斑驳病家系的遗传学病因分析和产前诊断多发性外生型骨疣家系的遗传学病因分析
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摘要
一.斑驳病家系的遗传学病因分析和产前诊断
背景斑驳病(Piebaldism)是一种少见的常染色体显性遗传病,由色素细胞发育异常所致。主要临床表现为皮肤发生成片白斑,主要区域包括头皮、前额、前胸和四肢。白斑区域一般不会随年龄增大而变化,白斑区可见明显色素沉着斑。约75%斑驳病患者由KIT基因杂合突变所致。
目的本室收集到一斑驳病家系,疾病在该家系中已遗传了三代,家系成员共14人,患者6人。先证者的大姐及妹妹皆为患者且各生育一患儿,先证者因害怕生育相似患儿已人流7次,给先证者本人及家庭带来巨大的痛苦。对该家系行分子遗传学分析,明确该家系的致病突变,将来为家系成员生育提供准确的产前诊断。
方法运用PCR、逆转录PCR和DNA测序对家系成员KIT基因进行基因检测。
结果先证者的KIT基因存在c.2472+1G>A的杂合突变,该突变使第17号外显子3’端剪接位点丢失,导致KIT基因所编码的mRNA第17号外显子缺失,家系中其他患者均存在相同突变,家系中正常个体中没有此突变。该突变是一种尚未见报道的新突变。
结论(1)KIT基因的c.2472+1G>A杂合突变是导致该家系成员发生斑驳病的致病突变；(2)通过产前诊断,先证者的胎儿未遗传该家系的致病突变。
二.多发性外生型骨疣家系的遗传学病因分析
背景多发性外生性骨疣(multiple exostoses)是一种常染色体显性遗传病,以骨骼系统多发性外生性骨疣为主要特征,骨疣通常发生在肱骨、前臂、膝部、踝关节等部位。多发性外生性骨疣在出生时即可发生,并且在大小和数目上不断增长,直到青春期骨骼停止生长为止。该病通常引起身材矮小和骨骼畸形,主要并发症为影响关节功能、压迫临近组织和引起癌变。多发性外生型骨疣具有遗传异质性,主要相关基因包括EXT1和EXT2。
目的对一遗传性多发性外生型骨疣家系行分子遗传学分析,疾病在该家系中遗传了三代,共有患者4名。鉴于明显的遗传特征,先证者女儿一直不敢怀孕。明确该家系的致病突变,为家系成员生育提供遗传咨询和产前基因诊断。
方法运用聚合酶链式反应(PCR)和DNA测序直接对家系成员的EXT1及EXT2基因进行基因检测,并利用变性高效液相色谱分析(DHPLC)技术进行突变筛查。
结果家系先证者的EXT1基因存在c.2009-2012del(TCAA)的杂合缺失突变,该突变导致EXT1基因所编码蛋白的第681位氨基酸由苏氨酸转变为终止密码子而产生截短蛋白,家系中其他患者均存在相同突变,在50例遗传非相关正常个体中没有此突变。该突变是一种尚未见报道的新突变。
结论(1)EXTl基因的c.2009-2012del(TCAA)杂合缺失是导致该家系成员发生多发性外生型骨疣的致病突变；(2)通过突变分析及筛查,确定家系成员Ⅲ3为患者。
1.The etiopathogenisis analysis and prenatal testing of a piebaldism family
Background:Piebaldism is a rare genetic disorder of the development of melanocytes. Piebaldism is an autosomal dominantly inherited disorder characterized by congenital white patches of skin.Depigmented areas are mainly found on the scalp,forehead,trunk and limbs.The leukoderma is usually stable throughout life.Heterozygous mutations in the KIT gene have been demonstrated in about 75% of patients with piebaldism.
Objective We collected a piebaldism family of which three generations had been affacted. The family has 14 members,6 of them have severe phenotype.Two sisters of the proband are patients,each of them has an affected offspring.The proband have suffered artificial abortion 7 times,because she is afraid of having a similar child. The molecular genetics analysis was performed in the family to find the disease-causing mutation, and make the prenatal diagnosis available for the affected family members.
Methods Ploymerase chain reaction(PCR), reverse transcription PCR and DNA sequencing were used to detect the mutation of KIT gene.
Results We found a novel heterozygous mutation c.2472+1G>A in KIT gene of proband, which has not been reported and result in the loss of 3' splicing site and then absence of 17 exon in mRNA. The mutation was found in all affected members, while not in the unaffected ones of the family.
Conclusion (1)The novel mutation c.2472+1 G>A is the disease-causing mutation in the piebaldism family.(2) The fetus of proband hasn't inheriting the mutation KIT allele of the family.
2. The etiopathogenisis analysis of a hereditay multiple exostose
Background:Hereditay multiple exostoses (HME) is an autosomal dominant condition characterized by the development of multiple exostoses from the metaepiphyseal areas of the long bones.The disorder usually involves the bones of the skeleton symmetrically,most commonly involved bones are the humerus,forearm and the bones about the knee and ankle. The exostoses vary widely in size and mumber, they can be present at birth and continue to appear and grow throughout childhood and into puberty.HME is genetically heterogeneous.The predominant relate-genes include EXT1 and EXT2.
Objective The molecular genetics analysis was performed in a hereditay multiple exostose(HME) family.The disease was inherited three generations in the family,4 persons were affacted. Because apparente heredity traits of the disease,the proband's daughter was not dare to pregnant.Genetics test was performed to find the disease-causing mutation for providing genetic counseling and prenatal diagosis for the family members.
Methods Ploymerase chain reaction and DNA sequencing were used to detect the muation of EXT1 and EXT2 genes,while denaturing high-performance liquid chormatography was performed to screen the mutation.
Results We found a novel heterozygous deletion mutation c.2009-2012del(TCAA) in EXT1 gene of patients,which resulted in forming a lopping protein.The mutation was found in the else affected family members,and didn't find in the 50 unrelated normal individuals,which was unreported before.
Conclusion (1)The novel mutation c.2009-2012del(TCAA) is the disease-causing mutation in the HME family. (2) The memberⅢ3 of the family has the same mutation c.2009-2012del(TCAA),.We have a conclusion that she is a patient of HME.
背景斑驳病(Piebaldism)是一种少见的常染色体显性遗传病,由色素细胞发育异常所致。主要临床表现为皮肤发生成片白斑,主要区域包括头皮、前额、前胸和四肢。白斑区域一般不会随年龄增大而变化,白斑区可见明显色素沉着斑。约75%斑驳病患者由KIT基因杂合突变所致。
目的本室收集到一斑驳病家系,疾病在该家系中已遗传了三代,家系成员共14人,患者6人。先证者的大姐及妹妹皆为患者且各生育一患儿,先证者因害怕生育相似患儿已人流7次,给先证者本人及家庭带来巨大的痛苦。对该家系行分子遗传学分析,明确该家系的致病突变,将来为家系成员生育提供准确的产前诊断。
方法运用PCR、逆转录PCR和DNA测序对家系成员KIT基因进行基因检测。
结果先证者的KIT基因存在c.2472+1G>A的杂合突变,该突变使第17号外显子3’端剪接位点丢失,导致KIT基因所编码的mRNA第17号外显子缺失,家系中其他患者均存在相同突变,家系中正常个体中没有此突变。该突变是一种尚未见报道的新突变。
结论(1)KIT基因的c.2472+1G>A杂合突变是导致该家系成员发生斑驳病的致病突变；(2)通过产前诊断,先证者的胎儿未遗传该家系的致病突变。
二.多发性外生型骨疣家系的遗传学病因分析
背景多发性外生性骨疣(multiple exostoses)是一种常染色体显性遗传病,以骨骼系统多发性外生性骨疣为主要特征,骨疣通常发生在肱骨、前臂、膝部、踝关节等部位。多发性外生性骨疣在出生时即可发生,并且在大小和数目上不断增长,直到青春期骨骼停止生长为止。该病通常引起身材矮小和骨骼畸形,主要并发症为影响关节功能、压迫临近组织和引起癌变。多发性外生型骨疣具有遗传异质性,主要相关基因包括EXT1和EXT2。
目的对一遗传性多发性外生型骨疣家系行分子遗传学分析,疾病在该家系中遗传了三代,共有患者4名。鉴于明显的遗传特征,先证者女儿一直不敢怀孕。明确该家系的致病突变,为家系成员生育提供遗传咨询和产前基因诊断。
方法运用聚合酶链式反应(PCR)和DNA测序直接对家系成员的EXT1及EXT2基因进行基因检测,并利用变性高效液相色谱分析(DHPLC)技术进行突变筛查。
结果家系先证者的EXT1基因存在c.2009-2012del(TCAA)的杂合缺失突变,该突变导致EXT1基因所编码蛋白的第681位氨基酸由苏氨酸转变为终止密码子而产生截短蛋白,家系中其他患者均存在相同突变,在50例遗传非相关正常个体中没有此突变。该突变是一种尚未见报道的新突变。
结论(1)EXTl基因的c.2009-2012del(TCAA)杂合缺失是导致该家系成员发生多发性外生型骨疣的致病突变；(2)通过突变分析及筛查,确定家系成员Ⅲ3为患者。
1.The etiopathogenisis analysis and prenatal testing of a piebaldism family
Background:Piebaldism is a rare genetic disorder of the development of melanocytes. Piebaldism is an autosomal dominantly inherited disorder characterized by congenital white patches of skin.Depigmented areas are mainly found on the scalp,forehead,trunk and limbs.The leukoderma is usually stable throughout life.Heterozygous mutations in the KIT gene have been demonstrated in about 75% of patients with piebaldism.
Objective We collected a piebaldism family of which three generations had been affacted. The family has 14 members,6 of them have severe phenotype.Two sisters of the proband are patients,each of them has an affected offspring.The proband have suffered artificial abortion 7 times,because she is afraid of having a similar child. The molecular genetics analysis was performed in the family to find the disease-causing mutation, and make the prenatal diagnosis available for the affected family members.
Methods Ploymerase chain reaction(PCR), reverse transcription PCR and DNA sequencing were used to detect the mutation of KIT gene.
Results We found a novel heterozygous mutation c.2472+1G>A in KIT gene of proband, which has not been reported and result in the loss of 3' splicing site and then absence of 17 exon in mRNA. The mutation was found in all affected members, while not in the unaffected ones of the family.
Conclusion (1)The novel mutation c.2472+1 G>A is the disease-causing mutation in the piebaldism family.(2) The fetus of proband hasn't inheriting the mutation KIT allele of the family.
2. The etiopathogenisis analysis of a hereditay multiple exostose
Background:Hereditay multiple exostoses (HME) is an autosomal dominant condition characterized by the development of multiple exostoses from the metaepiphyseal areas of the long bones.The disorder usually involves the bones of the skeleton symmetrically,most commonly involved bones are the humerus,forearm and the bones about the knee and ankle. The exostoses vary widely in size and mumber, they can be present at birth and continue to appear and grow throughout childhood and into puberty.HME is genetically heterogeneous.The predominant relate-genes include EXT1 and EXT2.
Objective The molecular genetics analysis was performed in a hereditay multiple exostose(HME) family.The disease was inherited three generations in the family,4 persons were affacted. Because apparente heredity traits of the disease,the proband's daughter was not dare to pregnant.Genetics test was performed to find the disease-causing mutation for providing genetic counseling and prenatal diagosis for the family members.
Methods Ploymerase chain reaction and DNA sequencing were used to detect the muation of EXT1 and EXT2 genes,while denaturing high-performance liquid chormatography was performed to screen the mutation.
Results We found a novel heterozygous deletion mutation c.2009-2012del(TCAA) in EXT1 gene of patients,which resulted in forming a lopping protein.The mutation was found in the else affected family members,and didn't find in the 50 unrelated normal individuals,which was unreported before.
Conclusion (1)The novel mutation c.2009-2012del(TCAA) is the disease-causing mutation in the HME family. (2) The memberⅢ3 of the family has the same mutation c.2009-2012del(TCAA),.We have a conclusion that she is a patient of HME.
引文
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[34]Bovee, J. V. Multiple osteochondromas. Orphanet Journal of Rare Diseases 2008,3:3.
[35]Oefner PJ,Underhill PA.Comparative DNA Sequencing by denatureing high-performance liquid chromatography (DHPLC).Am J Hum Genet.1995.57(suppl):A266
[36]Ellis LA, Taylor CF, Taylor GR. A comparison of fluorescent SSCP and denaturing HPLC for high throughput mutation scanning. Hum Mutat. 2000.15:556-564
[37]Mogensen J, Bahl A, Kubo T, Elanko N, Taylor R, McKenna WJ. Comparison of fluorescent SSCP and denaturing HPLC analysis with direct sequencing for mutation screening in hypertrophic cardiomyopathy. J Med Genet.2003.40:e59.
[38]谢志国,胡正茂,潘乾等.EXT1基因1633-26(C→A)突变可能致多发性外生性骨疣。中华医学遗传学杂志2006.2：147-150.
[1]Howitz J, Brodthagen H, Schwartz M,et al. Prevalence of vitiligo: epidemiological survey on the Isle of Bornholm,Denmark. Arch Dermatol 1977.113:47-52.
[2]Boisseau-Garsaud AM, Garsaud P,Cales-Quist D, et al. Epidemiology of vitiligo in the French West Indies (Isle of Martinique).Int J Dermatol 2000;39:18-20.
[3]Bhatia PS, Mohan L, Pandey ON,et al. Genetic nature of vitiligo. J Dermatol Sci.1992. Nov;4(3):180-184.
[4]Yoshida H,Kunisada T,Kusakabe M,et al. Distinct stages of melanocyte differentiation revealed by analysis of nonuniform pigmentation patterns. Development,1996.122(4):1207-1214.
[5]Mollet I, Ongenae K, Naeyaert J M. Origin, clinical presentation and diagnosis of hypomelanotic skin disorders. Dermatol Clin 2007.25:363-371.
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[8]Hornyak T J. The developmental biology of melanocytes and its application to understanding human congenital disorders of pigmentation. Adv Dermatol.2006. 22:201-218.
[9]Boissy R E, Nordlund J J. Molecular basis of congenital hypopigmentary disorders in humans:a review. Pigment Cell Res 1997.10:12-24.
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[36]Ellis LA, Taylor CF, Taylor GR. A comparison of fluorescent SSCP and denaturing HPLC for high throughput mutation scanning. Hum Mutat. 2000.15:556-564
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[1]Howitz J, Brodthagen H, Schwartz M,et al. Prevalence of vitiligo: epidemiological survey on the Isle of Bornholm,Denmark. Arch Dermatol 1977.113:47-52.
[2]Boisseau-Garsaud AM, Garsaud P,Cales-Quist D, et al. Epidemiology of vitiligo in the French West Indies (Isle of Martinique).Int J Dermatol 2000;39:18-20.
[3]Bhatia PS, Mohan L, Pandey ON,et al. Genetic nature of vitiligo. J Dermatol Sci.1992. Nov;4(3):180-184.
[4]Yoshida H,Kunisada T,Kusakabe M,et al. Distinct stages of melanocyte differentiation revealed by analysis of nonuniform pigmentation patterns. Development,1996.122(4):1207-1214.
[5]Mollet I, Ongenae K, Naeyaert J M. Origin, clinical presentation and diagnosis of hypomelanotic skin disorders. Dermatol Clin 2007.25:363-371.
[6]Ortonne J P, Bahadoran P, Fitzpatrick T B et al. Hypomelanoses and hypermelanoses.In:Freedberg I M, Eisen A Z, Wolff K et al., eds. Fitzpatrick's Dermatology in General Medicine,6th edn. USA:The McGraw-Hill Companies, Inc,2003.836-881.
[7]Lin J Y, Fisher D E. Melanocyte biology and skin pigmentation. Nature 2007.445:843-850.
[8]Hornyak T J. The developmental biology of melanocytes and its application to understanding human congenital disorders of pigmentation. Adv Dermatol.2006. 22:201-218.
[9]Boissy R E, Nordlund J J. Molecular basis of congenital hypopigmentary disorders in humans:a review. Pigment Cell Res 1997.10:12-24.
[10]Price E R, Fischer D E. Sensorineural deafness and pigmentation genes: melanocytes and the Mitf transcriptional network. Neuron.2001.30:15-18
[11]Steingrimsson E, Copeland N G, Jenkins N A. Melanocytes and the microphthalmia transcription factor network. Annu Rev Genet.2004. 38:365-411.
[12]Morrison-Graham K, Takahashi Y:Steel factor and c-Kit receptor:from mutants to a growth factor system. BioEssays.1993.15:77-83.
[13]Giebel L B, Spritz R A. Mutation of the KIT (mast/stem-cell factor receptor) proto-oncogene in human piebaldism. Proc Natl Acad Sci USA.1991. 88:8696-8699.
[14]Fleischman R A, Saltman D L, Stastny V et al. Deletion of c-kit proto-oncogene in the human developmental defect piebaldism trait. Proc Natl Acad Sci USA.1991.88:10885-10889.
[15]Shears D, Conlon H, Murakami T et al. Molecular heterogeneity in two families with auditory pigmentary syndromes:the role of neuroimaging and genetic analysis in deafness. Clin Genet 2004:65:384-389.
[16]Spritz RA. Molecular basis of human piebaldism. J Invest Dermatol.1994.103:137s-40s.
[17]Giebel LB, Strunk KM, Holmes SA, Spritz RA:Organization and nucleotide sequence of the human KIT (mast/stem eell growth factor receptor) proto-oncogene.Ofico∧CTic 1992.7:2207-2217.
[18]Tomita Y, Suzuki T. Genetics of pigmentary disorders. Am J Med Genet C Semin Med Genet 2004:131C:75-81
[19]Spritz R A. The molecular basis of human piebaldism. Pigment Cell Res. 1992:5:340-343.
[20]Sanchez-Martin M, Perez-Losada J, Rodriguez-Garcia A et al. Deletion of the SLUG (SNAI2) gene results in human piebaldism. Am J Med Genet 2003: 122:125-132.
[21]Puffenberger E G, Hosoda K, Washington S S et al. A missense mutation of the endothelin-B receptor gene in multigenic Hirchsprung's disease. Cell 1994.79: 1257-1266.
[22]Mccallion A S, Chakravarti A. EDNR B/EDN3 and Hirchsprung disease type II. Pigment Cell Res 2001.14:161-169.
[23]Smith S D, Kelley P M, Kenyon J. Tietz syndrome (hypopigmentation/ deafness) caused by mutation of MITF. J Med Genet 2000.37:446-448
[24]Slominski A, Tobin D J, Shibahara S et al. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev 2004.84:1155-1228.
[25]Oetting W S, Fryer J P, Shriram S et al. Oculocutaneous albinism type 1:the last 100 years. Pigment Cell Res 2003.16:307-311.
[26]Schallreuter K U, Kothari S, Chavan B. Regulation of melanogenesis-controversiesand new concepts. Exp Dermatol 2008.17:395-404.
[27]Giebel L B, Tripathi R K, Strunk K M et al. Tyrosinase gene mutations associated with type 1B ('yellow') oculocutaneous albinism. Am J Hum Genet 1991.48:1159-1167.
[28]Matsunaga J, Dakeishi-Hara M, Tanita M et al. A splicing mutation of the tyrosinase gene causes yellow oculocutaneous albinism in Japanese patients with a pigmented phenotype. Dermatology 1999.199:124-129.
[29]King R A, Townsend D, Oetting W et al. Temparature-sensitive tyrosinase associated with peripheral pigmentation in oculocutaneous albinism. J Clin Invest.1991.87:1046-1053.
[30]Giebel L B, Tripathi R K, King R A et al. A tyrosinase gene missense in temparature-sensitive type 1 oculocutaneous albinism. A human homologue to the Siamese cat and the Himalayan mouse. J Clin Invest 1991.87:1119-1122.
[31]Kushimoto T, Valencia J C, Costin G-E et al. The melanosome:an ideal model to study cellular differentiation. Pigment Cell Res 2003.16:237-244.
[32]Spritz R A, Chiang P-W, Oiso N et al. Human and mouse disorders of pigmentation.Curr Opin Genet Dev 2003.13:284-289
[33]Graf J, Voisey J, Hughes I et al. Promoter polymorphisms in the MATP (SLC45A2) gene are associated with normal human skin color variation. HumMutat 2007.28:710-717.
[34]Wei M L. Hermansky-Pudlak syndrome:a disease of protein trafficking and organelle function. Pigment Cell Res 2006.19:19-42.
[35]Dessinioti C,Alexander J,Rigopoulos D,et al.A review of genetic disorders of hypopigmentation:lessons learned from the biology of melanocytes. Experimental Dermatology.2009.18:741-749.
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