Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family
Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family
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DOI：
10.1086/382196
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发表时间：
2004-03-01
影响因子：
9.8
通讯作者：
Müller, U
中科院分区：
文献类型：
--
作者：
Niemann, S;Zhao, CF;Müller, U
四肢畸形症是一种罕见的人类遗传病，其特征是四肢完全缺失和其他异常。我们研究了一个有四个患病胎儿的血缘家庭，这些胎儿表现为常染色体隐性遗传性四釉畸形以及头面部和泌尿生殖系统缺陷。经纯合作图，该基因座位于染色体17q21上，在标记D17S931、D17S1785、D17SS1827和D17S1868上的最大多点LOD得分为2.9。进一步的精细定位确定了D17S1299和D17S797之间类似于8.9Mb的临界区间。我们在该家系患病胎儿中发现了WNT3基因的纯合子无义突变(Q83X)。WNT3是果蝇无翼基因的人类同源基因，编码WNT家族的一个成员，已知在胚胎发育中发挥关键作用。Q83X突变在其氨基末端截短WNT3，这表明功能丧失是导致这种疾病的最有可能的原因。我们的发现与WNT3零等位基因纯合子小鼠的早期致死性观察形成对比。据我们所知，这是第一个与孟德尔疾病相关的WNT基因突变的报告。对四配子中WNT3突变的鉴定表明，WNT3在人类肢体形成的最早阶段以及头面部和泌尿生殖系统的发育中是必需的。
Tetra-amelia is a rare human genetic disorder characterized by complete absence of all four limbs and other anomalies. We studied a consanguineous family with four affected fetuses displaying autosomal recessive tetraamelia and craniofacial and urogenital defects. By homozygosity mapping, the disease locus was assigned to chromosome 17q21, with a maximum multipoint LOD score of 2.9 at markers D17S931, D17S1785, D17SS1827, and D17S1868. Further fine mapping defined a critical interval of similar to 8.9 Mb between D17S1299 and D17S797. We identified a homozygous nonsense mutation ( Q83X) in the WNT3 gene in affected fetuses of the family. WNT3, a human homologue of the Drosophila wingless gene, encodes a member of the WNT family known to play key roles in embryonic development. The Q83X mutation truncates WNT3 at its amino terminus, suggesting that loss of function is the most likely cause of the disorder. Our findings contrast with the observation of early lethality in mice homozygous for null alleles of Wnt3. To our knowledge, this is the first report of a mutation in a WNT gene associated with a Mendelian disorder. The identification of a WNT3 mutation in tetra-amelia indicates that WNT3 is required at the earliest stages of human limb formation and for craniofacial and urogenital development.