A defect in the TUSC3 gene is associated with autosomal recessive mental retardation
A defect in the TUSC3 gene is associated with autosomal recessive mental retardation
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DOI：
10.1016/j.ajhg.2008.03.018
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发表时间：
2008-05-01
影响因子：
9.8
通讯作者：
Kuss, Andreas Walter
中科院分区：
文献类型：
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作者：
Garshasbi, Masoud;Hadavi, Valeh;Kuss, Andreas Walter
最近的研究表明，常染色体隐性遗传性智力低下(ARMR)是非常不同的，有理由相信潜在的基因缺陷的数量数以千计。然而，到目前为止，只有四个基因与非综合征ARMR(NS-ARMR)有关：PRSS12(神经胰蛋白酶)、CRBN(Cereblon)、CC2D1A和GRIK2。作为正在进行的旨在确定ARMR基因的系统研究的一部分，我们调查了一个大型血缘家庭，其中包括四个同胞中的七名非综合征性ARMR患者。全基因组SNP分型使我们能够将相关的遗传缺陷定位在8号染色体上4.6 Mbp的区间。单倍型分析和拷贝数研究导致在所有患者中鉴定出纯合子缺失，部分去除了TUSC3(N33)。该家系的所有专性携带者都是杂合子，但来自同一人群的192名无关的健康个体中没有一人携带该缺失。我们通过测序排除了连锁区间内所有基因编码区的其他致病突变；此外，我们通过RT-PCR验证了所有患者中完全缺乏功能性TUSC3转录本。TUSC3被认为编码内质网结合的寡糖转移酶复合体的一个亚单位，该亚单位催化蛋白质N-糖基化过程中的关键步骤。我们的数据表明，与其他糖基化的遗传缺陷相反，TUSC3的失活会导致非综合征性MR，这一结论得到了本期AJHG的另一篇报告的支持。TUSC3只是NS-ARMR中涉及的第五个基因，也是第一个在多个家庭中报告发生突变的基因。
Recent studies have shown that autosomal recessive mental retardation (ARMR) is extremely heterogeneous, and there is reason to believe that the number of underlying gene defects goes into the thousands. To date, however, only four genes have been implicated in nonsyndromic ARMR (NS-ARMR): PRSS12 (neurotrypsin), CRBN (cereblon), CC2D1A, and GRIK2. As part of an ongoing systematic study aiming to identify ARMR genes, we investigated a large consanguineous family comprising seven patients with nonsyndromic ARMR in four sibships. Genome-wide SNP typing enabled us to map the relevant genetic defect to a 4.6 Mbp interval on chromosome 8. Haplotype analyses and copy-number studies led to the identification of a homozygous deletion partly removing TUSC3 (N33) in all patients. All obligate carriers of this family were heterozygous, but none of 192 unrelated healthy individuals from the same population carried this deletion. We excluded other disease-causing mutations in the coding regions of all genes within the linkage interval by sequencing; moreover, we verified the complete absence of a functional TUSC3 transcript in all patients through RT-PCR. TUSC3 is thought to encode a subunit of the endoplasmic reticulum-bound oligosaccharyltransferase complex that catalyzes a pivotal step in the protein N-glycosylation process. Our data suggest that in contrast to other genetic defects of glycosylation, inactivation of TUSC3 causes nonsyndromic MR, a conclusion that is supported by a separate report in this issue of AJHG. TUSC3 is only the fifth gene implicated in NS-ARMR and the first for which mutations have been reported in more than one family.