Novel mutations in the TRIM37 gene in Mulibrey Nanism.
Novel mutations in the TRIM37 gene in Mulibrey Nanism.
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DOI：
10.1002/humu.9233
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发表时间：
2004-05-01
期刊：
影响因子：
3.9
通讯作者：
Lehesjoki, Anna-Elina
中科院分区：
文献类型：
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作者：
Hamalainen, Riikka H;Avela, Kristiina;Lehesjoki, Anna-Elina
多胎综合征是一种常染色体隐性遗传性产前发育性发育障碍，发病机制不明。主要的临床特征是出生前和出生后的生长障碍，特征性的畸形的头面部特征，心脏病和肝脏肿大。此前已有报道在Mulibrey Nanism患者中发现了TRIM37基因的五个截断突变。TRIM37蛋白编码一种新的功能未知的蛋白。它包含一个三部分基序(TRIM，也表示环B盒卷曲或RBCC结构域)和一个TRAF(肿瘤坏死因子受体相关因子)结构域。TRIM37定位于过氧酶体，将多发性纳米病归类为过氧酶体疾病。在这里，我们描述了TRIM37基因的基因组结构，它有24个外显子，跨越大约109 kb的基因组DNA。此外，我们报告了六个新的疾病相关突变，其中五个预测了截短蛋白：c.745C>；T(p.Gln249X)，c.1411C>；T(p.Arg471X)，c.2056C>；T(p.Arg686X)，以及8.6kb的基因组缺失(c.1314+507_1668-207del导致p.Arg439fsX4)。第六个突变(c.965G>；T)是第一个与多丝纳米症相关的错义突变(p.Gly322Val)。它影响TRIM37的TRAF结构域，导致突变的TRIM37蛋白的亚细胞定位改变，进一步表明它是致病的。
Mulibrey nanism is an autosomal recessive prenatal-onset growth disorder of unknown pathogenesis. The main clinical features are pre- and postnatal growth failure, characteristic dysmorphic craniofacial features, heart disease, and hepatomegaly. Five truncating mutations in the TRIM37 gene have previously been reported in Mulibrey nanism patients. The TRIM37 protein encodes a novel protein of unknown function. It contains a tripartite motif (TRIM, also denoted the RING-B-box-Coiled-coil or RBCC domain) and a TRAF (tumor necrosis factor-receptor associated factor) domain. TRIM37 localizes to peroxisomes classifying Mulibrey nanism as a peroxisomal disorder. Here we have characterized the genomic structure of the TRIM37 gene, which has 24 exons spanning approximately 109 kb of genomic DNA. Further, we report six novel disease-associated mutations, five of which predict a truncated protein: c.745C>T (p.Gln249X), c.1411C>T (p.Arg471X), c.2056C>T (p.Arg686X), and an 8.6 kb genomic deletion (c.1314+507_1668-207del resulting in p.Arg439fsX4). The sixth mutation (c.965G>T) is the first missense mutation (p.Gly322Val) associated with Mulibrey nanism. It affects the TRAF domain of TRIM37 and results in altered subcellular localization of the mutant TRIM37 protein, further suggesting that it is pathogenic.