March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
FYCO1 Mutations And Function In Autosomal Recessive Congenital Cataract
Author Affiliations & Notes
  • James F. Hejtmancik
    MOGS/OGVFB, National Eye Institute, Bethesda, Maryland
  • Jianjun Chen
    MOGS/OGVFB, National Eye Institute, Bethesda, Maryland
  • Zhiwei Ma
    MOGS/OGVFB, National Eye Institute, Bethesda, Maryland
  • Xiaodong Jiao
    MOGS/OGVFB, National Eye Institute, Bethesda, Maryland
  • Wanda L. Kantorow
    Department of Biomedical Science, Florida Atlantic University, Boca Raton, Florida
  • Eran Pras
    Department of Ophthalmology,, Sackler School of Medicine, Tel Aviv, Israel
  • Moshe Frydman
    The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel
  • Sheikh Riazuddin
    National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Oman
  • Marc Kantorow
    Department of Biomedical Science, Florida Atlantic University, Boca Raton, Florida
  • S. Amer Riazuddin
    The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • Footnotes
    Commercial Relationships  James F. Hejtmancik, None; Jianjun Chen, None; Zhiwei Ma, None; Xiaodong Jiao, None; Wanda L. Kantorow, None; Eran Pras, None; Moshe Frydman, None; Sheikh Riazuddin, None; Marc Kantorow, None; S. Amer Riazuddin, None
  • Footnotes
    Support  EY000272
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 1054. doi:
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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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : 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.

Methods: : 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.

Results: : 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.

Conclusions: : 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.

Keywords: cataract • linkage analysis • mutations 
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