Gomot Marie, Ronce Nathalie, Dessay Sabine, Zemni Ramzi, Ayrault Anne-Dominique, Moizard Marie-Pierre, Nivelon Annie, Gilgenkrantz Simone, Dourlens Julliette, Des Portes Vincent, Chelly Jamel, Moraine Claude
Service de Génétique, INSERM 4316 CHU Bretonneau, Tours, France.
Am J Med Genet. 2002 Nov 1;112(4):400-4. doi: 10.1002/ajmg.10564.
The TM4SF2 gene (localized at Xp11.4 between the loci DXS564 and DXS556) has been found to be mutated in one MRX family. In order to define the corresponding behavioral phenotype, global IQ and specific cognitive skills were assessed in seven males and three females of this family, independent of subject status. Mental retardation (MR) was mild in three patients and moderate in three others. Despite the broad variability of severity of MR, a cognitive profile specific to the MR in this family was documented. It was characterized by language disorder that was more marked in the articulatory component and spatial/verbal short-term memory dissociation with larger mnemonic span for spatial than for verbal cues. Linkage analysis was then performed on the basis of the cognitively determined status. Recombinations were observed with the loci DXS556 at Xp11.4 and DXS441 at Xq13.2 (maximum LOD score = 2.23 at theta = 0 for ALAS2). This localization region does not include the TM4SF2 gene that has been found mutated in both patients with MR and in one non-MR male subject of this family. The present results suggest two main hypotheses. First, TM4SF2 gene mutation could be involved in MR in this family, therefore representing accentuated intra familial phenotypic variability. Second, the structural particularity detected in the TM4SF2 gene might reflect a rare polymorphism rather than a pathogenic mutation, with the gene responsible for MR in this family being therefore more likely to be searched for in the pericentromeric region of the X chromosome.
已发现TM4SF2基因（定位于Xp11.4，在DXS564和DXS556位点之间）在一个MRX家系中发生了突变。为了确定相应的行为表型，对该家系的7名男性和3名女性进行了全智商和特定认知技能评估，与受试者状态无关。3例患者智力发育迟缓（MR）为轻度，另外3例为中度。尽管MR严重程度差异很大，但该家系中MR的特定认知特征得到了记录。其特征为语言障碍，在发音部分更为明显，以及空间/言语短期记忆分离，空间记忆跨度大于言语线索。然后根据认知确定的状态进行连锁分析。在Xp11.4的DXS556位点和Xq13.2的DXS441位点观察到重组（ALAS2在θ = 0时最大LOD分数 = 2.23）。该定位区域不包括在该家系的MR患者和一名非MR男性受试者中均发现发生突变的TM4SF2基因。目前的结果提出了两个主要假设。第一，TM4SF2基因突变可能与该家系中的MR有关，因此代表了家族内表型变异性加剧。第二，在TM4SF2基因中检测到的结构特殊性可能反映了一种罕见的多态性而非致病突变，因此该家系中导致MR的基因更有可能在X染色体的着丝粒周围区域寻找。
