Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome
Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome
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DOI：
10.1086/421532
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发表时间：
2004-06-01
影响因子：
9.8
通讯作者：
Wieacker, P
中科院分区：
文献类型：
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作者：
Wieland, I;Jakubiczka, S;Wieacker, P
颅额鼻综合征 (CFNS) 是一种 X 连锁颅面疾病，具有不寻常的表现模式，其中受影响的女性表现出多种骨骼畸形，而遗传缺陷在男性携带者中不会导致或仅导致轻微异常。最近，我们在 X 染色体的着丝粒周围区域绘制了一个 CFNS 基因，该区域包含 EFNB1 基因，该基因编码 Eph 受体的肝配蛋白-B1 配体。由于 Efnb1 突变小鼠表现出一系列畸形和不寻常的遗传，让人想起 CFNS，因此我们分析了三个患有 CFNS 家族的 EFNB1 基因。在一个家族中，在一名专性携带者男性、其轻度受影响的兄弟以及受影响的女性中发现了外显子 2-5 的缺失。在另外两个家族中，检测到 EFNB1 的错义突变，导致氨基酸交换 P54L 和 T111I。这两种突变都位于 ephrin-B1 胞外域内的多聚化和受体相互作用基序中。在所有病例中，在男性专性携带者、临床受影响的男性和受影响的杂合女性中一致发现了突变。我们得出结论，EFNB1 突变会导致 CFNS。
Craniofrontonasal syndrome (CFNS) is an X-linked craniofacial disorder with an unusual manifestation pattern, in which affected females show multiple skeletal malformations, whereas the genetic defect causes no or only mild abnormalities in male carriers. Recently, we have mapped a gene for CFNS in the pericentromeric region of the X chromosome that contains the EFNB1 gene, which encodes the ephrin-B1 ligand for Eph receptors. Since Efnb1 mutant mice display a spectrum of malformations and an unusual inheritance reminiscent of CFNS, we analyzed the EFNB1 gene in three families with CFNS. In one family, a deletion of exons 2-5 was identified in an obligate carrier male, his mildly affected brother, and in the affected females. In the two other families, missense mutations in EFNB1 were detected that lead to amino acid exchanges P54L and T111I. Both mutations are located in multimerization and receptor-interaction motifs found within the ephrin-B1 extracellular domain. In all cases, mutations were found consistently in obligate male carriers, clinically affected males, and affected heterozygous females. We conclude that mutations in EFNB1 cause CFNS.