Targeted gene sequencing of FYCO1 identified a novel mutation in a Pakistani family for autosomal recessive congenital cataract

Abstract

Background Congenital cataract is causing one‐third of blindness worldwide. Congenital cataract is heterogeneous in its inheritance patterns. The current study is aimed to explore the unknown genetic causes underlying congenital cataracts. Methods Blood samples from affected and normal individuals of n = 25 Pakistani families identified with congenital cataracts were collected. Genomic DNA was extracted and Sanger sequencing was performed to identify novel pathogenic variants in the FYCO1 (MIM#607182) gene. Later structural bioinformatics tools and molecular dynamics simulations were performed to analyze the impact of these variants on protein structure and function. Results Sanger sequencing resulted in the identification of a novel splice site mutation (NM_024513.3: c.3151‐29_3151‐7del) segregating in an autosomal recessive manner. This novel variant was confirmed to be absent in the n = 300 population controls. Further, bioinformatics tools revealed the formation of a mutant protein with a loss of the Znf domain. In addition, we also found a previously known (c.4127 T > C; p.Leu1376Pro) mutation in four families. We also report a novel heterozygous variant (c.3419G > A; p.Arg1140Gln) in another family. Conclusions In conclusion, we report a novel deletion (NM_024513.3: c.3151‐29_3151‐7del) in one family and a frequent homozygous missense mutation (c.4127 T > C; p.Leu1376Pro) in four Pakistani families. The current research highlights the importance of autophagy in lens development and maintaining its transparency.

Identification and Functional Characterization of Mutation in FYCO1 in Families with Congenital Cataract

“…This gene encodes a protein that contains 1478 amino acids and has a mass of 166.9k daltons. Functional protein analysis found four domains in FYCO1: RUN domain with 36–173 amino acid residues; coiled-coil domain carrying a sequence of 224–1154 residues; Znf domain comprising a sequence of 1166–1231 residues; and GOLD domain with a sequence of 1339–1466 residues [ 14 ].…”

“…Until the present, out of the total reported mutations detected in FYCO1 associated with CC, nineteen variants resulted in truncation of protein vulnerable with GOLD or coiled-coil protein domains [ 8 ]. In particular, an earlier study identified frameshift and nonsense mutation of FYCO1 associated CC in thirteen unrelated families [ 14 ]. Additionally, another report determining the disease linked genetic abnormalities in three consanguineous families investigated one previously known and two naïve nucleotide variants in the FYCO1 gene.…”

“…It has been comprehended that nearly 15% of FYCO1 genetic variants contributed to overall rates of autosomal recessive CC [ 8 ]. In near recent reports, FYCO1 mutations detected in different ethnic groups include c.1387 G > T [ 13 ]; p.Gly463Ter; c.1621C > T [ 15 ]; p. Gln541Ter; and c.2365 C>T [ 14 ]. On the other hand, the largest exon 10 deletion and splice-site variant is c.3150 + 1G>T [ 14 , 16 ].…”

“…In 50-63% of CC, the etiology is idiopathic, while 30% are monogenic with autosomal dominant pattern [ 12 ]. To date, more than 1400 etiologic variations have been described for this disease [ 11 , 13 , 14 , 15 , 16 ]. Non-syndromic cataract is linked to 39 causative genes or loci.…”

“…Non-syndromic cataract is linked to 39 causative genes or loci. Autosomal recessive CC has been mapped to 14 loci, but the genes for some loci have not been identified yet [ 14 ]. Several causative genes of CC include EPHA2 (OMIM 176946), GJA8 (OMIM 600897) , FOXE (OMIM 601094) , FYCO1 (OMIM 607182) , GCNT2 (OMIM 600429) , AGK (OMIM 610345) , AKR1E2 (OMIM 617451) , RNLS (OMIM 609360) , HSF4 (OMIM 602438) , LIM2 (OMIM 154045) , CRYBA1 (OMIM 123610) , LSS (OMIM 600909) , CRYBB3 (OMIM 123630) , and GALK1 (OMIM 604313) [ 11 ].…”