gene mutational characteristics of cathepsin C(CTSC) gene in a Chinese patient with Papillon-Lefèvre syndrome(PLS) and further confirm the genetic basis for the phenotype of PLS.Methods Peripheral blood samples were obtained from the PLS proband and his family members(his parents and younger brother) for genomic DNA extraction.The coding region and exon boundaries of the CTSC gene were amplified and sequenced by polymerase chain reaction and direct sequencing of DNA.Results Compound heterozygous mutations of CTSC gene were identified in the patient.A heterozygous missense mutation occurred in the 800 th base of exon 6,and the base T in the base pair was replaced by C(c.800 T>C).The encoded amino acid leucine changed to proline(p.L267 P).A heterozygous missense mutation occurred in the 1015 th base of exon 7,and base C in the base pair was replaced by T(c.1015 C>T).The encoded amino acid arginine changed to cysteine(p.R339 C).Among the mutations,c.800 T>C originated from the mother,c.1015 C>T was identified from the father.No mutations were detected in the younger brother.Conclusion Mutations of CTSC gene are responsible for the phenotype of PLS.
Objective This study aimed to investigate the gene mutational characteristics of cathepsin C(CTSC) gene in a Chinese patient with Papillon-Lefèvre syndrome(PLS) and further confirm the genetic basis for the phenotype of PLS.Methods Peripheral blood samples were obtained from the PLS proband and his family members(his parents and younger brother) for genomic DNA extraction.The coding region and exon boundaries of the CTSC gene were amplified and sequenced by polymerase chain reaction and direct sequencing of DNA.Results Compound heterozygous mutations of CTSC gene were identified in the patient.A heterozygous missense mutation occurred in the 800 th base of exon 6,and the base T in the base pair was replaced by C(c.800 T>C).The encoded amino acid leucine changed to proline(p.L267 P).A heterozygous missense mutation occurred in the 1015 th base of exon 7,and base C in the base pair was replaced by T(c.1015 C>T).The encoded amino acid arginine changed to cysteine(p.R339 C).Among the mutations,c.800 T>C originated from the mother,c.1015 C>T was identified from the father.No mutations were detected in the younger brother.Conclusion Mutations of CTSC gene are responsible for the phenotype of PLS.
引文
[1]Papillon MM,Lefevre P.Two cases of symmetrically familial palmar and plantar hyperkeratosis(Meleda disease)withinbrother andsister combined with severe dental alterations in both cases[J].Bull Soc Fr Dermatol Syphiligr,1924,31(2):82-87.
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[4]Dhanawade SS,Shah SD,Kakade GM.Papillon-lefevre syndrome with liver abscess[J].Indian Pediatr,2009,46(8):723-725.
[5]Toomes C,James J,Wood AJ,et al.Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis[J].Nat Genet,1999,23(4):421-424.
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[7]Siragusa M,Romano C,Batticane N,et al.A new family with Papillon-Lefèvre syndrome:effectiveness of etretinate treatment[J].Cutis,2000,65(3):151-155.
[8]Hart TC,Hart PS,Bowden DW,et al.Mutations of the cathepsin C gene are responsible for Papillon-Lefèvre syndrome[J].J Med Genet,1999,36(12):881-887.
[9]Hart TC,Bowden DW,Ghaffar KA,et al.Sublocalization of the Papillon-Lefevre syndrome locus on 11q14-q21[J].Am J Med Genet,1998,79(2):134-139.
[10]Nagy N,Vályi P,Csoma Z,et al.CTSC and Papillon-Lefèvre syndrome:detection of recurrent mutations in Hungarianpatients,a review of published variants and database update[J].Mol Genet Genomic Med,2014,2(3):217-228.
[11]李晓峰,张雄,章锦才,等.一个掌跖角化牙周病变综合征家系的组织蛋白酶C基因突变分析[J].中华医学遗传学杂志,2008,25(5):502-505.Li XF,Zhang X,Zhang JC,et al.Mutational analysis of the cathepsin C gene in a family of Hart nationality with Papillon-Lefevre syndrome[J].Chin J Med Genet,2008,25(5):502-505.
[12]杨嫒,白小文,宋淑娟,等.侵袭性牙周炎家系组织蛋白酶C基因的突变分析[J].现代口腔医学杂志,2006,20(5):479-481.Yang Y,Bai XW,Song SJ,et al.Cathepsin C gene mutations in a Chinese aggressive periodontitis pedigree[J].JModern Stomatol,2006,20(5):479-481.
[13]杨媛,白小文,刘宏胜,等.掌跖角化牙周病综合征患者组织蛋白酶C基因的新突变[J].中华口腔医学杂志,2006,41(10):602-605.Yang Y,Bai XW,Liu HS,et al.Novel mutations of cathepsin C gene in two Chinese patients with Papillon-Lefèvre syndrome[J].Chin J Stomatol,2006,41(10):602-605.
[14]Nakano A,Nomura K,Nakano H,et al.Papillon-Lefèvre syndrome:mutations and polymorphisms in the cathepsin C gene[J].J Invest Dermatol,2001,116(2):339-343.
[15]S?rensen OE,Clemmensen SN,Dahl SL,et al.PapillonLefèvre syndrome patient reveals species-dependent requirements for neutrophil defenses[J].J Clin Invest,2014,124(10):4539-4548.
[16]Hart TC,Bowden DW,Ghaffar KA,et al.Sublocalization of the Papillon-Lefevre syndrome locus on 11q14-q21[J].Am J Med Genet,1998,79(2):134-139.
[17]陈远娇,李晨军.掌跖角化-牙周破坏综合征个案患者家系组织蛋白酶C的基因突变分析[J].华西口腔医学杂志,2016,34(4):346-349.Chen YJ,Li CJ.Gene mutational analyses of the cathepsin C gene in families with Papillon-Lefèvre syndrome[J].West Chin J Stomatol,2016,34(4):346-349.
[18]Rai R,Thiagarajan S,Mohandas S,et al.Haim Munk syndrome and Papillon Lefevre syndrome:allelic mutations in cathepsin C with variation in phenotype[J].Int J Dermatol,2010,49(5):541-543.
[19]Lux CJ,Kugel B,Komposch G,et al.Orthodontic treatment in a patient with papillon-lefèvre syndrome[J].J Periodontol,2005,76(4):642-650.
[20]Almuneef M,Al Khenaizan S,Al Ajaji S,et al.Pyogenic liver abscess and Papillon-Lefèvre syndrome:not a rare association[J].Pediatrics,2003,111(1):e85-e88.
[21]Wang X,Liu Y,Liu Y,et al.Long-term change of disease behavior in Papillon-Lefèvre syndrome:seven years followup[J].Eur J Med Genet,2015,58(3):184-187.
[2]Gorlin RJ,Pindborg J,Cohen MM.Syndromes of the head and neck[M].2nd ed.New York:McGraw-Hill Publishing House,1976:373-376.
[3]Cury VF,Costa JE,Gomez RS,et al.A novel mutation of the cathepsin C gene in Papillon-Lefèvre syndrome[J].JPeriodontol,2002,73(3):307-312.
[4]Dhanawade SS,Shah SD,Kakade GM.Papillon-lefevre syndrome with liver abscess[J].Indian Pediatr,2009,46(8):723-725.
[5]Toomes C,James J,Wood AJ,et al.Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis[J].Nat Genet,1999,23(4):421-424.
[6]Hart PS,Zhang Y,Firatli E,et al.Identification of cathepsin C mutations in ethnically diverse papillon-Lefèvre syndromepatients[J].J Med Genet,2000,37(12):927-932.
[7]Siragusa M,Romano C,Batticane N,et al.A new family with Papillon-Lefèvre syndrome:effectiveness of etretinate treatment[J].Cutis,2000,65(3):151-155.
[8]Hart TC,Hart PS,Bowden DW,et al.Mutations of the cathepsin C gene are responsible for Papillon-Lefèvre syndrome[J].J Med Genet,1999,36(12):881-887.
[9]Hart TC,Bowden DW,Ghaffar KA,et al.Sublocalization of the Papillon-Lefevre syndrome locus on 11q14-q21[J].Am J Med Genet,1998,79(2):134-139.
[10]Nagy N,Vályi P,Csoma Z,et al.CTSC and Papillon-Lefèvre syndrome:detection of recurrent mutations in Hungarianpatients,a review of published variants and database update[J].Mol Genet Genomic Med,2014,2(3):217-228.
[11]李晓峰,张雄,章锦才,等.一个掌跖角化牙周病变综合征家系的组织蛋白酶C基因突变分析[J].中华医学遗传学杂志,2008,25(5):502-505.Li XF,Zhang X,Zhang JC,et al.Mutational analysis of the cathepsin C gene in a family of Hart nationality with Papillon-Lefevre syndrome[J].Chin J Med Genet,2008,25(5):502-505.
[12]杨嫒,白小文,宋淑娟,等.侵袭性牙周炎家系组织蛋白酶C基因的突变分析[J].现代口腔医学杂志,2006,20(5):479-481.Yang Y,Bai XW,Song SJ,et al.Cathepsin C gene mutations in a Chinese aggressive periodontitis pedigree[J].JModern Stomatol,2006,20(5):479-481.
[13]杨媛,白小文,刘宏胜,等.掌跖角化牙周病综合征患者组织蛋白酶C基因的新突变[J].中华口腔医学杂志,2006,41(10):602-605.Yang Y,Bai XW,Liu HS,et al.Novel mutations of cathepsin C gene in two Chinese patients with Papillon-Lefèvre syndrome[J].Chin J Stomatol,2006,41(10):602-605.
[14]Nakano A,Nomura K,Nakano H,et al.Papillon-Lefèvre syndrome:mutations and polymorphisms in the cathepsin C gene[J].J Invest Dermatol,2001,116(2):339-343.
[15]S?rensen OE,Clemmensen SN,Dahl SL,et al.PapillonLefèvre syndrome patient reveals species-dependent requirements for neutrophil defenses[J].J Clin Invest,2014,124(10):4539-4548.
[16]Hart TC,Bowden DW,Ghaffar KA,et al.Sublocalization of the Papillon-Lefevre syndrome locus on 11q14-q21[J].Am J Med Genet,1998,79(2):134-139.
[17]陈远娇,李晨军.掌跖角化-牙周破坏综合征个案患者家系组织蛋白酶C的基因突变分析[J].华西口腔医学杂志,2016,34(4):346-349.Chen YJ,Li CJ.Gene mutational analyses of the cathepsin C gene in families with Papillon-Lefèvre syndrome[J].West Chin J Stomatol,2016,34(4):346-349.
[18]Rai R,Thiagarajan S,Mohandas S,et al.Haim Munk syndrome and Papillon Lefevre syndrome:allelic mutations in cathepsin C with variation in phenotype[J].Int J Dermatol,2010,49(5):541-543.
[19]Lux CJ,Kugel B,Komposch G,et al.Orthodontic treatment in a patient with papillon-lefèvre syndrome[J].J Periodontol,2005,76(4):642-650.
[20]Almuneef M,Al Khenaizan S,Al Ajaji S,et al.Pyogenic liver abscess and Papillon-Lefèvre syndrome:not a rare association[J].Pediatrics,2003,111(1):e85-e88.
[21]Wang X,Liu Y,Liu Y,et al.Long-term change of disease behavior in Papillon-Lefèvre syndrome:seven years followup[J].Eur J Med Genet,2015,58(3):184-187.