A missense founder mutation in VLDLR is associated with Dysequilibrium Syndrome without quadrupedal locomotion.
A missense founder mutation in VLDLR is associated with Dysequilibrium Syndrome without quadrupedal locomotion.
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DOI：
10.1186/1471-2350-13-80
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发表时间：
2012-09-14
影响因子：
--
通讯作者：
Al-Gazali L
中科院分区：
文献类型：
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作者：
Ali BR;Silhavy JL;Gleeson MJ;Gleeson JG;Al-Gazali L
平衡失调综合征是一种常染色体隐性、非进行性小脑性共济失调和智力低下的遗传异质性疾病。该病被分为小脑性共济失调、智力低下和不平衡综合征1型(CAMRQ1)、2型(CAMRQ2)和3型(CAMRQ3)，并分别归因于VLDLR、CA8和WDR81基因的突变。据报道，这种综合征的四足运动与所有三个基因的突变有关。对1个阿联酋血缘关系密切的阿曼家系进行SNP定位和候选基因测序，以鉴定该突变。在第二个无血缘关系的阿曼家族中，使用了大规模平行外显子测序。我们在两个家系的同一受影响的单倍型区块上发现了VLDLR基因的一个纯合子错义突变(c.2117 G >； T，p.C706F)，这是第一个报道的VLDLR的纯合子错义突变，它发生在一个高度保守的残基中，并被预测会损害蛋白质功能。我们在两个阿曼家庭中描述了与平衡失调综合征相关的表型，并在阿拉伯半岛东南部发现了第一个可能具有创始人效应的VLDLR基因纯合错义致病突变。
Dysequilibrium syndrome is a genetically heterogeneous condition that combines autosomal recessive, nonprogressive cerebellar ataxia with mental retardation. The condition has been classified into cerebellar ataxia, mental retardation and disequilibrium syndrome types 1 (CAMRQ1), 2 (CAMRQ2) and 3 (CAMRQ3) and attributed to mutations in VLDLR, CA8 and WDR81 genes, respectively. Quadrupedal locomotion in this syndrome has been reported in association with mutations in all three genes. SNP mapping and candidate gene sequencing in one consanguineous Omani family from the United Arab Emirates with cerebellar hypoplasia, moderate mental retardation, delayed ambulation and truncal ataxia was used to identify the mutation. In a second unrelated consanguineous Omani family, massively parallel exonic sequencing was used. We identified a homozygous missense mutation (c.2117 G > T, p.C706F) in the VLDLR gene in both families on a shared affected haplotype block.This is the first reported homozygous missense mutation in VLDLR and it occurs in a highly conserved residue and predicted to be damaging to protein function. We have delineated the phenotype associated with dysequilibrium syndrome in two Omani families and identified the first homozygous missense pathogenic mutation in VLDLR gene with likely founder effect in the southeastern part of the Arabian Peninsula.