Mutations in FYCO1 Cause Autosomal-Recessive Congenital Cataracts
Mutations in FYCO1 Cause Autosomal-Recessive Congenital Cataracts
复制标题
DOI：
10.1016/j.ajhg.2011.05.008
复制
发表时间：
2011-06-10
影响因子：
9.8
通讯作者：
Hejtmancik, J. Fielding
中科院分区：
文献类型：
--
作者：
Chen, Jianjun;Ma, Zhiwei;Hejtmancik, J. Fielding
先天性白内障(CCS)约占婴儿失明的三分之一，是全球儿童视力丧失的主要原因。常染色体隐性遗传性先天性白内障(ARCC)是一组临床上多样且遗传异质性的晶状体疾病。为了确定巴基斯坦血缘关系家系中ARCC的遗传原因，我们进行了全基因组连锁分析和精细定位，确定了与3p21-p22的连锁，总的LOD得分为33.42。在12个巴基斯坦家庭和一个阿拉伯以色列家庭中发现了编码FYVE和包含1(FTCO1)的卷曲线圈结构域的基因突变，其中ARCC先前被定位在重叠的CATC2区域。FTCO1是一个PI(3)P结合蛋白家族成员，与自噬小体外部相关，介导微管+末端定向囊泡运输。发现了9种不同的突变，包括c.3755Delc(p.Ala1252AspfsX71)、c.3858_3862dupGGAAT(p.Leu1288TrpfsX37)、c.1045C>；T(p.Gln349X)、c.2206C>；T(p.Gln736X)、c.2761C>；T(p.Arg921X)、c.2830C&gT；T(p.Arg944X)、c.3150+1G&gT；T、c.4127T>；C(p.Leu1376Pro)和c.1546C>；T(p.Gln516X)。Fyco1在小鼠胚胎和成体晶状体中表达，在P12d达到高峰。表达的突变蛋白p.Leu1288TrpfsX37和p.Gln736X在免疫印迹上被截断。野生型和p.L1376P FYCO1，唯一已发现的错义突变，以预期的分子质量迁移。在人晶状体上皮细胞中表达的野生型和P.Leu1376Pro FYCO1蛋白都部分共存于微管，并与高尔基体相邻，但它们主要共存于自噬小体。因此，FYCO1与人类的晶状体发育和透明度有关，该基因的突变是巴基斯坦人ARCC最常见的原因之一。
Congenital cataracts (CCs), responsible for about one-third of blindness in infants, are a major cause of vision loss in children worldwide. Autosomal-recessive congenital cataracts (arCC) form a clinically diverse and genetically heterogeneous group of disorders of the crystalline lens. To identify the genetic cause of arCC in consanguineous Pakistani families, we performed genome-wide linkage analysis and fine mapping and identified linkage to 3p21-p22 with a summed LOD score of 33.42. Mutations in the gene encoding FYVE and coiled-coil domain containing 1 (FTCO1), a PI(3) P-binding protein family member that is associated with the exterior of autophagosomes and mediates microtubule plus-end-directed vesicle transport, were identified in 12 Pakistani families and one Arab Israeli family in which arCC had previously been mapped to the overlapping CATC2 region. Nine different mutations were identified, including c.3755 delC (p.Ala1252AspfsX71), c.3858_3862dupGGAAT (p.Leu1288TrpfsX37), c.1045 C > T (p.Gln349X), c.2206C > T (p.Gln736X), c.2761C > T (p.Arg921X), c.2830C > T (p.Arg944X), c.3150+1 G > T, c.4127T > C (p.Leu1376Pro), and c.1546C > T (p.Gln516X). Fyco1 is expressed in the mouse embryonic and adult lens and peaks at P12d. Expressed mutant proteins p.Leu1288TrpfsX37 and p.Gln736X are truncated on immunoblots. Wild-type and p.L1376P FYCO1, the only missense mutant identified, migrate at the expected molecular mass. Both wild-type and p. Leu1376Pro FYCO1 proteins expressed in human lens epithelial cells partially colocalize to microtubules and are found adjacent to Golgi, but they primarily colocalize to autophagosomes. Thus, FYCO1 is involved in lens development and transparency in humans, and mutations in this gene are one of the most common causes of arCC in the Pakistani population.