Mutations in LOXHD1, a recessive-deafness locus, cause dominant late-onset Fuchs corneal dystrophy

Sheikh Amer Riazuddin, David S. Parker, Elyse McGlumphy, Edwin C. Oh, Benjamin W. Iliff, Thore Schmedt, Ula Jurkunas, Robert Schleif, Nicholas Katsanis, John D Gottsch

Research output: Contribution to journalArticle

Abstract

Fuchs corneal dystrophy (FCD) is a genetic disorder of the corneal endothelium and is the most common cause of corneal transplantation in the United States. Previously, we mapped a late-onset FCD locus, FCD2, on chromosome 18q. Here, we present next-generation sequencing of all coding exons in the FCD2 critical interval in a multigenerational pedigree in which FCD segregates as an autosomal-dominant trait. We identified a missense change in LOXHD1, a gene causing progressive hearing loss in humans, as the sole variant capable of explaining the phenotype in this pedigree. We observed LOXHD1 mRNA in cultured human corneal endothelial cells, whereas antibody staining of both human and mouse corneas showed staining in the corneal epithelium and endothelium. Corneal sections of the original proband were stained for LOXHD1 and demonstrated a distinct increase in antibody punctate staining in the endothelium and Descemet membrane; punctate staining was absent from both normal corneas and FCD corneas negative for causal LOXHD1 mutations. Subsequent interrogation of a cohort of >200 sporadic affected individuals identified another 15 heterozygous missense mutations that were absent from >800 control chromosomes. Furthermore, in silico analyses predicted that these mutations reside on the surface of the protein and are likely to affect the protein's interface and protein-protein interactions. Finally, expression of the familial LOXHD1 mutant allele as well as two sporadic mutations in cells revealed prominent cytoplasmic aggregates reminiscent of the corneal phenotype. All together, our data implicate rare alleles in LOXHD1 in the pathogenesis of FCD and highlight how different mutations in the same locus can potentially produce diverse phenotypes.

Original languageEnglish (US)
Pages (from-to)533-539
Number of pages7
JournalAmerican Journal of Human Genetics
Volume90
Issue number3
DOIs
StatePublished - Mar 9 2012

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Fuchs' Endothelial Dystrophy
Deafness
Mutation
Cornea
Staining and Labeling
Corneal Endothelium
Pedigree
Phenotype
Chromosomes
Alleles
Descemet Membrane
Corneal Epithelium
Inborn Genetic Diseases
Proteins
Corneal Transplantation
Antibodies
Missense Mutation
Hearing Loss
Computer Simulation
Endothelium

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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Mutations in LOXHD1, a recessive-deafness locus, cause dominant late-onset Fuchs corneal dystrophy. / Riazuddin, Sheikh Amer; Parker, David S.; McGlumphy, Elyse; Oh, Edwin C.; Iliff, Benjamin W.; Schmedt, Thore; Jurkunas, Ula; Schleif, Robert; Katsanis, Nicholas; Gottsch, John D.

In: American Journal of Human Genetics, Vol. 90, No. 3, 09.03.2012, p. 533-539.

Research output: Contribution to journalArticle

Riazuddin, Sheikh Amer ; Parker, David S. ; McGlumphy, Elyse ; Oh, Edwin C. ; Iliff, Benjamin W. ; Schmedt, Thore ; Jurkunas, Ula ; Schleif, Robert ; Katsanis, Nicholas ; Gottsch, John D. / Mutations in LOXHD1, a recessive-deafness locus, cause dominant late-onset Fuchs corneal dystrophy. In: American Journal of Human Genetics. 2012 ; Vol. 90, No. 3. pp. 533-539.
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AU - McGlumphy, Elyse

AU - Oh, Edwin C.

AU - Iliff, Benjamin W.

AU - Schmedt, Thore

AU - Jurkunas, Ula

AU - Schleif, Robert

AU - Katsanis, Nicholas

AU - Gottsch, John D

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N2 - Fuchs corneal dystrophy (FCD) is a genetic disorder of the corneal endothelium and is the most common cause of corneal transplantation in the United States. Previously, we mapped a late-onset FCD locus, FCD2, on chromosome 18q. Here, we present next-generation sequencing of all coding exons in the FCD2 critical interval in a multigenerational pedigree in which FCD segregates as an autosomal-dominant trait. We identified a missense change in LOXHD1, a gene causing progressive hearing loss in humans, as the sole variant capable of explaining the phenotype in this pedigree. We observed LOXHD1 mRNA in cultured human corneal endothelial cells, whereas antibody staining of both human and mouse corneas showed staining in the corneal epithelium and endothelium. Corneal sections of the original proband were stained for LOXHD1 and demonstrated a distinct increase in antibody punctate staining in the endothelium and Descemet membrane; punctate staining was absent from both normal corneas and FCD corneas negative for causal LOXHD1 mutations. Subsequent interrogation of a cohort of >200 sporadic affected individuals identified another 15 heterozygous missense mutations that were absent from >800 control chromosomes. Furthermore, in silico analyses predicted that these mutations reside on the surface of the protein and are likely to affect the protein's interface and protein-protein interactions. Finally, expression of the familial LOXHD1 mutant allele as well as two sporadic mutations in cells revealed prominent cytoplasmic aggregates reminiscent of the corneal phenotype. All together, our data implicate rare alleles in LOXHD1 in the pathogenesis of FCD and highlight how different mutations in the same locus can potentially produce diverse phenotypes.

AB - Fuchs corneal dystrophy (FCD) is a genetic disorder of the corneal endothelium and is the most common cause of corneal transplantation in the United States. Previously, we mapped a late-onset FCD locus, FCD2, on chromosome 18q. Here, we present next-generation sequencing of all coding exons in the FCD2 critical interval in a multigenerational pedigree in which FCD segregates as an autosomal-dominant trait. We identified a missense change in LOXHD1, a gene causing progressive hearing loss in humans, as the sole variant capable of explaining the phenotype in this pedigree. We observed LOXHD1 mRNA in cultured human corneal endothelial cells, whereas antibody staining of both human and mouse corneas showed staining in the corneal epithelium and endothelium. Corneal sections of the original proband were stained for LOXHD1 and demonstrated a distinct increase in antibody punctate staining in the endothelium and Descemet membrane; punctate staining was absent from both normal corneas and FCD corneas negative for causal LOXHD1 mutations. Subsequent interrogation of a cohort of >200 sporadic affected individuals identified another 15 heterozygous missense mutations that were absent from >800 control chromosomes. Furthermore, in silico analyses predicted that these mutations reside on the surface of the protein and are likely to affect the protein's interface and protein-protein interactions. Finally, expression of the familial LOXHD1 mutant allele as well as two sporadic mutations in cells revealed prominent cytoplasmic aggregates reminiscent of the corneal phenotype. All together, our data implicate rare alleles in LOXHD1 in the pathogenesis of FCD and highlight how different mutations in the same locus can potentially produce diverse phenotypes.

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