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Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p.

Publication ,  Journal Article
Riazuddin, SA; Zaghloul, NA; Al-Saif, A; Davey, L; Diplas, BH; Meadows, DN; Eghrari, AO; Minear, MA; Li, Y-J; Klintworth, GK; Afshari, N ...
Published in: Am J Hum Genet
January 2010

Fuchs corneal dystrophy (FCD) is a degenerative genetic disorder of the corneal endothelium that represents one of the most common causes of corneal transplantation in the United States. Despite its high prevalence (4% over the age of 40), the underlying genetic basis of FCD is largely unknown. Here we report missense mutations in TCF8, a transcription factor whose haploinsufficiency causes posterior polymorphous corneal dystrophy (PPCD), in a cohort of late-onset FCD patients. In contrast to PPCD-causing mutations, all of which are null, FCD-associated mutations encode rare missense changes suggested to cause loss of function by an in vivo complementation assay. Importantly, segregation of a recurring p.Q840P mutation in a large, multigenerational FCD pedigree showed this allele to be sufficient but not necessary for pathogenesis. Execution of a genome-wide scan conditioned for the presence of the 840P allele identified an additional late-onset FCD locus on chromosome 9p, whereas haplotype analysis indicated that the presence of the TCF8 allele and the disease haplotype on 9p leads to a severe FCD manifestation with poor prognosis. Our data suggest that PPCD and FCD are allelic variants of the same disease continuum and that genetic interaction between genes that cause corneal dystrophies can modulate the expressivity of the phenotype.

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Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

January 2010

Volume

86

Issue

1

Start / End Page

45 / 53

Location

United States

Related Subject Headings

  • Zinc Finger E-box-Binding Homeobox 1
  • Transcription Factors
  • Mutation, Missense
  • Middle Aged
  • Male
  • Humans
  • Homeodomain Proteins
  • Genetics & Heredity
  • Genetic Predisposition to Disease
  • Fuchs' Endothelial Dystrophy
 

Citation

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Riazuddin, S. A., Zaghloul, N. A., Al-Saif, A., Davey, L., Diplas, B. H., Meadows, D. N., … Katsanis, N. (2010). Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p. Am J Hum Genet, 86(1), 45–53. https://doi.org/10.1016/j.ajhg.2009.12.001
Riazuddin, S Amer, Norann A. Zaghloul, Amr Al-Saif, Lisa Davey, Bill H. Diplas, Danielle N. Meadows, Allen O. Eghrari, et al. “Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p.Am J Hum Genet 86, no. 1 (January 2010): 45–53. https://doi.org/10.1016/j.ajhg.2009.12.001.
Riazuddin SA, Zaghloul NA, Al-Saif A, Davey L, Diplas BH, Meadows DN, et al. Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p. Am J Hum Genet. 2010 Jan;86(1):45–53.
Riazuddin, S. Amer, et al. “Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p.Am J Hum Genet, vol. 86, no. 1, Jan. 2010, pp. 45–53. Pubmed, doi:10.1016/j.ajhg.2009.12.001.
Riazuddin SA, Zaghloul NA, Al-Saif A, Davey L, Diplas BH, Meadows DN, Eghrari AO, Minear MA, Li Y-J, Klintworth GK, Afshari N, Gregory SG, Gottsch JD, Katsanis N. Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p. Am J Hum Genet. 2010 Jan;86(1):45–53.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

January 2010

Volume

86

Issue

1

Start / End Page

45 / 53

Location

United States

Related Subject Headings

  • Zinc Finger E-box-Binding Homeobox 1
  • Transcription Factors
  • Mutation, Missense
  • Middle Aged
  • Male
  • Humans
  • Homeodomain Proteins
  • Genetics & Heredity
  • Genetic Predisposition to Disease
  • Fuchs' Endothelial Dystrophy