Browse
Submit Data
Databases
API
Help

Dataset Information

39 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Does brittle cornea syndrome have a bone fragility phenotype?

ABSTRACT: Brittle cornea syndrome is a rare recessively inherited disorder (a sub-type of Ehlers-Danlos syndrome) with a clinical presentation dominated by corneal fragility and deafness. There have been suggestions that it may also have a bone fragility phenotype, but there has been little detailed description. We describe two siblings with brittle cornea syndrome due to compound heterozygous mutations in ZNF469 who had sustained ten or more fractures, the majority before the age of 15. When investigated as adults they had osteopenia, with lower z-scores than their parents who each carried one mutation. A bone biopsy from one sibling showed reduced cortical porosity. Both parents, who were heterozygous mutation carriers, had also suffered fractures but had normal bone density. This data supports the view that brittle cornea syndrome may have a bone fragility phenotype.

SUBMITTER: Cundy T

PROVIDER: S-EPMC8426531 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Does brittle cornea syndrome have a bone fragility phenotype?

Cundy Tim T Vincent Andrea A Robertson Stephen S

Bone reports 20210901

Brittle cornea syndrome is a rare recessively inherited disorder (a sub-type of Ehlers-Danlos syndrome) with a clinical presentation dominated by corneal fragility and deafness. There have been suggestions that it may also have a bone fragility phenotype, but there has been little detailed description. We describe two siblings with brittle cornea syndrome due to compound heterozygous mutations in ZNF469 who had sustained ten or more fractures, the majority before the age of 15. When inves ...[more]

PMID: 34522702

Similar Datasets

Case Series of Brittle Cornea Syndrome.

Project description:PurposeThis case series demonstrate diagnostic features, treatment options, and challenges for Brittle Cornea Syndrome. Observations. Three cases presented with bluish sclera and extremely thin cornea. Genetic workup was performed and confirmed the diagnosis of Brittle Cornea Syndrome, a rare autosomal recessive disorder characterized by corneal thinning and blue sclera. Case 1 was a 4-year-old boy who developed cataract and glaucoma after undergoing right tectonic penetrating keratoplasty (PK) secondary to a spontaneous corneal rupture. Glaucoma was controlled medically. Later, the kid underwent right transcorneal lensectomy and vitrectomy with synechiolysis. After 6 weeks, he sustained graft dehiscence that was repaired using onlay patch graft. Case 2 was a 7-year-old boy who underwent PK in the right eye, then a pericardial patch graft in the left eye following spontaneous corneal rupture. Glaucoma in both eyes was controlled medically. Case 3 was the 2-year-old sister of the 2nd case. She had a pachymetry of 238 μm OD and 254 μm OD and 254 .ConclusionsLong-term follow-up of children diagnosed with Brittle Cornea Syndrome is paramount to minimize the morbidity of corneal rupture and late-onset extraocular conditions.

| S-EPMC7109549 | biostudies-literature

Brittle cornea syndrome: recognition, molecular diagnosis and management.

Project description:Brittle cornea syndrome (BCS) is an autosomal recessive disorder characterised by extreme corneal thinning and fragility. Corneal rupture can therefore occur either spontaneously or following minimal trauma in affected patients. Two genes, ZNF469 and PRDM5, have now been identified, in which causative pathogenic mutations collectively account for the condition in nearly all patients with BCS ascertained to date. Therefore, effective molecular diagnosis is now available for affected patients, and those at risk of being heterozygous carriers for BCS. We have previously identified mutations in ZNF469 in 14 families (in addition to 6 reported by others in the literature), and in PRDM5 in 8 families (with 1 further family now published by others). Clinical features include extreme corneal thinning with rupture, high myopia, blue sclerae, deafness of mixed aetiology with hypercompliant tympanic membranes, and variable skeletal manifestations. Corneal rupture may be the presenting feature of BCS, and it is possible that this may be incorrectly attributed to non-accidental injury. Mainstays of management include the prevention of ocular rupture by provision of protective polycarbonate spectacles, careful monitoring of visual and auditory function, and assessment for skeletal complications such as developmental dysplasia of the hip. Effective management depends upon appropriate identification of affected individuals, which may be challenging given the phenotypic overlap of BCS with other connective tissue disorders.

| S-EPMC3659006 | biostudies-literature

Bruch's membrane abnormalities in PRDM5-related brittle cornea syndrome.

Project description: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.

| S-EPMC4642625 | biostudies-literature

Use of an onlay corneal lamellar graft for brittle cornea syndrome.

Project description:Brittle cornea syndrome (BCS1 OMIM #229200, BCS2 #614170) is a rare autosomal recessive condition characterised by diffuse thinning and fragility of the cornea. Affected individuals are at risk of globe rupture and blindness after relatively minor eye trauma. We describe a 9-year-old girl with BCS1, already blind in one eye following trauma, who had a 14 mm diameter corneoscleral onlay graft to her contralateral eye to reduce gross irregular corneal astigmatism and potentially to reduce further risk from accidental injury. Although there was a significant initial improvement in the unaided visual acuity, there was subsequent visual loss from secondary glaucoma. In addition, despite the onlay graft, an acute corneal hydrops developed approximately 2 years following surgery, suggesting that in BCS1, corneal tissue degeneration or resorption continues despite external support. Finally, because secondary glaucoma is not a feature of BCS1, we speculate that the onlay graft may have reduced aqueous outflow by compression of the thinned sclera.

| S-EPMC6101314 | biostudies-literature

Deleterious mutations in the Zinc-Finger 469 gene cause brittle cornea syndrome.

Project description:Brittle cornea syndrome (BCS) is an autosomal-recessive disorder characterized by a thin cornea that tends to perforate, causing progressive visual loss and blindness. Additional systemic symptoms such as joint hypermotility, hyperlaxity of the skin, and kyphoscoliosis place BCS among the connective-tissue disorders. Previously, we assigned the disease gene to a 4.7 Mb interval on chromosome 16q24. In order to clone the BCS gene, we first narrowed the disease locus to a 2.8 Mb interval and systematically sequenced genes expressed in connective tissue in this chromosomal segment. We have identified two frameshift mutations in the Zinc-Finger 469 gene (ZNF469). In five unrelated patients of Tunisian Jewish ancestry, we found a 1 bp deletion at position 5943 (5943 delA), and in an inbred Palestinian family we detected a single-nucleotide deletion at position 9527 (9527 delG). The function of ZNF469 is unknown. However, a 30% homology to a number of collagens suggests that it could act as a transcription factor involved in the synthesis and/or organization of collagen fibers.

| S-EPMC2427192 | biostudies-literature

A mouse model of brittle cornea syndrome caused by mutation in Zfp469.

Project description:Brittle cornea syndrome (BCS) is a rare recessive condition characterised by extreme thinning of the cornea and sclera. BCS results from loss-of-function mutations in the poorly understood genes ZNF469 or PRDM5. In order to determine the function of ZNF469 and to elucidate pathogenic mechanisms, we used genome editing to recapitulate a human ZNF469 BCS mutation in the orthologous mouse gene Zfp469. Ophthalmic phenotyping showed that homozygous Zfp469 mutation causes significant central and peripheral corneal thinning arising from reduced stromal thickness. Expression of key components of the corneal stroma in primary keratocytes from Zfp469BCS/BCS mice is affected, including decreased Col1a1 and Col1a2 expression. This alters the collagen type I/collagen type V ratio and results in collagen fibrils with smaller diameter and increased fibril density in homozygous mutant corneas, correlating with decreased biomechanical strength in the cornea. Cell-derived matrices generated by primary keratocytes show reduced deposition of collagen type I, offering an in vitro model for stromal dysfunction. Work remains to determine whether modulating ZNF469 activity will have therapeutic benefit in BCS or in conditions such as keratoconus in which the cornea thins progressively. This article has an associated First Person interview with the first author of the paper.

| S-EPMC8476817 | biostudies-literature

A role for repressive complexes and H3K9 di-methylation in PRDM5-associated brittle cornea syndrome.

Project description:Type 2 brittle cornea syndrome (BCS2) is an inherited connective tissue disease with a devastating ocular phenotype caused by mutations in the transcription factor PR domain containing 5 (PRDM5) hypothesized to exert epigenetic effects through histone and DNA methylation. Here we investigate clinical samples, including skin fibroblasts and retinal tissue from BCS2 patients, to elucidate the epigenetic role of PRDM5 and mechanisms of its dysregulation in disease. First we report abnormal retinal vascular morphology in the eyes of two cousins with BCS2 (PRDM5 Δ exons 9-14) using immunohistochemistry, and mine data from skin fibroblast expression microarrays from patients with PRDM5 mutations p.Arg590* and Δ exons 9-14, as well as from a PRDM5 ChIP-sequencing experiment. Gene ontology analysis of dysregulated PRDM5-target genes reveals enrichment for extracellular matrix (ECM) genes supporting vascular integrity and development. Q-PCR and ChIP-qPCR confirm upregulation of critical mediators of ECM stability in vascular structures (COL13A1, COL15A1, NTN1, CDH5) in patient fibroblasts. We identify H3K9 di-methylation (H3K9me2) at these PRDM5-target genes in fibroblasts, and demonstrate that the BCS2 mutation p.Arg83Cys diminishes interaction of PRDM5 with repressive complexes, including NuRD complex protein CHD4, and the repressive chromatin interactor HP1BP3, by co-immunoprecipitation combined with mass spectrometry. We observe reduced heterochromatin protein 1 binding protein 3 (HP1BP3) staining in the retinas of two cousins lacking exons 9-14 by immunohistochemistry, and dysregulated H3K9me2 in skin fibroblasts of three patients (p.Arg590*, p.Glu134* and Δ exons 9-14) by western blotting. These findings suggest that defective interaction of PRDM5 with repressive complexes, and dysregulation of H3K9me2, play a role in PRDM5-associated disease.

| S-EPMC4634368 | biostudies-literature

Variants in the ZNF469 gene in families with Brittle cornea syndrome and keratoconus.

Project description:BackgroundBrittle cornea syndrome 1 (BCS1) is a rare autosomal recessive disorder characterized by corneal and sclera thinning and fragility that is caused by zinc finger protein 469 (ZNF469) gene mutation. Keratoconus is another disease related to corneal thinning. Several reports have linked ZNF469 variants and keratoconus. We recruited a four-generation BCS1 family and two keratoconus families to explore pathogenic ZNF469 variants.MethodsThis study included 11 members from a family with BCS1, 2 families with keratoconus, 368 sporadic keratoconus patients and 325 unrelated healthy controls. Whole exome sequencing of DNA from peripheral blood and cross species conservation analysis was used to investigate and verify ZNF469 variants.ResultsA new homozygous frameshift mutation c. 6727del (p.Asp2243Thr fs*8) in ZNF469 was detected in the BSC1 family. Two ZNF469 heterozygous variants g.88494671G > A (c.793G > A, p.G265S, rs754776767) were detected in keratoconus family 1 and a heterozygous missense variant g.88498262G > A (c.4384G > A, p.D1462 N, rs577890057) was found in keratoconus family 2. Based on the American College of Medical Genetics and Genomics guidelines, rs577890057 and rs754776767 were predicted to be variants of uncertain significance. c. 6727del (p. Asp2243Thr fs*8) in ZNF469 was identified to be pathogenic.ConclusionsWe identified a new homozygous frameshift mutation and two heterozygous missense variations in ZNF469 in the three families. Our findings extend the spectrum of ZNF469 variants associated with keratoconus.

| S-EPMC10909740 | biostudies-literature

Homozygous Val6Gly Variation in PRDM5 Gene Causing Brittle Cornea Syndrome: A New Turkish Case.

Project description:IntroductionBrittle cornea syndrome (BCS) is a rare connective tissue disorder with ocular and systemic features. Extreme corneal thinning and fragility are the main hallmarks of BCS.Case reportA 4-year-old boy presented with recurrent spontaneous corneal perforation. He had blue sclera, corneal leucoma, irregular iris, shallow anterior chamber, corneal astigmatism, and bilateral corneal thinning. He also had several systemic features including hearing loss, skin hyperelasticity, joint hypermobility, scoliosis, and umbilical hernia. A diagnosis of BCS was confirmed with molecular analysis. A homozygous c.17T>G, p.(Val6Gly) variation was identified in the PRDM5 gene.Discussionp.(Val6Gly) variation in PRDM5 was previously reported in 2 patients with BCS. We also considered PRDM5 c.17T>G, p.(Val6Gly) variation as pathogenic based on the following features: the absence of the variation in population databases, in silico predictions, segregation analysis, and clinical signs of our patient. Extremely thin and brittle corneas lead to corneal perforation spontaneously or after minor trauma. Nearly all patients have lost their vision because of corneal rupture and scars. The key challenge in the management of BCS is the prevention of ocular rupture which relies on early diagnosis. Early diagnosis allows for taking prompt measures to prevent ocular rupture.

| S-EPMC10091010 | biostudies-literature

Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance.

Project description: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.

| S-EPMC3113239 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data