1.BACKGROUND
Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant genetic
disease with an incidence of 1:20000. Its main clinical symptoms are the
developmental malformation of the binocular anterior segment, which is
associated with craniofacial, umbilical and dental abnormalities (Sauer
et al.,2012; Ito et al.,2014). There are three common clinical variants
of this disease; defects that are limited to the peripheral part of the
anterior eye segment are called Axenfeld anomalies. Abnormal iris
hypoplasia combined with abnormalities in the periphery of the anterior
eye segment is referred to as Rieger anomaly, and combined ocular
abnormalities and systemic developmental defects are referred to as
Axenfeld-Rieger syndrome.
ARS is often considered autosomal dominant; some sporadic cases have
also been reported. ARS has genetic heterogeneity, and two pathogenic
genes of ARS, FOXC1 and PITX2, are located in the chromosome 6p25 and
4q25 regions, respectively (Seifi et al.,2018; Seifi al.,2018b). Four
families with diseases of the anterior eye segment (including ARS) were
reported, all of which were associated with mutations in the FOXC1 gene
located on chromosome 6p25. Through sequencing analysis, Nishimura et
al. found three missense mutations and a small fragment deletion of 11
bp in the FOXC1 gene.
The FOXC1 gene is located in the region of chromosome 6p25, and the
protein product of FOXC1 from the N end to the C end is the active
domain 1 (AD1), forkhead domain (FHD) and active domain 2 (AD2) (Berryet
al.,2007). The FHD is the DNA binding region for the FOXC1 protein.
Missense mutations in FHD significantly reduce protein stability and
transactivation capability and the ability of FOXC1 to bind to DNA.
Transcriptional activity and protein expression of FOXC1 are largely
regulated by posttranscriptional levels (Saleem et al.,2004).
Because of the heterogeneity of the ARS phenotype and genotype and the
overlap with the clinical manifestation of anterior segment dysgenesis
(ASD), challenges exist for accurate diagnosis and classification (Deml
et al.,2014). A correct diagnosis is often established only when the
mutation in one of the known associated genes is identified. In the
Chinese population, FOXC1 mutations in patients with ARS have not been
well described. Therefore, the purpose of this study was to identify a
new heterozygous mutation of the FOXC1 gene with ARS by using targeted
next-generation sequencing technology combined with bioinformatics and
expression profiling.