Metachromatic leukodystrophy in the Navajo Indian population: a splice site mutation in intron 4 of the arylsulfatase A gene.
Metachromatic leukodystrophy in the Navajo Indian population: a splice site mutation in intron 4 of the arylsulfatase A gene.
复制标题
纳瓦霍印第安人群体中的异染性脑白质营养不良：芳基硫酸酯酶 A 基因内含子 4 中的剪接位点突变。
DOI：
10.1002/humu.1380040305
复制
发表时间：
1994
期刊：
影响因子：
3.9
通讯作者：
Wenger,DA
中科院分区：
文献类型：
--
作者：
Pastor-Soler,NM;Rafi,MA;Hoffman,JD;Hu,D;Wenger,DA
异染性脑白质营养不良（MLD）是一种髓鞘代谢的常染色体隐性疾病，由无法正确降解3-磺基半乳糖神经酰胺（硫苷脂）引起。这种代谢阻滞通常是由于溶酶体酶芳基硫酸酯酶A（ARSA）的功能缺陷。未代谢的硫苷脂在CNS的白色物质和周围神经中积累，导致进行性脱髓鞘和死亡。已描述了MLD的晚期婴儿、青少年和成人临床变体。一名纳瓦霍印第安儿童被诊断为晚期婴儿MLD（LIMLD），他的ARSA基因在三个重叠区域被PCR扩增并测序。发现一个单一的突变：内含子4的第一个核苷酸（IVS 4 ntl）的G → A转换，取消了5′剪接位点的共有序列。在北方印迹中观察到可忽略量的ARSA mRNA。然而，ARSA cDNA的PCR扩增和测序显示，来自患者的所有mRNA种类都具有外显子4缺失。因此建立了一个新的阅读框架，其导致外显子5内的提前终止密码子。少数转录本有额外的剪接错误。父母双方都携带这种突变，父亲也携带假缺陷（PD）等位基因。通过等位基因特异性寡核苷酸（阿索）杂交，发现另外3例不相关的Navajo LIMLD患者为相同MLD致突变的纯合子。该方法可用于该人群的携带者和患者识别。© 1994 Wiley利斯公司
Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder of myelin metabolism, resulting from the inability to properly degrade 3‐sulfogalactosylceramide (sulfatide). This metabolic block is often due to defective functioning of the lysosomal enzyme arylsulfatase A (ARSA). Unmetabolized sulfatide accumulates in the white matter of the CNS and in the peripheral nerves, leading to progressive demyelination and death. Late infantile, juvenile and adult clinical variants of MLD have been described. A Navajo Indian child was diagnosed with late infantile MLD (LIMLD), and his ARSA gene was amplified in three overlapping regions by the PCR and sequenced. A single mutation was found: a G → A transition in the first nucleotide of intron 4 (IVS4ntl), which abolishes the 5′ splice site consensus sequence. Negligible amounts of ARSA mRNA were observed in Northern blots. However, PCR amplification and sequencing of the ARSA cDNA showed that all of the mRNA species from the patient have exon 4 deleted. A new reading frame is thus established which results in a premature stop codon within exon 5. A minority of transcripts had additional splicing errors. Both parents carry this mutation, and the father also carries the pseudodeficiency (PD) allele. Three additional unrelated Navajo LIMLD patients were found to be homozygous for the same MLD‐causing mutation by allele‐specific oligonucleotide (ASO) hybridization. This method could be used for carrier and patient identification in this population. © 1994 Wiley‐Liss, Inc.