title: Mutations in FYCO1 cause autosomal-recessive congenital cataracts.
abstract: 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 (FYCO1), 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.
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Jiao
authors.affiliation: Imaging Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Fariss
authors.affiliation: Department of Biomedical Science, Florida Atlantic University, room 207, Biomedical building, 777 Glades Rd. Boca Raton, FL, USA.
authors.forename: Wanda Lee
authors.initials: WL
authors.lastname: Kantorow
authors.affiliation: Department of Biomedical Science, Florida Atlantic University, room 207, Biomedical building, 777 Glades Rd. Boca Raton, FL, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Kantorow
authors.affiliation: Department of Ophthalmology, Assaf Harofeh Medical Center, Zerifin, Israel; affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Pras
authors.affiliation: The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel; affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Frydman
authors.affiliation: The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel; affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Elon
authors.initials: E
authors.lastname: Pras
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 53700, Pakistan; Allama Iqbal Medical College, Lahore 54550, Pakistan.
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 53700, Pakistan; The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: S Amer
authors.initials: SA
authors.lastname: Riazuddin
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: f3h@helix.nih.gov.
authors.forename: J Fielding
authors.initials: JF
authors.lastname: Hejtmancik
mesh_terms: D000595:Amino Acid Sequence; D002386:Cataract / Q000151:congenital* / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D005808:Genes, Recessive; D005820:Genetic Testing; D055106:Genome-Wide Association Study; D006801:Humans; D008869:Microtubule-Associated Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D010154:Pakistan; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C460141:FYCO1 protein, human; D008869:Microtubule-Associated Proteins; D014157:Transcription Factors