Garshasbi Masoud, Hadavi Valeh, Habibi Haleh, Kahrizi Kimia, Kariminejad Roxana, Behjati Farkhondeh, Tzschach Andreas, Najmabadi Hossein, Ropers Hans Hilger, Kuss Andreas Walter
Max Planck Institute for Molecular Genetics, D-14195 Berlin, Germany.
Am J Hum Genet. 2008 May;82(5):1158-64. doi: 10.1016/j.ajhg.2008.03.018. Epub 2008 May 1.
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.
近期研究表明，常染色体隐性智力迟钝（ARMR）具有高度异质性，并且有理由相信潜在基因缺陷的数量多达数千种。然而，迄今为止，仅有四个基因与非综合征性ARMR（NS-ARMR）相关：PRSS12（神经胰蛋白酶）、CRBN（脑啡肽）、CC2D1A和GRIK2。作为旨在鉴定ARMR基因的一项正在进行的系统性研究的一部分，我们调查了一个大家族，该家族由四个同胞关系中的七名非综合征性ARMR患者组成。全基因组SNP分型使我们能够将相关基因缺陷定位到8号染色体上一个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一个部分缺失TUSC3（N33）的纯合缺失。该家族所有必然携带者均为杂合子，但来自同一人群的192名无关健康个体中没有一人携带这种缺失。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证实所有患者中完全不存在功能性TUSC3转录本。TUSC3被认为编码内质网结合寡糖基转移酶复合物的一个亚基，该复合物催化蛋白质N-糖基化过程中的关键步骤。我们的数据表明，与其他糖基化遗传缺陷不同，TUSC3的失活导致非综合征性智力迟钝，这一结论得到了本期《美国人类遗传学杂志》另一篇报告的支持。TUSC3是与NS-ARMR相关的第五个基因，也是首个在多个家族中报道有突变的基因。
