A Cohesin Subunit Variant Identified from a Peripheral Sclerocornea Pedigree

Background Sclerocornea is a rare congenital disorder characterized with the opacification of the cornea. Here, we report a nonconsanguineous Chinese family with multiple peripheral sclerocornea patients spanning across three generations inherited in an autosomal dominant manner. Methods This is a retrospective case series of a peripheral sclerocornea pedigree. Comprehensive ophthalmic examinations were conducted and assessed on 14 pedigree members. Whole-exome sequencing was used to identify the genetic alterations in the affected pedigree members. Lymphoblastoid cell lines (LCLs) were established using blood samples from the family members. Functional tests were performed with these cell lines. Results Six affected and eight unaffected members of a family with peripheral sclerocornea were examined. All affected individuals showed features of scleralization over the peripheral cornea of both eyes. Mean horizontal and vertical corneal diameter were found significantly decreased in the affected members. Significant differences were also observed on the mean apex pachymetry between affected and unaffected subjects. These ophthalmic parameters did not resemble that of cornea plana. A RAD21C1348T variant was identified by whole-exome sequencing. Although this variant causes RAD21 R450C substitution at the separase cleavage site, cells from peripheral sclerocornea family members had no mitosis and ploidy defects. Conclusion We report a family of peripheral sclerocornea with no association with cornea plana. A RAD21 variant was found cosegregating with peripheral sclerocornea. Our results suggest that RAD21 functions, other than its cell cycle and chromosome segregation regulations, could underline the pathogenesis of peripheral sclerocornea.

[1]  F. Uhlmann.  SMC complexes: from DNA to chromosomes , 2016, Nature Reviews Molecular Cell Biology.

[2]  T. Hirano,et al.  Condensin-Based Chromosome Organization from Bacteria to Vertebrates , 2016, Cell.

[3]  Huanming Yang,et al.  Exome Sequencing Identifies ZNF644 Mutations in High Myopia , 2011, PLoS genetics.

[4]  M. DePristo,et al.  A framework for variation discovery and genotyping using next-generation DNA sequencing data , 2011, Nature Genetics.

[5]  M. McKibbin,et al.  Homozygous FOXE3 mutations cause non-syndromic, bilateral, total sclerocornea, aphakia, microphthalmia and optic disc coloboma , 2010, Molecular vision.

[6]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[7]  A. Jun,et al.  Differential gene expression patterns of the developing and adult mouse cornea compared to the lens and tendon. , 2008, Experimental eye research.

[8]  Arif O. Khan.  Sclerocornea and cornea plana are distinct entities. , 2007, Survey of ophthalmology.

[9]  A. Hardcastle,et al.  Clinical and molecular characterization of a family with autosomal recessive cornea plana. , 2005, Archives of ophthalmology.

[10]  K. Nasmyth,et al.  The structure and function of SMC and kleisin complexes. , 2005, Annual review of biochemistry.

[11]  P. Mathers,et al.  Mutations in the human RAX homeobox gene in a patient with anophthalmia and sclerocornea. , 2003, Human molecular genetics.

[12]  P. Bork,et al.  Human non-synonymous SNPs: server and survey. , 2002, Nucleic acids research.

[13]  J. Peters,et al.  Cohesin Cleavage by Separase Required for Anaphase and Cytokinesis in Human Cells , 2001, Science.

[14]  J. Murray,et al.  Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts. , 2001, Human molecular genetics.

[15]  Kim Nasmyth,et al.  Cleavage of Cohesin by the CD Clan Protease Separin Triggers Anaphase in Yeast , 2000, Cell.

[16]  R. Kobayashi,et al.  Identification and Characterization of Sa/Scc3p Subunits in the Xenopus and Human Cohesin Complexes , 2000, The Journal of cell biology.

[17]  S. Gupta,et al.  Penetrating Keratoplasty in Children , 2000, Cornea.

[18]  Friedrich Lottspeich,et al.  Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1 , 1999, Nature.

[19]  T. Hirano,et al.  Identification of Xenopus SMC protein complexes required for sister chromatid cohesion. , 1998, Genes & development.

[20]  S. I. Brown,et al.  Transplantation of congenitally opaque corneas , 1997, The British journal of ophthalmology.

[21]  R. Happle,et al.  MIDAS syndrome (microphthalmia, dermal aplasia, and sclerocornea): an X-linked phenotype distinct from Goltz syndrome. , 1993, American journal of medical genetics.

[22]  Heidemarie Neitzel,et al.  A routine method for the establishment of permanent growing lymphoblastoid cell lines , 1986, Human Genetics.

[23]  F. Polack,et al.  The fine structure of sclerocornea. , 1971, Investigative ophthalmology.

[24]  N. Bloch.  [The different types of sclerocornea, their hereditary modes and concomitant congenital malformations]. , 1965, Journal de genetique humaine.

[25]  S. Henikoff,et al.  Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm , 2009, Nature Protocols.

[26]  Claude-Alain H. Roten,et al.  Theoretical and practical advances in genome halving , 2004 .

[27]  J. H. Elliott,et al.  Hereditary sclerocornea. , 1985, Archives of ophthalmology.