Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome
Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome
复制标题
DOI：
10.1086/316915
复制
发表时间：
2000-12-01
影响因子：
9.8
通讯作者：
Glover, TW
中科院分区：
文献类型：
--
作者：
Fang, JM;Dagenais, SL;Glover, TW
淋巴水肿-双列睫状体病（LD）是一种常染色体显性遗传疾病，典型表现为四肢水肿，发病年龄不一，双列睫毛（双列睫）。其他并发症可能包括心脏缺陷、腭裂、硬膜外囊肿和恐惧症，这表明在发育过程中具有多效性作用的基因存在缺陷。我们以前曾报道过与Turner综合征相似的新生儿水肿，与t（Y;16）（q12;q24.3）易位有关。在Y染色体上没有发现候选基因，我们将我们的努力指向16号染色体断裂点。随后，LD的基因被映射，通过连锁研究，在16q24.3的16 cM区域。通过FISH，我们确定易位断裂点在这个关键区域内，并进一步将断裂点缩小到20-kb的间隔。因为易位似乎没有中断基因，所以我们考虑了可能因位置效应而失活的邻近区域的候选基因。在另外两个不相关的家庭与LD，我们确定了失活突变-无义突变和移码突变-在FOXC 2（MFH-1）基因。FOXC 2是叉头/翼螺旋转录因子家族的成员，其成员参与多种发育途径。FOXC 2基因敲除小鼠表现出与LD综合征相似的心血管、颅面和脊椎异常。我们的研究结果表明，FOXC 2单倍不足导致LD。FOXC 2代表了第二个已知的导致遗传性水肿的基因，LD是第二个已知由叉头家族基因突变引起的遗传性疾病。
Lymphedema-distichiasis (LD) is an autosomal dominant disorder that classically presents as lymphedema of the limbs, with variable age at onset, and double rows of eyelashes (distichiasis). Other complications may include cardiac defects, cleft palate, extradural cysts, and photophobia, suggesting a defect in a gene with pleiotrophic effects acting during development. We previously reported neonatal lymphedema, similar to that in Turner syndrome, associated with a t(Y;16)(q12;q24.3) translocation. A candidate gene was not found on the Y chromosome, and we directed our efforts toward the chromosome 16 breakpoint. Subsequently, a gene for LD was mapped, by linkage studies, to a 16-cM region at 16q24.3. By FISH, we determined that the translocation breakpoint was within this critical region and further narrowed the breakpoint to a 20-kb interval. Because the translocation did not appear to interrupt a gene,,ve considered candidate genes in the immediate region that might be inactivated by position effect. In two additional unrelated families with LD, we identified inactivating mutations-a nonsense mutation and a frameshift mutation-in the FOXC2 (MFH-1) gene. FOXC2 is a member of the forkhead/winged-helix family of transcription factors, whose members are involved in diverse developmental pathways. FOXC2 knockout mice display cardiovascular, craniofacial, and vertebral abnormalities similar to those seen in LD syndrome. Our findings show that FOXC2 haploinsufficiency results in LD. FOXC2 represents the second known gene to result in hereditary lymphedema, and LD is only the second hereditary disorder known to be caused by a mutation in a forkhead-family gene.