A Novel FOXC1 Nonsense Mutation Is Associated With Sensorineural Hearing Loss, Primary Empty Sella Syndrome and Anterior Segment Dysgenesis

Abstract

Purpose:: To identify the genetic defect in a family affected by autosomal dominant anterior segment dysgenesis, sensorineural hearing loss and primary empty sella syndrome.

Methods:: Twenty-three family members were analyzed in this study. Four individuals were affected by anterior segment dysgenesis (ASD), primary empty sella syndrome (PESS) and sensorineural hearing loss. One other individual was affected by ASD and PESS, but had no reported hearing loss. All five were also diagnosed with glaucoma as defined by intraocular pressure greater than 21 mmHg and visual field defects consistent with glaucomatous degeneration of the optic nerve. Candidate genes were evaluated by PCR amplification of individual exons, direct sequencing using BIGDYE chemistries and an automated ABI 3100 sequencer, and analysis with Vector NTI software.

Results:: The following candidate genes were screened for mutations by sequencing the entire coding sequence and splice sites: MAFB, EYA2, MSI2, SOX9, EFEMP2, CRYM, PNN, BMP4, OTX2, NR2F2, DACH1, SMAD9, and FOXC1. A novel nonsense mutation (Y26X) was identified in FOXC1 in all five affected family members and not in any unaffected family members. The mutation was also not found in 100 normal chromosomes. In addition to abnormal development of the ocular anterior segment, affected patients had a flat mid-face and primary empty sella with normal endocrine function. Four family members had sensorineural hearing loss with associated vestibular abnormalities consistent with Meniere’s disease, and one family member without hearing defects had recurrent syncopal episodes consistent with vestibular problems.

Conclusions:: Although hearing loss is a feature of the chromosome 6p deletion syndrome, mutations in FOXC1 have not been previously associated with hearing or vestibular problems, suggesting that a second gene on 6p is responsible for the hearing abnormalities. In this study we report a novel nonsense mutation that occurs early in the FOXC1 protein sequence creating essentially a null allele. All of the patients carrying this mutation had ocular, cranial, as well as vestibular abnormalities and all but one had abnormal hearing. These findings suggest that hemizygosity of FOXC1 may cause hearing and other cranial defects as well as abnormal ocular development.

Keywords: genetics • anterior segment • candidate gene analysis