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James F. Hejtmancik, Jianjun Chen, Zhiwei Ma, Xiaodong Jiao, Wanda L. Kantorow, Eran Pras, Moshe Frydman, Sheikh Riazuddin, Marc Kantorow, S. Amer Riazuddin; FYCO1 Mutations And Function In Autosomal Recessive Congenital Cataract. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1054.
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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. The purpose of this study was to identify the genetic causes of arCC in consanguineous Pakistani families as a means to elucidate biological pathways critical for lens development and transparency.
Genotyping was carried out using the ABI md-10 panels and linkage analysis used the lod score method as implemented in LINKAGE. Dideoxy sequencing used an ABI 3130 DNA Analysis System. Expression in zebrafish was knocked down using morpholino inhibition of translation.
Genome-wide linkage analysis and fine mapping identified a linked region on chromosome 3p22-p21 with a summed lod score of 33.42. Mutations in the gene encoding FYVE and coiled-coil domain containing 1 (FYCO1), were identified 12 Pakistani families and one Arab Israeli family mapping to the overlapping CATC2 region. Nine different mutations were identified, including c.3755delC (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; peaking at P12d. Expressed mutant proteins p.Leu1288TyrfsX37 and p.Gln736X are truncated on western blots. Wild type and p.L1376P FYCO1, the only missense mutant identified, migrates at the expected molecular mass. Knockdown of fyco1 in zebrafish embryos results in small dysmorphic lenses with cataract.
FYCO1 is a member of the PI(3)P-binding protein family associated with the exterior of autophagosomes and mediating microtubule plus end-directed vesicle transport. Loss of FYCO1 function causes cataract and dysmorphic lens development. FYCO1 mutations are found worldwide and are responsible for approximately 15% of arCC in the Pakistani population.
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