E. Simpson

SOX2 mutation causes anophthalmia, hearing loss, and brain anomalies

The SOX2 transcription factor is expressed early in the embryonic stem cells of the blastocyst and later in the neural stem cells. It is a member of the SOX family of proteins that carry a DNA‐binding high‐mobility group domain and additional domains that regulate embryonic development and cell fate determinations. We surveyed 93 patients with severe eye malformations for mutations in SOX2. Here, we report a novel nonsense mutation in one female patient with bilateral clinical anophthalmia, absence of all optic pathways, and other neurological abnormalities. The mutation, Q155X, creates a premature termination codon early in the transcriptional activation domain and is likely to be a null allele. Our data show that mutations in SOX2 can cause not only anophthalmia, but also aplasia of the optic nerve, chiasm and optic tract, as well as modest bilateral sensorineural hearing loss, and global developmental delay, underscoring the importance of SOX2 in early human eye and brain development.

An Arg311Gln NR2E3 mutation in a family with classic Goldmann-Favre syndrome

Goldmann-Favre syndrome (GFS) is one of the rarest inherited vitreoretinal dystrophies that manifests with hemeralopia, degenerative vitreous changes, peripheral and central retinoschisis, a liquefied vitreous cavity with preretinal band-shaped structures, macular oedema, cataract formation, and an abnormal electroretinogram (ERG).1–3 The term “clumped pigmentary retinal degeneration” (CPRD) describes a group of patients with decreased night and peripheral vision who have round and irregular clumps of pigment in the mid-peripheral fundus with little or no evidence of bone spicule formation.4 This pattern of pigmentation occurs in retinitis pigmentosa (RP) with preserved para-arteriolar retinal pigment epithelium (PPRPE),5 enhanced S-cone syndrome (ESCS), and GFS, and these disorders share common mutations in the NR2E3 gene, which is involved in retinal cell fate determination.6 We present clinical and molecular genetic studies of a family from the United Arab Emirates with a classic GFS phenotype and a mutation in the NR2E3 gene. Two affected siblings and two unaffected siblings from a consanguineous family in which there were nine unaffected siblings were examined. GFS was diagnosed according to previous clinical descriptions of the disease.1,2 Complete ocular examinations, fluorescein angiography (FA), ERG, and optical coherence tomography (OCT) were …

Mutation screen of the cone-specific gene, CLUL1, in 376 patients with age-related macular degeneration.

Clusterin is a secreted glycoprotein expressed ubiquitously in many tissues that appears to function as a molecular chaperone capable of protecting stressed proteins. It is upregulated in many different forms of neurodegeneration and is thought to represent a defense response against neuronal damage. Clusterin has been found to be a common protein identified in drusen preparations isolated from the retina of donor eyes of patients with age-related macular degeneration (AMD), the leading cause of blindness in the elderly population of developed countries. A retina-specific clusterin-like protein (CLUL1) showing nearly 25% identity to clusterin at the protein level was recently cloned and shown to be expressed specifically in cone photoreceptor cells. For these reasons, we investigated CLUL1 as a candidate gene for AMD. A mutation screen of the entire coding region of the CLUL1 gene in 376 unrelated patients with AMD uncovered three sequence variations, one isocoding change and two intronic changes. One intronic change appears significantly less frequent in patients with the more severe forms of AMD than in control subjects, suggesting that this variant may reduce the risk for AMD or may be linked to a nearby variant that may reduce AMD risk. Variant alleles of the CLUL1 gene were found; however, none are considered pathogenic. None of the variants identified are predicted to create or destroy splice donor or acceptor sites based on splice-site prediction software.