Bruch’s membrane abnormalities in PRDM5-related brittle cornea syndrome

Abstract

BackgroundBrittle cornea syndrome (BCS) is a rare, generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Recessive mutations in transcription factors ZNF469 and PRDM5 cause BCS. Both transcription factors are suggested to act on a common pathway regulating extracellular matrix genes, particularly fibrillar collagens. We identified bilateral myopic choroidal neovascularization as the presenting feature of BCS in a 26-year-old-woman carrying a novel PRDM5 mutation (p.Glu134*). We performed immunohistochemistry of anterior and posterior segment ocular tissues, as expression of PRDM5 in the eye has not been described, or the effects of PRDM5-associated disease on the retina, particularly the extracellular matrix composition of Bruch’s membrane.MethodsImmunohistochemistry using antibodies against PRDM5, collagens type I, III, and IV was performed on the eyes of two unaffected controls and two patients (both with Δ9-14 PRDM5). Expression of collagens, integrins, tenascin and fibronectin in skin fibroblasts of a BCS patient with a novel p.Glu134* PRDM5 mutation was assessed using immunofluorescence.ResultsPRDM5 is expressed in the corneal epithelium and retina. We observe reduced expression of major components of Bruch’s membrane in the eyes of two BCS patients with a PRDM5 Δ9-14 mutation. Immunofluorescence performed on skin fibroblasts from a patient with p.Glu134* confirms the generalized nature of extracellular matrix abnormalities in BCS.ConclusionsPDRM5-related disease is known to affect the cornea, skin and joints. Here we demonstrate, to the best of our knowledge for the first time, that PRDM5 localizes not only in the human cornea, but is also widely expressed in the retina. Our findings suggest that ECM abnormalities in PRDM5-associated disease are more widespread than previously reported.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0360-4) contains supplementary material, which is available to authorized users.

Brittle cornea syndrome: Disease-causing mutations in ZNF469 and two novel variants identified in a patient followed for 26 years

“…2,3 ) and PRDM5 (ref. 4,5 ) are known to be associated with BCS type 1 (BCS1; MIM #229200) and type 2 (BCS2; MIM #614170), respectively. The disease mechanism remains unclear.…”

“…The disease mechanism remains unclear. Both encoded proteins ZNF469 and PRDM5 are transcription factors regulating extracellular matrix components, particularly fibrillar collagens suggesting involvement in the same pathway 3,5,6 .…”

Brittle cornea syndrome: a case report and review of the literature

“…As we know, this is the first case of BCS reported in the Asia area. Although BCS is a rare genetic disease, it’s extreme corneal thinning (220–450 μm) (normal range 520–560 μm) affected individuals are at high risk of corneal rupture, leading to irreversible blindness [ 1 , 5 , 10 ]. So, It is urgent for us to better understanding this disease and taking timely measures to manage and follow-up this disease.…”

“…[ 11 – 13 ]. Mutations in the ZNF469 gene are causative for brittle cornea syndrome type1 (BCS1) and brittle cornea syndrome type2 (BCS2) is caused by mutations in the PRDM5 gene [ 5 , 10 ]. As transcriptional regulators, both ZNF469 and PRDM5 are participate in pathways regulating extracellular matrix.…”

Role of Glia in the Morphogenesis of the Human Eye Transparent Structure

“…Правильная дифференциация фоторецепторов представляет особый интерес из-за их участия в возникновении дегенеративных заболеваний сетчатки глаза [1]. Портером с соавторами (Porter L.F. et al, 2015) установлено сочетанное повреждение мембраны Бруха, имеющее генерализованный характер, с нарушениями в строме и эпителии роговицы [14].…”