六个先天性眼球震颤家系的分子遗传学研究
摘要
目的
对6个先天性眼球震颤家系,包括4个X连锁先天性特发性眼球震颤(X-linked congenital idiopathic nystagmus, XL-CIN)和2个伴有无虹膜的先天性感觉缺陷性眼球震颤(sensory defect nystagmus, SDN)家系进行分子遗传学研究,探讨其致病的分子基础。
方法
1、X连锁先天性特发性眼球震颤：收集4个XL-CIN家系的临床资料及采集家系成员外周静脉血各5m1,提取基因组DNA；以先证者基因组DNA为模板,PCR扩增XL-CIN候选致病基因FRMD7的全部外显子及其外显子-内含子拼接部的序列,DNA直接测序筛查突变位点；一旦发现致病性突变位点,则采用DNA直接测序方法在其家系成员进行疾病与致病突变共分离分析,进一步确认致病性突变位点。
2、先天性感觉缺陷性眼球震颤：对2个伴有无虹膜的SDN家系成员进行全面的眼部检查,采集这2个家系共6例患者和5名健康成员外周静脉血各5ml,提取基因组DNA；以先证者基因组DNA为模板,PCR扩增候选致病基因PAX6的14个外显子及其外显子-内含子拼接部的序列,DNA直接测序筛查突变位点；一旦发现可疑致病性突变位点,则采用DNA测序方法在其家系成员进行疾病与致病突变共分离分析及单核苷酸多态性(SNP)排除分析,进一步确认致病性突变位点。
结果
1、4个先天性特发性眼球震颤家系的遗传模式符合X-连锁显性遗传伴外显不全,FRMD7基因突变筛查发现其中2个家系携带已知致病性突变位点,即XL-CIN02家系患者在FRMD7基因外显子8存在c.G886C错义突变(GGT>CGT),导致FRMD7蛋白第296位的甘氨酸被精氨酸代替(p.G296R)；XL-CINO3家系患者在FRMD7基因外显子10存在c.C910T无义突变(CGA>TGA),导致该基因编码蛋白在304位的精氨酸提前终止(p.R304X),产生一个截短形式的变异多肽。
2、2个先天性感觉缺陷性眼球震颤家系皆伴有先天性无虹膜,呈常染色体显性遗传。SDN-01家系患者还合并双眼黄斑中心凹发育不良和早发性白内障(presenile cataract),PAX6基因突变筛查发现患者在该基因第5外显子存在一个杂合性复制突变(c.95_105dupll),该突变为一个de novo新突变,导致该基因编码蛋白在第36位甘氨酸提前终止(p.G36X),产生一个截短的多肽；SDN-02家系表现单纯性无虹膜,突变筛查发现患者在PAX6基因第8外显子存在一个c.C607T杂合性无义突变,导致编码蛋白在第203位精氨酸提前终止(p.R203X),产生一个截短的多肽。
结论
1、FRMD7G296R和R304X突变分别是导致XL-CIN02和XL-CIN03家系患者致病的分子基础。
2、在一个伴有双眼先天性无虹膜、黄斑中心凹发育不良和早发性白内障的先天性感觉缺陷性眼球震颤家系(SDN-01)中发现了一个de novo PAX6基因c.95_105dup11(p.G36X)新突变；在一个伴有单纯双眼先天性无虹膜的先天性感觉缺陷性眼球震颤家系(SDN-02)中发现了一个PAX6基因c.C607T(p.R203X)热点突变。
Objective
To identify the molecular defect of six Chinese congenital nystagmus families, including four X-linked congenital idiopathic nystagmus (XL-CIN) families and two sensory defect nystagmus(SDN) families with aniridia.
Methods
1. XL-CIN:The members of the four pedigrees were recruited, clinical examinations were performed, and genomic DNA was extracted from peripheral blood leukocytes. The coding exons and splice junctions of the human FRMD7gene were amplified by polymerase chain reaction (PCR). The PCR products were purified, and then were performed direct sequencing. The mutation detected was confirmed in available other family members through co-segregation analysis.
2. SDN: Eleven members of the two pedigrees were recruited, clinical examinations were performed, and genomic DNA was extracted from peripheral blood leukocytes. The coding exons and splice junctions of the human PAX6gene were amplified by polymerase chain reaction (PCR). The PCR products were purified and sequenced. When any interesting sequence variation suggestive of a mutation was found in the proband, it was later confirmed in parents and available relatives as well as in50normal unrelated individuals from the same ethnic background by directly sequencing the particular exon.
Results
1. The genetic models of four families with congenital idiopathic nystagmus were X-linked dominant inheritance with incomplete penetrance. FRMD7mutations were found in two of four families with XL-CIN:a missense mutation c.G886C(p.G296R) in exon8of FRMD7was detected in family XL-CIN02, and a nonsense mutation c. C910T (p.R304X) in exonlO of FRMD7gene in family XL-CIN03.
2. Two sensory defect congenital nystagmus families accompanying with congenital aniridia showed autosomal dominant inheritance. The patients of SDN-01family also showed macular dysplasia and presenile cataract. A heterozygous mutation c.95_105dup11of PAX6was found in all of two patients in family SDN-01, not in unaffected individuals. This mutation is predicted to result in the truncation of the protein product within the linker region of PAX6(p.G36X). SDN-02pedigree were simple aniridia, a heterozygous mutation c.C607T of PAX6was found in all of four patients in family SDN-02, not in unaffected individuals. This nonsense mutation is predicted to result in the truncation of the protein product within the linker region of PAX6(p.R203X).The mutations co-segregated with the disease phenotype in all available family members.
Conclusion
1. Two known FRMD7G296R and R304X mutations were identified in Chinese XL-CIN family XL-CIN02and XL-CIN03, respectively.
2. A de novo mutation of the PAX6gene (c.95_105dup11) was reported firstly in family SDN-01associated with aniridia, macular hypoplasia and presenile cataracts.
3. The known mutation R203X, one of the three common recurrent mutations in PAX6, was also presented in Chinese sensory defect nystagmus family(SDN-02) with simple aniridia.
对6个先天性眼球震颤家系,包括4个X连锁先天性特发性眼球震颤(X-linked congenital idiopathic nystagmus, XL-CIN)和2个伴有无虹膜的先天性感觉缺陷性眼球震颤(sensory defect nystagmus, SDN)家系进行分子遗传学研究,探讨其致病的分子基础。
方法
1、X连锁先天性特发性眼球震颤：收集4个XL-CIN家系的临床资料及采集家系成员外周静脉血各5m1,提取基因组DNA；以先证者基因组DNA为模板,PCR扩增XL-CIN候选致病基因FRMD7的全部外显子及其外显子-内含子拼接部的序列,DNA直接测序筛查突变位点；一旦发现致病性突变位点,则采用DNA直接测序方法在其家系成员进行疾病与致病突变共分离分析,进一步确认致病性突变位点。
2、先天性感觉缺陷性眼球震颤：对2个伴有无虹膜的SDN家系成员进行全面的眼部检查,采集这2个家系共6例患者和5名健康成员外周静脉血各5ml,提取基因组DNA；以先证者基因组DNA为模板,PCR扩增候选致病基因PAX6的14个外显子及其外显子-内含子拼接部的序列,DNA直接测序筛查突变位点；一旦发现可疑致病性突变位点,则采用DNA测序方法在其家系成员进行疾病与致病突变共分离分析及单核苷酸多态性(SNP)排除分析,进一步确认致病性突变位点。
结果
1、4个先天性特发性眼球震颤家系的遗传模式符合X-连锁显性遗传伴外显不全,FRMD7基因突变筛查发现其中2个家系携带已知致病性突变位点,即XL-CIN02家系患者在FRMD7基因外显子8存在c.G886C错义突变(GGT>CGT),导致FRMD7蛋白第296位的甘氨酸被精氨酸代替(p.G296R)；XL-CINO3家系患者在FRMD7基因外显子10存在c.C910T无义突变(CGA>TGA),导致该基因编码蛋白在304位的精氨酸提前终止(p.R304X),产生一个截短形式的变异多肽。
2、2个先天性感觉缺陷性眼球震颤家系皆伴有先天性无虹膜,呈常染色体显性遗传。SDN-01家系患者还合并双眼黄斑中心凹发育不良和早发性白内障(presenile cataract),PAX6基因突变筛查发现患者在该基因第5外显子存在一个杂合性复制突变(c.95_105dupll),该突变为一个de novo新突变,导致该基因编码蛋白在第36位甘氨酸提前终止(p.G36X),产生一个截短的多肽；SDN-02家系表现单纯性无虹膜,突变筛查发现患者在PAX6基因第8外显子存在一个c.C607T杂合性无义突变,导致编码蛋白在第203位精氨酸提前终止(p.R203X),产生一个截短的多肽。
结论
1、FRMD7G296R和R304X突变分别是导致XL-CIN02和XL-CIN03家系患者致病的分子基础。
2、在一个伴有双眼先天性无虹膜、黄斑中心凹发育不良和早发性白内障的先天性感觉缺陷性眼球震颤家系(SDN-01)中发现了一个de novo PAX6基因c.95_105dup11(p.G36X)新突变；在一个伴有单纯双眼先天性无虹膜的先天性感觉缺陷性眼球震颤家系(SDN-02)中发现了一个PAX6基因c.C607T(p.R203X)热点突变。
Objective
To identify the molecular defect of six Chinese congenital nystagmus families, including four X-linked congenital idiopathic nystagmus (XL-CIN) families and two sensory defect nystagmus(SDN) families with aniridia.
Methods
1. XL-CIN:The members of the four pedigrees were recruited, clinical examinations were performed, and genomic DNA was extracted from peripheral blood leukocytes. The coding exons and splice junctions of the human FRMD7gene were amplified by polymerase chain reaction (PCR). The PCR products were purified, and then were performed direct sequencing. The mutation detected was confirmed in available other family members through co-segregation analysis.
2. SDN: Eleven members of the two pedigrees were recruited, clinical examinations were performed, and genomic DNA was extracted from peripheral blood leukocytes. The coding exons and splice junctions of the human PAX6gene were amplified by polymerase chain reaction (PCR). The PCR products were purified and sequenced. When any interesting sequence variation suggestive of a mutation was found in the proband, it was later confirmed in parents and available relatives as well as in50normal unrelated individuals from the same ethnic background by directly sequencing the particular exon.
Results
1. The genetic models of four families with congenital idiopathic nystagmus were X-linked dominant inheritance with incomplete penetrance. FRMD7mutations were found in two of four families with XL-CIN:a missense mutation c.G886C(p.G296R) in exon8of FRMD7was detected in family XL-CIN02, and a nonsense mutation c. C910T (p.R304X) in exonlO of FRMD7gene in family XL-CIN03.
2. Two sensory defect congenital nystagmus families accompanying with congenital aniridia showed autosomal dominant inheritance. The patients of SDN-01family also showed macular dysplasia and presenile cataract. A heterozygous mutation c.95_105dup11of PAX6was found in all of two patients in family SDN-01, not in unaffected individuals. This mutation is predicted to result in the truncation of the protein product within the linker region of PAX6(p.G36X). SDN-02pedigree were simple aniridia, a heterozygous mutation c.C607T of PAX6was found in all of four patients in family SDN-02, not in unaffected individuals. This nonsense mutation is predicted to result in the truncation of the protein product within the linker region of PAX6(p.R203X).The mutations co-segregated with the disease phenotype in all available family members.
Conclusion
1. Two known FRMD7G296R and R304X mutations were identified in Chinese XL-CIN family XL-CIN02and XL-CIN03, respectively.
2. A de novo mutation of the PAX6gene (c.95_105dup11) was reported firstly in family SDN-01associated with aniridia, macular hypoplasia and presenile cataracts.
3. The known mutation R203X, one of the three common recurrent mutations in PAX6, was also presented in Chinese sensory defect nystagmus family(SDN-02) with simple aniridia.
引文
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