September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
FBN1 mutations implicated in PCG in a South African family
Author Affiliations & Notes
  • Susan E I Williams
    Neurosciences, University of the Witwatersrand, Johannesburg, South Africa
  • Nadia Carstens
    Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa
  • Saadiah Goolam
    Neurosciences, University of the Witwatersrand, Johannesburg, South Africa
  • Scott Hazelhurst
    School of Electrical and Information Engineering, University of the Witwatersrand, Johannesburg, South Africa
    Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa
  • Trevor R Carmichael
    Neurosciences, University of the Witwatersrand, Johannesburg, South Africa
  • Michele Ramsay
    Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa
  • Footnotes
    Commercial Relationships   Susan Williams, None; Nadia Carstens, None; Saadiah Goolam, None; Scott Hazelhurst, None; Trevor Carmichael, None; Michele Ramsay, None
  • Footnotes
    Support  South African Medical Research Council Self Initiated Research grant - T R Carmichael; Novartis internship - N Carstens
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 801. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Susan E I Williams, Nadia Carstens, Saadiah Goolam, Scott Hazelhurst, Trevor R Carmichael, Michele Ramsay; FBN1 mutations implicated in PCG in a South African family. Invest. Ophthalmol. Vis. Sci. 2016;57(12):801.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose : Primary congenital glaucoma (PCG), an important cause of childhood blindness, has known genetic associations with CYP1B1 and LTBP2, however mutations in these genes are uncommon in South Africans with PCG. The aim of this study was to identify the cause of PCG in an admixed South African family with two affected children.

Methods : The affected children were phenotyped and their DNA was extracted for genetic analysis as was that from both parents and two of their unaffected siblings. Microscopy was performed on the skin of the mother and one of the affected children. Whole exome sequencing on the six family members, to an average depth of 43x, was used for mutation identification. Variant filtering to identify the PCG-causal mutation included the inheritance pattern (autosomal recessive), variant minor allele frequency and potential functional impact.

Results : Both affected children had isolated bilateral primary infantile glaucoma. Neither had systemic features to suggest Marfan or Weill-Marchesani syndromes; however both were found to be osteopenic on bone densitometry. Light and electron microscopy on skin samples revealed extracellular matrix abnormalities and sparser collagen fibres compared to controls. The findings were more severe in the child than his mother. There were no potentially pathogenic homozygous mutations identified within the exome by variant filtering. Twelve compound heterozygous mutations in five genes were identified and evaluated. The most likely causal gene was FBN1 that contained two extremely rare splice-site mutations that segregated with PCG in this family.

Conclusions : FBN1 codes for an ubiquitous extracellular matrix glycoprotein, fibrillin-1. Mutations in FBN1 are mainly causal for Marfan syndrome but have also been described in Weill-Marchesani syndrome and in isolated ectopia lentis. They have not before been implicated in PCG, but fibrillin-1 is a member of a superfamily of extracellular matrix proteins that includes LTBP2 and it interacts with LTBP2. PCG-causing LTBP2 mutations are associated with extracellular matrix and bone mineral density variations similar to the ones identified in this family. FBN1 is therefore an important candidate gene for PCG. We are currently investigating the effects of the FBN1 mutations on splicing and nonsense-mediated decay. Gene expression studies are underway. Our findings could potentially increase current understanding of the disease mechanisms underlying PCG.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×