Fang J, Dagenais S L, Erickson R P, Arlt M F, Glynn M W, Gorski J L, Seaver L H, Glover T W
Department of Pediatrics, University of Michigan, Ann Arbor, MI, 48109, USA.
Am J Hum Genet. 2000 Dec;67(6):1382-8. doi: 10.1086/316915. Epub 2000 Nov 8.
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, we 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.
淋巴水肿-双行睫综合征（LD）是一种常染色体显性疾病，典型表现为四肢淋巴水肿，发病年龄不一，伴有双排睫毛（双行睫）。其他并发症可能包括心脏缺陷、腭裂、硬膜外囊肿和畏光，提示在发育过程中起作用的具有多效性的基因存在缺陷。我们之前报道过与t(Y;16)(q12;q24.3)易位相关的新生儿淋巴水肿，类似于特纳综合征中的情况。在Y染色体上未发现候选基因，于是我们将研究重点转向16号染色体的断点。随后，通过连锁研究将LD基因定位到16q24.3的一个16厘摩区域。通过荧光原位杂交（FISH），我们确定易位断点在这个关键区域内，并将断点进一步缩小到一个20千碱基对的区间。由于该易位似乎并未打断一个基因，我们考虑了紧邻区域可能因位置效应而失活的候选基因。在另外两个无关的LD家族中，我们在FOXC2（MFH-1）基因中鉴定出失活突变——一个无义突变和一个移码突变。FOXC2是叉头/翼状螺旋转录因子家族的成员，该家族成员参与多种发育途径。FOXC2基因敲除小鼠表现出与LD综合征中所见类似的心血管、颅面和脊椎异常。我们的研究结果表明，FOXC2单倍体不足导致LD。FOXC2是导致遗传性淋巴水肿的第二个已知基因，而LD是已知由叉头家族基因突变引起的第二种遗传性疾病。
