一个异染性脑白质营养不良家系ARSA基因突变分析

Analysis of ARSA mutations in a Chinese family with metachromatic leukodystrophy

目的分析并确定一个异染性脑白质营养不良(metachromaticleukodystrophy,MLD)家系芳基硫酸酯酶A(arylsulftaseA,ARSA)的基因(ARSA)突变及遗传特征。方法收集先证者及其家系成员临床资料,采用聚合酶链反应和DNA直接测序方法进行ARSA突变检测,确定基因突变的位点,分析基因型与表型的关系。结果该家系先证者的ARSA基因同时存在第2外显子G251A(R84Q)与G296T(G99V)两个杂合突变,具有相似表型的胞弟与先证者的测序结果完全一致,先证者之父母分别携带ARSA基因第2外显子G251A(R84Q)与G296T(G99V)的杂合突变,表型正常的先证者之姐未发现这些突变。结论该家系中两位患儿均为ARSA基因复合杂合突变致病,其G251A(R84Q)突变来自父亲,G296T(G99V)突变来自母亲,其父母均为表型正常的基因突变携带者。

Objective To identify arylsulftase A gone （ARSA） mutations in a Chinese family with MLD. Methods There were two MLD patients in the investigated family. The proband, an ll-year-old girl, was well until the age of 5 years, when she began to experience difficult walking and mental regression. Magnetic resonance imaging （MRI） of her brain showed widespread demyelination, nerve conduction velocity reduced, and ARSA activity measured in white blood cells was zero. So, the child was diagnosed having MLD. The proband＇s young brother also got the same phenotype except clinical symptom being milder than hers. Their parents and elder sister all had normal phenotypes. Genomic DNA samples were extracted from peripheral bloods of the proband and all her family members. All 8 exons and exon-intron boundaries of ARSA gone were amplified by polymerase chain reaction （PCR） and followed by direct DNA sequencing. Results Two heterozygous mutations of ARSA, which were named as, G251A （R84Q） and G296T （G99V） were identified in the proband. The two mutations were located in exon 2. The same genotype was found in the proband＇ s young brother, but these mutations were not detected in proband＇ s elder sister. The proband＇ s mother had the heterozygous mutations G296T （G99V）, and her father had the heterozygous mutation G251A （R84Q）. Condusion These two MLD patients are with both compound heterozygous mutations, which mean one allele with the G296T（G99V） mutation was from their mother, and the other allele with the G251A（R84Q） mutation got from their father. The parents are both carrier with normal phenotype.