Roll Patrice, Rudolf Gabrielle, Pereira Sandrine, Royer Barbara, Scheffer Ingrid E, Massacrier Annick, Valenti Maria-Paola, Roeckel-Trevisiol Nathalie, Jamali Sarah, Beclin Christophe, Seegmuller Caroline, Metz-Lutz Marie-Noëlle, Lemainque Arnaud, Delepine Marc, Caloustian Christophe, de Saint Martin Anne, Bruneau Nadine, Depétris Danièle, Mattéi Marie-Geneviève, Flori Elisabeth, Robaglia-Schlupp Andrée, Lévy Nicolas, Neubauer Bernd A, Ravid Rivka, Marescaux Christian, Berkovic Samuel F, Hirsch Edouard, Lathrop Mark, Cau Pierre, Szepetowski Pierre
INSERM UMR491, Université de la Méditerranée, 13385 Marseille, France.
Hum Mol Genet. 2006 Apr 1;15(7):1195-207. doi: 10.1093/hmg/ddl035. Epub 2006 Feb 23.
The rolandic and sylvian fissures divide the human cerebral hemispheres and the adjacent areas participate in speech processing. The relationship of rolandic (sylvian) seizure disorders with speech and cognitive impairments is well known, albeit poorly understood. We have identified the Xq22 gene SRPX2 as being responsible for rolandic seizures (RSs) associated with oral and speech dyspraxia and mental retardation (MR). SRPX2 is a secreted sushi-repeat containing protein expressed in neurons of the human adult brain, including the rolandic area. The disease-causing mutation (N327S) resulted in gain-of-glycosylation of the secreted mutant protein. A second mutation (Y72S) was identified within the first sushi domain of SRPX2 in a male with RSs and bilateral perisylvian polymicrogyria and his female relatives with mild MR or unaffected carrier status. In cultured cells, both mutations were associated with altered patterns of intracellular processing, suggesting protein misfolding. In the murine brain, Srpx2 protein expression appeared in neurons at birth. The involvement of SRPX2 in these disorders suggests an important role for SRPX2 in the perisylvian region critical for language and cognitive development.
中央沟和外侧裂将人类大脑半球分开，相邻区域参与言语处理。中央沟（外侧裂）癫痫发作障碍与言语及认知障碍之间的关系虽广为人知，但却了解甚少。我们已确定Xq22基因SRPX2是导致与口部和言语失用症及智力迟钝（MR）相关的中央沟癫痫发作（RSs）的原因。SRPX2是一种分泌型含寿司重复序列的蛋白质，在人类成人大脑的神经元中表达，包括中央沟区域。致病突变（N327S）导致分泌型突变蛋白的糖基化增加。在一名患有RSs和双侧外侧裂周围多小脑回的男性及其患有轻度MR或未受影响的携带者状态的女性亲属中，在SRPX2的第一个寿司结构域内鉴定出第二个突变（Y72S）。在培养细胞中，这两种突变均与细胞内加工模式的改变有关，提示蛋白质错误折叠。在小鼠大脑中，Srpx2蛋白在出生时出现在神经元中。SRPX2参与这些疾病表明其在对语言和认知发育至关重要的外侧裂周围区域中发挥重要作用。
