Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of fuchs corneal dystrophy

John D Gottsch, Olof H. Sundin, Sammy H. Liu, Albert Jun, Karl W. Broman, Walter J. Stark, Elizabeth C L Vito, Amol K. Narang, John M. Thompson, Malcolm Magovern

Research output: Contribution to journalArticle

Abstract

PURPOSE. To characterize the genetic basis and phenotype of inherited Fuchs corneal dystrophy (FCD). METHODS. DNA from blood was used for genome-wide linkage scans with tandem repeat polymorphisms. Mutation detection involved sequencing PCR-amplified exons. Families with FCD were clinically evaluated and graded on the Krachmer severity scale. Confocal specular microscopy visualized the morphology of endothelial guttae, small protrusions of Descemet's membrane that are characteristic of FCD. RESULTS. Linkage was obtained to 1p34.3-p32 for the autosomal dominant kindred originally reported by Magovern in 1979. All 21 cases with FCD and one with posterior polymorphous dystrophy were heterozygous for L450W, a novel point mutation in the COL8A2 gene. Of 62 independent cases of familial FCD, none had the previously reported mutations in COL8A2. Corneal guttae in COL8A2 patients were small, rounded, and associated with the endothelial cell center. This contrasts with common FCD, in which guttae were larger, sharply peaked, and initially positioned at edges of endothelial cells. The profile of age and disease severity for the L450W FCD kindred suggested that disease onset occurred in infancy, compared with an average age of onset of 50 years estimated for 201 familial FCD patients in 62 other families. CONCLUSIONS. A novel pathogenic L450W COL8A2 mutation was identified and its highly distinctive pathology characterized. This indicates that COL8A2 mutations give rise to a rare subtype of FCD. This study also provides the first direct evidence that COL8A2-FCD progresses from early to late stages in 25 years, a rate similar to that estimated for late-onset FCD.

Original languageEnglish (US)
Pages (from-to)1934-1939
Number of pages6
JournalInvestigative Ophthalmology and Visual Science
Volume46
Issue number6
DOIs
StatePublished - Jun 2005

Fingerprint

Fuchs' Endothelial Dystrophy
Mutation
Endothelial Cells
Descemet Membrane
Tandem Repeat Sequences
Age of Onset
Point Mutation
Confocal Microscopy
Exons

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of fuchs corneal dystrophy. / Gottsch, John D; Sundin, Olof H.; Liu, Sammy H.; Jun, Albert; Broman, Karl W.; Stark, Walter J.; Vito, Elizabeth C L; Narang, Amol K.; Thompson, John M.; Magovern, Malcolm.

In: Investigative Ophthalmology and Visual Science, Vol. 46, No. 6, 06.2005, p. 1934-1939.

Research output: Contribution to journalArticle

Gottsch, JD, Sundin, OH, Liu, SH, Jun, A, Broman, KW, Stark, WJ, Vito, ECL, Narang, AK, Thompson, JM & Magovern, M 2005, 'Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of fuchs corneal dystrophy', Investigative Ophthalmology and Visual Science, vol. 46, no. 6, pp. 1934-1939. https://doi.org/10.1167/iovs.04-0937
Gottsch, John D ; Sundin, Olof H. ; Liu, Sammy H. ; Jun, Albert ; Broman, Karl W. ; Stark, Walter J. ; Vito, Elizabeth C L ; Narang, Amol K. ; Thompson, John M. ; Magovern, Malcolm. / Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of fuchs corneal dystrophy. In: Investigative Ophthalmology and Visual Science. 2005 ; Vol. 46, No. 6. pp. 1934-1939.
@article{b0f00d8479e4450cac8d45f574574858,
title = "Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of fuchs corneal dystrophy",
abstract = "PURPOSE. To characterize the genetic basis and phenotype of inherited Fuchs corneal dystrophy (FCD). METHODS. DNA from blood was used for genome-wide linkage scans with tandem repeat polymorphisms. Mutation detection involved sequencing PCR-amplified exons. Families with FCD were clinically evaluated and graded on the Krachmer severity scale. Confocal specular microscopy visualized the morphology of endothelial guttae, small protrusions of Descemet's membrane that are characteristic of FCD. RESULTS. Linkage was obtained to 1p34.3-p32 for the autosomal dominant kindred originally reported by Magovern in 1979. All 21 cases with FCD and one with posterior polymorphous dystrophy were heterozygous for L450W, a novel point mutation in the COL8A2 gene. Of 62 independent cases of familial FCD, none had the previously reported mutations in COL8A2. Corneal guttae in COL8A2 patients were small, rounded, and associated with the endothelial cell center. This contrasts with common FCD, in which guttae were larger, sharply peaked, and initially positioned at edges of endothelial cells. The profile of age and disease severity for the L450W FCD kindred suggested that disease onset occurred in infancy, compared with an average age of onset of 50 years estimated for 201 familial FCD patients in 62 other families. CONCLUSIONS. A novel pathogenic L450W COL8A2 mutation was identified and its highly distinctive pathology characterized. This indicates that COL8A2 mutations give rise to a rare subtype of FCD. This study also provides the first direct evidence that COL8A2-FCD progresses from early to late stages in 25 years, a rate similar to that estimated for late-onset FCD.",
author = "Gottsch, {John D} and Sundin, {Olof H.} and Liu, {Sammy H.} and Albert Jun and Broman, {Karl W.} and Stark, {Walter J.} and Vito, {Elizabeth C L} and Narang, {Amol K.} and Thompson, {John M.} and Malcolm Magovern",
year = "2005",
month = "6",
doi = "10.1167/iovs.04-0937",
language = "English (US)",
volume = "46",
pages = "1934--1939",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "6",

}

TY - JOUR

T1 - Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of fuchs corneal dystrophy

AU - Gottsch, John D

AU - Sundin, Olof H.

AU - Liu, Sammy H.

AU - Jun, Albert

AU - Broman, Karl W.

AU - Stark, Walter J.

AU - Vito, Elizabeth C L

AU - Narang, Amol K.

AU - Thompson, John M.

AU - Magovern, Malcolm

PY - 2005/6

Y1 - 2005/6

N2 - PURPOSE. To characterize the genetic basis and phenotype of inherited Fuchs corneal dystrophy (FCD). METHODS. DNA from blood was used for genome-wide linkage scans with tandem repeat polymorphisms. Mutation detection involved sequencing PCR-amplified exons. Families with FCD were clinically evaluated and graded on the Krachmer severity scale. Confocal specular microscopy visualized the morphology of endothelial guttae, small protrusions of Descemet's membrane that are characteristic of FCD. RESULTS. Linkage was obtained to 1p34.3-p32 for the autosomal dominant kindred originally reported by Magovern in 1979. All 21 cases with FCD and one with posterior polymorphous dystrophy were heterozygous for L450W, a novel point mutation in the COL8A2 gene. Of 62 independent cases of familial FCD, none had the previously reported mutations in COL8A2. Corneal guttae in COL8A2 patients were small, rounded, and associated with the endothelial cell center. This contrasts with common FCD, in which guttae were larger, sharply peaked, and initially positioned at edges of endothelial cells. The profile of age and disease severity for the L450W FCD kindred suggested that disease onset occurred in infancy, compared with an average age of onset of 50 years estimated for 201 familial FCD patients in 62 other families. CONCLUSIONS. A novel pathogenic L450W COL8A2 mutation was identified and its highly distinctive pathology characterized. This indicates that COL8A2 mutations give rise to a rare subtype of FCD. This study also provides the first direct evidence that COL8A2-FCD progresses from early to late stages in 25 years, a rate similar to that estimated for late-onset FCD.

AB - PURPOSE. To characterize the genetic basis and phenotype of inherited Fuchs corneal dystrophy (FCD). METHODS. DNA from blood was used for genome-wide linkage scans with tandem repeat polymorphisms. Mutation detection involved sequencing PCR-amplified exons. Families with FCD were clinically evaluated and graded on the Krachmer severity scale. Confocal specular microscopy visualized the morphology of endothelial guttae, small protrusions of Descemet's membrane that are characteristic of FCD. RESULTS. Linkage was obtained to 1p34.3-p32 for the autosomal dominant kindred originally reported by Magovern in 1979. All 21 cases with FCD and one with posterior polymorphous dystrophy were heterozygous for L450W, a novel point mutation in the COL8A2 gene. Of 62 independent cases of familial FCD, none had the previously reported mutations in COL8A2. Corneal guttae in COL8A2 patients were small, rounded, and associated with the endothelial cell center. This contrasts with common FCD, in which guttae were larger, sharply peaked, and initially positioned at edges of endothelial cells. The profile of age and disease severity for the L450W FCD kindred suggested that disease onset occurred in infancy, compared with an average age of onset of 50 years estimated for 201 familial FCD patients in 62 other families. CONCLUSIONS. A novel pathogenic L450W COL8A2 mutation was identified and its highly distinctive pathology characterized. This indicates that COL8A2 mutations give rise to a rare subtype of FCD. This study also provides the first direct evidence that COL8A2-FCD progresses from early to late stages in 25 years, a rate similar to that estimated for late-onset FCD.

UR - http://www.scopus.com/inward/record.url?scp=22144445323&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=22144445323&partnerID=8YFLogxK

U2 - 10.1167/iovs.04-0937

DO - 10.1167/iovs.04-0937

M3 - Article

C2 - 15914606

AN - SCOPUS:22144445323

VL - 46

SP - 1934

EP - 1939

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 6

ER -