Rare FOXC1 variants in congenital glaucoma: identification of translation regulatory sequences

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:C4G, c.-429C4G, rs730882054:c.1134_144del(CGGCGGCGCGG), p.(G380Rfs*144) and rs35717904:A4T, c.*734A4T) and decreased (rs185790394: C4T, c.-244C4T and rs79691946:C4T, 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:C4T, c.*454C4T). Bioinformatics and functional analyses provided novel information on three of these variants. c.-429C4G potentially disrupts a consensus sequence for a terminal oligopyrimidine tract, whereas c.-244C4T 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.

Whole-Exome Sequencing of Congenital Glaucoma Patients Reveals Hypermorphic Variants in GPATCH3, a New Gene Involved in Ocular and Craniofacial Development

“…In addition, approximately 5% of the patients in these cohorts carried GPATCH3 rare variants in the heterozygous state. Segregation analysis of these variants failed to reveal a monogenic inheritance, but their elevated frequency among patients and the predicted functional impact for most of them suggest that they are disease-causing variants that may be involved in non-monogenic congenital glaucoma in accordance with our previous findings671219. Also in accordance with this hypothesis, a recent study reported that 10 of 189 unrelated PCG families carried heterozygous rare variants in the TEK gene with dominant transmission and highly variable expressivity, which was explained by stochastic developmental events or oligogenic/digenic inheritance24.…”

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

“…Indeed, many studies have shown that variants in non-coding regions of the genome can cause ocular disorders (Bhatia et al 2013;Chatterjee and Pal 2009;Cipriani et al 2017;Conte et al 2015;Davidson et al 2016;Small et al 2016;Volkmann et al 2011). Although ocular genetic diseases generally follow a Mendelian pattern of inheritance, mutations in the non-coding regions of the genome (as well as some coding regions) have also been associated with non-Mendelian inheritance (Medina-Trillo et al 2016). Variants in non-coding regions (~98% of the genome) represent almost 2% of known gene disruptions responsible for human inherited disease according to the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/index.php).…”

CPAMD8 loss-of-function underlies non-dominant congenital glaucoma with variable anterior segment dysgenesis and abnormal extracellular matrix

“…The first identified and most prevalent cause of recessive PCG is CYP1B1 loss-of-function (LoF) (Sarfarazi and Stoilov 2000;Stoilov et al 1997), which is present in 18%-48% of non-consanguineous European patients (Campos-Mollo et al 2009;Colomb et al 2003;López-Garrido et al 2013;Weisschuh et al 2009). Additional genes reported to play a role in this pathology are LTBP2 (Ali et al 2009), MYOC (Kaur et al 2005), FOXC1 (Medina-Trillo et al 2016;Medina-Trillo et al 2015), TEK (Souma et al 2016) and GPATCH3 (Ferre-Fernández et al 2017), illustrating the genetic heterogeneity of this disease.…”