全基因组外显子测序发现Marie Unna遗传性少毛症致病基因EPS8L3
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摘要
研究背景Marie Unna遗传性少毛症(Marie Unna hereditary hypotrichosis,MUHH,MIM146550/612841)是一种罕见的呈常染色体显性遗传模式的遗传性毛发疾病。Marie Unna于1925年首次报道1例德国患者。该病发病无男女性别差异,但男性患者病情比女性严重。其临床特点为：患者出生时头发正常或稀少或缺乏,随后开始缓慢生长,但已生长的头发粗糙、不规则扭曲呈金属丝样外观,至青春期头发弥漫性脱落且逐渐加重,严重者可呈全秃。此外,睫毛可缺如,眉毛、腋毛、阴毛和男性胡须稀少,但不伴有其他外胚层结构异常,且体格检查和智力均正常。组织病理学显示毛囊周围有少量炎性细胞浸润或纤维化,但成熟的毛囊数量显著减少、毛囊缩小；光学显微镜镜检显示毛发呈扁平、粗糙和不规则扭曲状；扫描电镜显示可有纵嵴、纵沟、纵裂、不规则横断面、毛小皮广泛的剥脱和毛鞘异常。自1999年至2004年,多个研究小组分别对来自荷兰、英国、德国、比利时、美国和中国等不同种族的MUHH家系进行了连锁和单倍型分析,均将MUHH的致病基因位点定位于8p21。前期许多研究小组先后针对定位区域内人类无毛基因(Human hairless gene,HR)的编码区和剪接位点进行突变分析,但均未检测到HR基因的致病性突变。2009年,张学教授在来自不同种族的19个MUHH家系中发现了HR基因U2HR区域的13种不同突变,建立了MUHH遗传突变谱。随后多个研究小组也在中国、土耳其、德国家系或散发病例中发现了HR基因U2HR区域的致病突变。
2004年Yan等通过微卫星标记研究对1个4代的MUHH家系进行分析,发现该家系的致病基因与8p区域不连锁,提示MUHH具有遗传异质性；2005年Yang等对该家系进行全基因组扫描研究,证实该家系致病基因与8p区域不连锁,并将致病基因定位于1p21.1-1q21.3上D1S248和D1S2345之间的17.5cM区域。随着新一代测序技术的迅猛发展,全基因组外显子测序策略已成功应用于单基因病的致病基因研究,癌症和多基因病易感基因的筛查以及临床上疑难病例的诊断,全基因组外显子测序得到了迅猛的发展。
目的结合前期的全基因组定位信息,运用全基因组外显子测序技术搜寻MUHH的致病基因,为将来基因诊断、基因治疗奠定基础。
方法(1)从家系1中挑选出2个临床表型典型的患者和1个家系内对照,进行全基因组外显子测序；(2)通过逐步滤过dbSNP数据库和家系内对照中的常见突变,并且结合前期定位信息获得候选基因集；(3)利用Sanger测序,在家系内患者和对照中对候选基因集的突变位点进行测序验证,分析突变点是否与疾病共分离,获得候选基因；(4)在独立的家系2和其他4个散发病例中,对候选基因的编码区外显子和外显子与内含子交界区的序列进行测序,以期在其他病例中发现候选基因的突变；(5)采用PCR反应扩增HR基因U2HR区域,用直接测序方法对候选基因突变筛查阴性的病例对HR基因U2HR区域进行突变检测,并通过PubMed及中国生物医学光盘CBM,对已报道的关于HR基因U2HR区域的突变报道进行总结,以其发现其基因型与表型的关系。
结果(1)通过全基因组外显子测序,获得3个全基因组外显子测序样本的SNPs、 indels的数据集合；(2)考虑到引起疾病的变异是罕见的,在家系内对照和公共数据库中(如dbSNP135)中不存在,通过逐步滤过后,满足2个患者共有、dbSNP135和家系内对照不存在的条件的突变点有91个。其中EPS8L3基因上一个错义突变即c.22G>A位于定位区域lp21.1-1q21.3,该突变导致了丙氨酸变成苏氨酸,且ANNOVAR和PhastCons软件预测为有害突变,EPS8L3基因作为候选基因作进一步研究；(3)通过Sanger测序对家系内成员(包括全基因组外显子测序的2个患者和1个对照)的该位点进行测序验证,证实8个患者均存在该错义突变,3个对照均无该突变；(4)通过筛查676例正常对照和781例有其他疾病的病例的全基因组外显子测序数据,在676例正常对照和781例其他疾病的病例中均未发现该位点突变,从而说明该突变是一个致病性突变而非多态性变化；(5)通过对家系2的先证者和4例散发病例的EPS8L3基因编码区进行测序,未发现EPS8L3基因潜在性的致病性突变；(6)在家系2的先证者和其母亲中检测到HR基因U2HR区域的1个错义突变：c.73C>G(p.pro25ala),而先证者的父亲(正常人)中不存在该突变,该突变曾在荷兰、英国、意大利种族的MUHH患者中报道过；(7)目前已报道HR基因U2HR区域的突变有16种,包括5个起始密码子突变,2个无义突变,7个错义突变,2个终止密码子突变,总结了MUHH临床特点和突变类型,但尚未发现基因型与表型之间的关系。
结论(1)结合全基因组连锁分析的定位研究,通过全基因组外显子测序发现了一个中国汉族Maire Unna遗传性少毛症家系的致病基因—EPS8L3基因。证实了全基因组外显子测序结合全基因组定位信息鉴定单基因病致病基因的有效性。(2)通过直接测序的方法在另外1个中国MUHH家系中检测出HR基因U2HR区域错义突变c.73C>G(p.pro25ala),丰富了U2HR遗传突变谱,为将来的遗传咨询、产前诊断及基因治疗打下理论基础；同时表明MUHH具有遗传异质性,不同家系致病基因可能不同。
Background Marie Unna hereditary hypotrichosis(MUHH, MIM146550/612841) is a rare autosomal dominant inheritance congenital hair disease. MUHH was first reported by Marie Unna in1925.The incidence of men and women was alike, but the clinical manifestations of male patient is more serious than female patient. MUHH is characterized by normal, sparse or absent hair at birth, then develop to coarse, twisted and wiry hair during childhood and progress during puberty to an almost complete alopecia. Eyebrows, eyelashes, armpit hair, pubic hair and beard hair are also markedly diminished or absent. But no other ectodermal abnormalities are observed. The physical and intelligence of all patients are normal. The histopathological examination showed that hair follicle is surrounded by a small amount of inflammatory cell infiltration or fibrosis, but the number of mature hair follicles is a significant reduction and hair follicles were shrink. Optical microscopy showed that the hair was flat, rough and irregular-shaped distortions.Scanning electron microscopic studies display an irregularly twisted hair, longitudinal fractures, longitudinal split, irregular cross section, mild peeling and irregular hair shafts in MUHH. Many genetic linkage studies have mapped the MUHH locus to chromosome8p21, but no genes responsible for MUHH were identified, including HR (Human hairless gene) gene. In2009, Professor Zhang Xue found13different disease-causing mutations in the U2HR region of HR gene and established MUHH genetic mutation spectrum through international cooperation in19different ethnic MUHH families. Followed by multiple research groups had found the pathogenic mutation of U2HR.
In2004, Yan et al excluded a four-generation MUHH pedigree by microsatellite markers, which indicated that MUHH is a heterogeneous disorder. In2005, Yang et al found a locus for MUHH on chromosome1p21.1-1q21.3to a17.5cM region between markers D1S248and D1S2345in this family. With the rapid development of next-generation sequencing technology, whole genome exome sequencing strategy has been successfully applied to identify causing gene of Mendel disease, susceptibility genes of cancer and complex disease, as well as helped for clinical diagnosis which difficult to diagnose cases.
Objective We used whole genome exome sequencing strategy and combined with the result of genome-wide linkage study to identify the causative gene of this family.
Methods (1) We conducted exome sequencing in two affected individuals and one unaffected individual from this MUHH family.(2) We got the candidate gene set which filter the mutations of exited in dbSNP database(version135) and unaffected individua step by step and located in location region.(3) To identify complete co-segregation between the mutation and MUHH phenotype, we sequenced the mutation of the candidate gene set in the extended pedigree of this family.(4) We sequenced all coding exons and flanking introns of the candidate genes in one family and four sporadic patients in order to discovery new mutations.(5) We sequenced the U2HR in one pedigree and four sporadic patients with MUHH. We also searched for the mutation reports of U2HR through Chinese Biology Medicine (CBM) disk and Pubmed, and find the relationship between genotype and phenotype.
Results (1) We obtained SNP and indels of three samples by whole genome exome sequencing.(2) We focused our analyses primarily on nonsynonymous variants (NS), splice acceptor/donor site mutations (SS) and coding insertions/deletions (indels) that are more likely to be pathogenic mutations. In addition, we predicted that variants underlying MUHH are rare and thus unlikely identified previously. We therefore selected the variants that were absent from most updated dbSNP database (version135) for further analysis. Assuming a dominant model, we found91novel NS/SS/indels that were shared by the two affected individuals but absent in the unaffected individual in this family. Of the91variants, only one heterozygous mutation in EPS8L3(c.22G>A [p.Ala8Thr]) was found to be located within the linkage region on1p21.1-1q21.3established in our previous linkage study. The mutation was predicted to be "damaging" by ANNOVAR program and affect a conserved amino-acid residue by PhastCons software.(3) We analyzed the mutation in all the available affected and unaffected individuals (including three samples performed with exome sequencing) of this family by Sanger sequencing. All the eight affected individuals carried this heterozygous mutation in EPS8L3(c.22G>A [p.Ala8Thr]) which was absent in the three unaffected family members, suggesting complete co-segregation between the mutation and MUHH phenotype.(4) This mutation was not detected in additional exome sequencing data of676unrelated, ethnically and geographically matched controls. In addition, we also checked the exome sequencing data of781unrelated, ethnically and geographically matched patients of other disease and did not found the mutation. All these results suggested that this mutation is a causal variant for MUHH, instead of a rare polymorphism.(5) We did not find mutation of EPS8L3gene in the other family2and four sporadic patients.(6) We identified one missense mutation c.73C G (p.pro25ala) in U2HR of proband and his mother from family2, but the mutation was not detected in the patient's unaffected father.(7) There are16species mutations of U2HR which had been reported, including5initiation codon mutations, two nonsense mutations, seven missense mutations, two stop codon mutations. And we did not observe obvious genotype-phenotype correlation in MUHH patients.
Conclusion (1) Our study identified EPS8L3as a novel disease gene for MUHH by combining exome sequencing with previously established linkage information in a large multi-generation MUHH family of Chinese population. Our study has also demonstrated the effectiveness of exome sequencing, combined with linkage analysis, in discovering disease genes for Mendelian disorders.(2) We had found a missense mutation (c.73C>G, p.pro25ala) of U2HR which had been reported in family2. This study contributes to lay the foundation for future genetic counseling, prenatal diagnosis, gene therapy and suggested that MUHH is a genetically heterogeneous disorder.
2004年Yan等通过微卫星标记研究对1个4代的MUHH家系进行分析,发现该家系的致病基因与8p区域不连锁,提示MUHH具有遗传异质性；2005年Yang等对该家系进行全基因组扫描研究,证实该家系致病基因与8p区域不连锁,并将致病基因定位于1p21.1-1q21.3上D1S248和D1S2345之间的17.5cM区域。随着新一代测序技术的迅猛发展,全基因组外显子测序策略已成功应用于单基因病的致病基因研究,癌症和多基因病易感基因的筛查以及临床上疑难病例的诊断,全基因组外显子测序得到了迅猛的发展。
目的结合前期的全基因组定位信息,运用全基因组外显子测序技术搜寻MUHH的致病基因,为将来基因诊断、基因治疗奠定基础。
方法(1)从家系1中挑选出2个临床表型典型的患者和1个家系内对照,进行全基因组外显子测序；(2)通过逐步滤过dbSNP数据库和家系内对照中的常见突变,并且结合前期定位信息获得候选基因集；(3)利用Sanger测序,在家系内患者和对照中对候选基因集的突变位点进行测序验证,分析突变点是否与疾病共分离,获得候选基因；(4)在独立的家系2和其他4个散发病例中,对候选基因的编码区外显子和外显子与内含子交界区的序列进行测序,以期在其他病例中发现候选基因的突变；(5)采用PCR反应扩增HR基因U2HR区域,用直接测序方法对候选基因突变筛查阴性的病例对HR基因U2HR区域进行突变检测,并通过PubMed及中国生物医学光盘CBM,对已报道的关于HR基因U2HR区域的突变报道进行总结,以其发现其基因型与表型的关系。
结果(1)通过全基因组外显子测序,获得3个全基因组外显子测序样本的SNPs、 indels的数据集合；(2)考虑到引起疾病的变异是罕见的,在家系内对照和公共数据库中(如dbSNP135)中不存在,通过逐步滤过后,满足2个患者共有、dbSNP135和家系内对照不存在的条件的突变点有91个。其中EPS8L3基因上一个错义突变即c.22G>A位于定位区域lp21.1-1q21.3,该突变导致了丙氨酸变成苏氨酸,且ANNOVAR和PhastCons软件预测为有害突变,EPS8L3基因作为候选基因作进一步研究；(3)通过Sanger测序对家系内成员(包括全基因组外显子测序的2个患者和1个对照)的该位点进行测序验证,证实8个患者均存在该错义突变,3个对照均无该突变；(4)通过筛查676例正常对照和781例有其他疾病的病例的全基因组外显子测序数据,在676例正常对照和781例其他疾病的病例中均未发现该位点突变,从而说明该突变是一个致病性突变而非多态性变化；(5)通过对家系2的先证者和4例散发病例的EPS8L3基因编码区进行测序,未发现EPS8L3基因潜在性的致病性突变；(6)在家系2的先证者和其母亲中检测到HR基因U2HR区域的1个错义突变：c.73C>G(p.pro25ala),而先证者的父亲(正常人)中不存在该突变,该突变曾在荷兰、英国、意大利种族的MUHH患者中报道过；(7)目前已报道HR基因U2HR区域的突变有16种,包括5个起始密码子突变,2个无义突变,7个错义突变,2个终止密码子突变,总结了MUHH临床特点和突变类型,但尚未发现基因型与表型之间的关系。
结论(1)结合全基因组连锁分析的定位研究,通过全基因组外显子测序发现了一个中国汉族Maire Unna遗传性少毛症家系的致病基因—EPS8L3基因。证实了全基因组外显子测序结合全基因组定位信息鉴定单基因病致病基因的有效性。(2)通过直接测序的方法在另外1个中国MUHH家系中检测出HR基因U2HR区域错义突变c.73C>G(p.pro25ala),丰富了U2HR遗传突变谱,为将来的遗传咨询、产前诊断及基因治疗打下理论基础；同时表明MUHH具有遗传异质性,不同家系致病基因可能不同。
Background Marie Unna hereditary hypotrichosis(MUHH, MIM146550/612841) is a rare autosomal dominant inheritance congenital hair disease. MUHH was first reported by Marie Unna in1925.The incidence of men and women was alike, but the clinical manifestations of male patient is more serious than female patient. MUHH is characterized by normal, sparse or absent hair at birth, then develop to coarse, twisted and wiry hair during childhood and progress during puberty to an almost complete alopecia. Eyebrows, eyelashes, armpit hair, pubic hair and beard hair are also markedly diminished or absent. But no other ectodermal abnormalities are observed. The physical and intelligence of all patients are normal. The histopathological examination showed that hair follicle is surrounded by a small amount of inflammatory cell infiltration or fibrosis, but the number of mature hair follicles is a significant reduction and hair follicles were shrink. Optical microscopy showed that the hair was flat, rough and irregular-shaped distortions.Scanning electron microscopic studies display an irregularly twisted hair, longitudinal fractures, longitudinal split, irregular cross section, mild peeling and irregular hair shafts in MUHH. Many genetic linkage studies have mapped the MUHH locus to chromosome8p21, but no genes responsible for MUHH were identified, including HR (Human hairless gene) gene. In2009, Professor Zhang Xue found13different disease-causing mutations in the U2HR region of HR gene and established MUHH genetic mutation spectrum through international cooperation in19different ethnic MUHH families. Followed by multiple research groups had found the pathogenic mutation of U2HR.
In2004, Yan et al excluded a four-generation MUHH pedigree by microsatellite markers, which indicated that MUHH is a heterogeneous disorder. In2005, Yang et al found a locus for MUHH on chromosome1p21.1-1q21.3to a17.5cM region between markers D1S248and D1S2345in this family. With the rapid development of next-generation sequencing technology, whole genome exome sequencing strategy has been successfully applied to identify causing gene of Mendel disease, susceptibility genes of cancer and complex disease, as well as helped for clinical diagnosis which difficult to diagnose cases.
Objective We used whole genome exome sequencing strategy and combined with the result of genome-wide linkage study to identify the causative gene of this family.
Methods (1) We conducted exome sequencing in two affected individuals and one unaffected individual from this MUHH family.(2) We got the candidate gene set which filter the mutations of exited in dbSNP database(version135) and unaffected individua step by step and located in location region.(3) To identify complete co-segregation between the mutation and MUHH phenotype, we sequenced the mutation of the candidate gene set in the extended pedigree of this family.(4) We sequenced all coding exons and flanking introns of the candidate genes in one family and four sporadic patients in order to discovery new mutations.(5) We sequenced the U2HR in one pedigree and four sporadic patients with MUHH. We also searched for the mutation reports of U2HR through Chinese Biology Medicine (CBM) disk and Pubmed, and find the relationship between genotype and phenotype.
Results (1) We obtained SNP and indels of three samples by whole genome exome sequencing.(2) We focused our analyses primarily on nonsynonymous variants (NS), splice acceptor/donor site mutations (SS) and coding insertions/deletions (indels) that are more likely to be pathogenic mutations. In addition, we predicted that variants underlying MUHH are rare and thus unlikely identified previously. We therefore selected the variants that were absent from most updated dbSNP database (version135) for further analysis. Assuming a dominant model, we found91novel NS/SS/indels that were shared by the two affected individuals but absent in the unaffected individual in this family. Of the91variants, only one heterozygous mutation in EPS8L3(c.22G>A [p.Ala8Thr]) was found to be located within the linkage region on1p21.1-1q21.3established in our previous linkage study. The mutation was predicted to be "damaging" by ANNOVAR program and affect a conserved amino-acid residue by PhastCons software.(3) We analyzed the mutation in all the available affected and unaffected individuals (including three samples performed with exome sequencing) of this family by Sanger sequencing. All the eight affected individuals carried this heterozygous mutation in EPS8L3(c.22G>A [p.Ala8Thr]) which was absent in the three unaffected family members, suggesting complete co-segregation between the mutation and MUHH phenotype.(4) This mutation was not detected in additional exome sequencing data of676unrelated, ethnically and geographically matched controls. In addition, we also checked the exome sequencing data of781unrelated, ethnically and geographically matched patients of other disease and did not found the mutation. All these results suggested that this mutation is a causal variant for MUHH, instead of a rare polymorphism.(5) We did not find mutation of EPS8L3gene in the other family2and four sporadic patients.(6) We identified one missense mutation c.73C G (p.pro25ala) in U2HR of proband and his mother from family2, but the mutation was not detected in the patient's unaffected father.(7) There are16species mutations of U2HR which had been reported, including5initiation codon mutations, two nonsense mutations, seven missense mutations, two stop codon mutations. And we did not observe obvious genotype-phenotype correlation in MUHH patients.
Conclusion (1) Our study identified EPS8L3as a novel disease gene for MUHH by combining exome sequencing with previously established linkage information in a large multi-generation MUHH family of Chinese population. Our study has also demonstrated the effectiveness of exome sequencing, combined with linkage analysis, in discovering disease genes for Mendelian disorders.(2) We had found a missense mutation (c.73C>G, p.pro25ala) of U2HR which had been reported in family2. This study contributes to lay the foundation for future genetic counseling, prenatal diagnosis, gene therapy and suggested that MUHH is a genetically heterogeneous disorder.
引文
1. He, P.P., C.D. He, Y. Cui, et al., Refined localization of dyschromatosis symmetrica hereditaria gene to a 9.4-cM region at 1q21-22 and a literature review of 136 cases reported in China. Br J Dermatol,2004.150(4):p.633-9.
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