Department of Pathology, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
BMC Med Genet. 2012 Sep 14;13:80. doi: 10.1186/1471-2350-13-80.
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.
平衡失调综合征是一种遗传异质性疾病，表现为常染色体隐性、进行性小脑性共济失调合并智力障碍。该病已分为小脑性共济失调、智力障碍和平衡失调综合征 1 型（CAMRQ1）、2 型（CAMRQ2）和 3 型（CAMRQ3），分别归因于 VLDLR、CA8 和 WDR81 基因突变。在该综合征中，四肢运动与这三种基因的突变有关。
采用 SNP 图谱和候选基因测序，对来自阿拉伯联合酋长国的一个小脑发育不良、中度智力障碍、行走延迟和躯干共济失调的近亲阿曼家庭进行分析，以确定突变。在第二个无关的近亲阿曼家庭中，采用大规模平行外显子测序。
我们在两个受影响的家族中发现了 VLDLR 基因上的纯合错义突变（c.2117 G > T，p.C706F），位于共享的受影响单倍型块上。这是 VLDLR 中首次报道的纯合错义突变，发生在高度保守的残基上，预计会对蛋白质功能造成损害。
我们在两个阿曼家族中描绘了平衡失调综合征的表型，并确定了 VLDLR 基因中第一个纯合错义致病性突变，可能在阿拉伯半岛东南部存在创始效应。
