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.

Genomic analysis of pediatric cataract in Saudi Arabia reveals novel candidate disease genes

“…17 FYCO1, encoding FYVE and coiled-coil domain containing 1, was only very recently reported to cause autosomal recessive cataract in 12 Pakistani families and one Arab family. 18 Our study, therefore, represents the second report of FYCO1 mutation in congenital cataract.…”

Deletion of Autophagy-related 5 (Atg5) and Pik3c3 Genes in the Lens Causes Cataract Independent of Programmed Organelle Degradation

“…Recently, mutations in the FYCO1 gene were identified in patients with autosomalrecessive congenital cataracts (48). It was reported that FYVE and coiled-coil domain containing 1 (FYCO1) protein interact with PtdIns(3)P, LC3, and Rab7 and are involved in positioning of autophagosomes (49).…”

FYCO1 Contains a C-terminally Extended, LC3A/B-preferring LC3-interacting Region (LIR) Motif Required for Efficient Maturation of Autophagosomes during Basal Autophagy

“…FYCO1 is a 1478-amino acid-long phosphatidylinositol 3-phosphatebinding protein and Rab7 effector that interacts with LC3, and is involved in the transport of autophagosomes along microtubules in the plus end direction (21). Mutations in FYCO1 cause autosomal-recessive congenital cataracts, suggesting that FYCO1 is required for human lens development, transparency, or both (23). FYCO1 is recruited by LC3 to Dectin-1 phagosomes during LC3-associated phagocytosis to facilitate maturation of early p40phox-containing phagosomes into late LAMP1-positive phagosomes (24).…”