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Rare FOXC1 variants in congenital glaucoma: identification of translation regulatory sequences.
- Source :
-
European journal of human genetics : EJHG [Eur J Hum Genet] 2016 May; Vol. 24 (5), pp. 672-80. Date of Electronic Publication: 2015 Jul 29. - Publication Year :
- 2016
-
Abstract
- Primary congenital glaucoma (PCG) is the cause of a significant proportion of inherited visual loss in children, but the underlying mechanism is poorly understood. In this study, we assessed the relationship between PCG and FOXC1 variants by Sanger sequencing the proximal promoter and transcribed sequence of FOXC1 from a cohort of 133 PCG families with no known CYP1B1 or MYOC mutations. The pathogenicity of the identified variants was evaluated by functional analyses. Ten patients (7.5%) with no family history of glaucoma carried five different rare heterozygous FOXC1 variants with both increased (rs77888940:C>G, c.-429C>G, rs730882054:c.1134_144del(CGGCGGCGCGG), p.(G380Rfs*144) and rs35717904:A>T, c.*734A>T) and decreased (rs185790394: C>T, c.-244C>T and rs79691946:C>T, p.(P297S)) transactivation, ranging from 50 to 180% of the wild-type activity. The five variants did not show monogenic segregation, and four of them were absent in a control group (n=233). To the best of our knowledge, one of these variants (p.(G380Rfs*144)) has not previously been described. One of the FOXC1 variant carriers (p.(P297S)) also coinherited a functionally altered rare PITX2 heterozygous variant (rs6533526:C>T, c.*454C>T). Bioinformatics and functional analyses provided novel information on three of these variants. c.-429C>G potentially disrupts a consensus sequence for a terminal oligopyrimidine tract, whereas c.-244C>T may alter the RNA secondary structure in the 5'-untranslated region (UTR) that affects mRNA translation. In addition, p.(G380Rfs*144) led to increased protein stability. In summary, these data reveal the presence of translation regulatory sequences in the UTRs of FOXC1 and provide evidence for a possible role of rare FOXC1 variants as modifying factors of goniodysgenesis in PCG.
- Subjects :
- Case-Control Studies
Child, Preschool
Female
Forkhead Transcription Factors metabolism
Glaucoma genetics
HEK293 Cells
Heterozygote
Homeodomain Proteins genetics
Humans
Infant
Male
Protein Stability
RNA, Messenger chemistry
RNA, Messenger genetics
RNA, Messenger metabolism
Transcription Factors genetics
Homeobox Protein PITX2
5' Untranslated Regions
Forkhead Transcription Factors genetics
Glaucoma congenital
Polymorphism, Single Nucleotide
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5438
- Volume :
- 24
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- European journal of human genetics : EJHG
- Publication Type :
- Academic Journal
- Accession number :
- 26220699
- Full Text :
- https://doi.org/10.1038/ejhg.2015.169