Mutations in PRDM5 in Brittle Cornea Syndrome Identify a Pathway Regulating Extracellular Matrix Development and Maintenance

Abstract

Extreme corneal fragility and thinning, which have a high risk of catastrophic spontaneous rupture, are the cardinal features of brittle cornea syndrome (BCS), an autosomal-recessive generalized connective tissue disorder. Enucleation is frequently the only management option for this condition, resulting in blindness and psychosocial distress. Even when the cornea remains grossly intact, visual function could also be impaired by a high degree of myopia and keratoconus. Deafness is another common feature and results in combined sensory deprivation. Using autozygosity mapping, we identified mutations in PRDM5 in families with BCS. We demonstrate that regulation of expression of extracellular matrix components, particularly fibrillar collagens, by PRDM5 is a key molecular mechanism that underlies corneal fragility in BCS and controls normal corneal development and maintenance. ZNF469, encoding a zinc finger protein of hitherto undefined function, has been identified as a quantitative trait locus for central corneal thickness, and mutations in this gene have been demonstrated in Tunisian Jewish and Palestinian kindreds with BCS. We show that ZNF469 and PRDM5, two genes that when mutated cause BCS, participate in the same regulatory pathway.

Brittle Cornea Syndrome: Case Report with Novel Mutation in thePRDM5Gene and Review of the Literature

“…Other typical mutations in brittle cornea syndrome type 2 are located on chromosome 4 on the PRDM5 gene, with cytogenetic location 4q27 or c.1768C>T [6, 9, 10]. The ZNF469 gene mutations at chromosome 14 are responsible for brittle cornea syndrome type 1.…”

“…Corneal thickness is strongly associated with ZNF469 and PRDM5 gene products [1, 3, 5]. It is obscure how mutations in these genes cause typical features of this syndrome, but the gene products, both containing DNA binding zinc finger domains, seem to play a role in the transcriptional regulation of extracellular matrix genes, including corneal fibrillar collagens [5, 6]. Alterations in this pathway lead to changes in corneal integrity due to corneal thinning [5–7].…”

“…Since brittle cornea syndrome is part of a generalized connective tissue disease, ZNF469 and PRDM5 gene products concern the development of extracellular matrix [3]. Mutations in these genes are supposed to work like “loss-of-function alleles” [3] affecting fibroblasts [3, 6]. Such mutations in fibroblasts cause different disorders in collagens, integrin, or fibronectin [5], determining extraocular dysfunctions as a generalized connective tissue disorder including auditory, skin, and musculoskeletal features [6].…”

Use of an onlay corneal lamellar graft for brittle cornea syndrome

“…BCS is a rare autosomal recessive connective tissue disorder caused by mutations in either the ZNF469(4) or PRMD5 genes 5. The principal ophthalmic manifestations are a diffusely thinned and fragile cornea, which is susceptible to rupture following relatively minor trauma.…”

The Genetic Background of Keratoconus: A Review on Keratoconus Genes

“…Fibroblasts from BCS patients with both PRDM5 and ZNF469 mutations were investigated and revealed similar cellular phenotypes, with disruption in the deposition of several collagens, fibronectin and integrins [46]. Microtriplication 11q24.1 has been associated with facial dysmorphisms, short stature with small extremities, keratoconus, overweight, and intellectual disability [47].…”