title: ZNF469 frequently mutated in the brittle cornea syndrome (BCS) is a single exon gene possibly regulating the expression of several extracellular matrix components.
abstract: Brittle cornea syndrome (BCS; MIM 229200) is an autosomal recessive generalized connective tissue disorder caused by mutations in ZNF469 and PRDM5. It is characterized by extreme thinning and fragility of the cornea that may rupture in the absence of significant trauma leading to blindness. Keratoconus or keratoglobus, high myopia, blue sclerae, hyperelasticity of the skin without excessive fragility, and hypermobility of the small joints are additional features of BCS. Transcriptional regulation of extracellular matrix components, particularly of fibrillar collagens, by PRDM5 and ZNF469 suggests that they might be part of the same pathway, the disruption of which is likely to cause the features of BCS. In the present study, we have performed molecular analysis of a cohort of 23 BCS affected patients on both ZNF469 and PRDM5, including those who were clinically reported previously [1]; the clinical description of three additional patients is reported in detail. We identified either homozygous or compound heterozygous mutations in ZNF469 in 18 patients while, 4 were found to be homozygous for PRDM5 mutations. In one single patient a mutation in neither ZNF469 nor PRDM5 was identified. Furthermore, we report the 12 novel ZNF469 variants identified in our patient cohort, and show evidence that ZNF469 is a single exon rather than a two exon gene.
authors.affiliation: Division of Metabolism, Connective Tissue Unit and Children's Research Center, University Children's Hospital, Zurich, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Rohrbach
authors.forename: Helen L
authors.initials: HL
authors.lastname: Spencer
authors.forename: Louise F
authors.initials: LF
authors.lastname: Porter
authors.forename: Emma M M
authors.initials: EM
authors.lastname: Burkitt-Wright
authors.forename: Céline
authors.initials: C
authors.lastname: Bürer
authors.forename: Andreas
authors.initials: A
authors.lastname: Janecke
authors.forename: Madhura
authors.initials: M
authors.lastname: Bakshi
authors.forename: David
authors.initials: D
authors.lastname: Sillence
authors.forename: Hailah
authors.initials: H
authors.lastname: Al-Hussain
authors.forename: Matthias
authors.initials: M
authors.lastname: Baumgartner
authors.forename: Beat
authors.initials: B
authors.lastname: Steinmann
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Black
authors.forename: Forbes D C
authors.initials: FD
authors.lastname: Manson
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giunta
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D004535:Ehlers-Danlos Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D005091:Exons; D005109:Extracellular Matrix / Q000235:genetics*; D005124:Eye Abnormalities; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D007593:Joint Instability / Q000151:congenital; D009154:Mutation; D012868:Skin Abnormalities; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C487762:PRDM5 protein, human; D014157:Transcription Factors; C530065:ZNF469 protein, human