The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation
The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation
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DOI：
10.1136/jmg.2005.035709
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发表时间：
2006-03-01
影响因子：
4
通讯作者：
Shohat, M
中科院分区：
文献类型：
--
作者：
Basel-Vanagaite, L;Attia, R;Shohat, M
背景资料：常染色体隐性遗传性非综合征型精神发育迟滞（NSMR）的分子基础知之甚少，主要是由于异质性和缺乏临床标准进行连锁分析的家庭分组。只有两个常染色体基因，即位于染色体4q26上的PRSS 12基因和位于染色体3p26上的CRBN基因被证明是常染色体隐性遗传性非小细胞肺癌的致病基因，且每一个基因只存在于一个家系中。通过纯合性作图建立的候选区域在染色体19p13.12上从2.4Mb缩小到0.9Mb。在9个严重常染色体隐性遗传非小细胞症家系中发现一个CC2D1A基因的蛋白质截短突变。证实了患者的淋巴母细胞样细胞中不存在野生型蛋白。CC2D1A是一个以前未表征的基因家族的成员，该家族携带两个保守的基序，C2结构域和DM14结构域。C2结构域存在于钙依赖性磷脂结合的蛋白质中; DM14结构域是CC2D1A蛋白质家族所特有的，其作用尚不清楚。CC2D1A是一种参与I-κ B激酶/NF κ B级联反应的信号转导分子。CC2D1A mRNA的表达在胚胎脑室区和发育中的皮质板分期小鼠胚胎，持续到成年，在大脑皮层和海马中的表达最高。结论：一个以前未知的信号转导通路是重要的人类认知发育。
Background: The molecular basis of autosomal recessive non-syndromic mental retardation (NSMR) is poorly understood, mostly owing to heterogeneity and absence of clinical criteria for grouping families for linkage analysis. Only two autosomal genes, the PRSS12 gene on chromosome 4q26 and the CRBN on chromosome 3p26, have been shown to cause autosomal recessive NSMR, each gene in only one family.Objective: To identify the gene causing autosomal recessive NSMR on chromosome 19p13.12.Results: The candidate region established by homozygosity mapping was narrowed down from 2.4 Mb to 0.9 Mb on chromosome 19p13.12. A protein truncating mutation was identified in the gene CC2D1A in nine consanguineous families with severe autosomal recessive NSMR. The absence of the wild type protein in the lymphoblastoid cells of the patients was confirmed. CC2D1A is a member of a previously uncharacterised gene family that carries two conserved motifs, a C2 domain and a DM14 domain. The C2 domain is found in proteins which function in calcium dependent phospholipid binding; the DM14 domain is unique to the CC2D1A protein family and its role is unknown. CC2D1A is a putative signal transducer participating in positive regulation of I-kappa B kinase/NF kappa B cascade. Expression of CC2D1A mRNA was shown in the embryonic ventricular zone and developing cortical plate in staged mouse embryos, persisting into adulthood, with highest expression in the cerebral cortex and hippocampus.Conclusions: A previously unknown signal transduction pathway is important in human cognitive development.