Photoreceptor Degeneration, Azoospermia, Leukoencephalopathy, And Abnormal RPE Cell Function In Mice Expressing An Early Stop Mutation In CLCN2

Malia M. Edwards, Caralina Marín de Evsikova, Gayle B. Collin, Elaine Gifford, Jiang Wu, Wanda L. Hicks, Carrie Whiting, Nicholas H. Varvel, Bruce Lamb, Nicole Maphis, Jürgen K. Naggert, Patsy M. Nishina, Neal S. Peachey

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Purpose. To determine the molecular basis and the pathologic consequences of a chemically induced mutation in a mouse model of photoreceptor degeneration, nmf240.Methods. Mice from a G3 N-ethyl-N-nitrosourea mutagenesis program were screened by indirect ophthalmoscopy for abnormal fundi. A chromosomal position for the recessive nmf240 mutatiaon was determined by a genome-wide linkage analysis by use of simple sequence length polymorphic markers in an F2 intercross. The critical region was refined, and candidate genes were screened by direct sequencing. The nmf240 phe-notype was characterized by histologic analysis of the retina, brain, and male reproductive organs and by electroretinogram (ERG)-based studies of the retina and retinal pigment epithelium (RPE).Results. Clinically, homozygous nmf240 mutants exhibit a grainy retina that progresses to panretinal patches of depig-mentation. The mutation was localized to a region on chromosome 16 containing Clcn2, a gene associated with retinal degeneration. Sequencing identified a missense C-T mutation at nucleotide 1063 in Clcn2 that converts a glutamine to a stop codon. Mice homozygous for the Clcn2nmf240 mutation experience a severe loss of photoreceptor cells at 14 days of age that is preceded by an elongation of RPE apical microvilli. Homozygous mutants also experience leukoencephalopathy in multiple brain areas and male sterility. Despite a normal retinal histology in nmf240 heterozygotes, the ERG light peak, generated by the RPE, is reduced.Conclusions. The nmf240 phenotype closely resembles that reported for Clcn2 knockout mice. The observation that heterozygous nmf240 mice present with a reduced ERG lightpeak component suggests that CLCN2 is necessary for the generation of this response component.

Original languageEnglish (US)
Pages (from-to)3264-3272
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume51
Issue number6
DOIs
StatePublished - Jun 2010
Externally publishedYes

Fingerprint

Leukoencephalopathies
Azoospermia
Retinal Pigment Epithelium
Retina
Mutation
Ethylnitrosourea
Chromosomes, Human, Pair 16
Ophthalmoscopy
Photoreceptor Cells
Retinal Degeneration
Terminator Codon
Male Infertility
Brain
Heterozygote
Microvilli
Glutamine
Knockout Mice
Mutagenesis
Genes
Histology

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Photoreceptor Degeneration, Azoospermia, Leukoencephalopathy, And Abnormal RPE Cell Function In Mice Expressing An Early Stop Mutation In CLCN2. / Edwards, Malia M.; de Evsikova, Caralina Marín; Collin, Gayle B.; Gifford, Elaine; Wu, Jiang; Hicks, Wanda L.; Whiting, Carrie; Varvel, Nicholas H.; Lamb, Bruce; Maphis, Nicole; Naggert, Jürgen K.; Nishina, Patsy M.; Peachey, Neal S.

In: Investigative Ophthalmology and Visual Science, Vol. 51, No. 6, 06.2010, p. 3264-3272.

Research output: Contribution to journalArticle

Edwards, MM, de Evsikova, CM, Collin, GB, Gifford, E, Wu, J, Hicks, WL, Whiting, C, Varvel, NH, Lamb, B, Maphis, N, Naggert, JK, Nishina, PM & Peachey, NS 2010, 'Photoreceptor Degeneration, Azoospermia, Leukoencephalopathy, And Abnormal RPE Cell Function In Mice Expressing An Early Stop Mutation In CLCN2', Investigative Ophthalmology and Visual Science, vol. 51, no. 6, pp. 3264-3272. https://doi.org/10.1167/iovs.09-4887
Edwards, Malia M. ; de Evsikova, Caralina Marín ; Collin, Gayle B. ; Gifford, Elaine ; Wu, Jiang ; Hicks, Wanda L. ; Whiting, Carrie ; Varvel, Nicholas H. ; Lamb, Bruce ; Maphis, Nicole ; Naggert, Jürgen K. ; Nishina, Patsy M. ; Peachey, Neal S. / Photoreceptor Degeneration, Azoospermia, Leukoencephalopathy, And Abnormal RPE Cell Function In Mice Expressing An Early Stop Mutation In CLCN2. In: Investigative Ophthalmology and Visual Science. 2010 ; Vol. 51, No. 6. pp. 3264-3272.
@article{13e0384af5cd4fb799e89fdc40999c06,
title = "Photoreceptor Degeneration, Azoospermia, Leukoencephalopathy, And Abnormal RPE Cell Function In Mice Expressing An Early Stop Mutation In CLCN2",
abstract = "Purpose. To determine the molecular basis and the pathologic consequences of a chemically induced mutation in a mouse model of photoreceptor degeneration, nmf240.Methods. Mice from a G3 N-ethyl-N-nitrosourea mutagenesis program were screened by indirect ophthalmoscopy for abnormal fundi. A chromosomal position for the recessive nmf240 mutatiaon was determined by a genome-wide linkage analysis by use of simple sequence length polymorphic markers in an F2 intercross. The critical region was refined, and candidate genes were screened by direct sequencing. The nmf240 phe-notype was characterized by histologic analysis of the retina, brain, and male reproductive organs and by electroretinogram (ERG)-based studies of the retina and retinal pigment epithelium (RPE).Results. Clinically, homozygous nmf240 mutants exhibit a grainy retina that progresses to panretinal patches of depig-mentation. The mutation was localized to a region on chromosome 16 containing Clcn2, a gene associated with retinal degeneration. Sequencing identified a missense C-T mutation at nucleotide 1063 in Clcn2 that converts a glutamine to a stop codon. Mice homozygous for the Clcn2nmf240 mutation experience a severe loss of photoreceptor cells at 14 days of age that is preceded by an elongation of RPE apical microvilli. Homozygous mutants also experience leukoencephalopathy in multiple brain areas and male sterility. Despite a normal retinal histology in nmf240 heterozygotes, the ERG light peak, generated by the RPE, is reduced.Conclusions. The nmf240 phenotype closely resembles that reported for Clcn2 knockout mice. The observation that heterozygous nmf240 mice present with a reduced ERG lightpeak component suggests that CLCN2 is necessary for the generation of this response component.",
author = "Edwards, {Malia M.} and {de Evsikova}, {Caralina Mar{\'i}n} and Collin, {Gayle B.} and Elaine Gifford and Jiang Wu and Hicks, {Wanda L.} and Carrie Whiting and Varvel, {Nicholas H.} and Bruce Lamb and Nicole Maphis and Naggert, {J{\"u}rgen K.} and Nishina, {Patsy M.} and Peachey, {Neal S.}",
year = "2010",
month = "6",
doi = "10.1167/iovs.09-4887",
language = "English (US)",
volume = "51",
pages = "3264--3272",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "6",

}

TY - JOUR

T1 - Photoreceptor Degeneration, Azoospermia, Leukoencephalopathy, And Abnormal RPE Cell Function In Mice Expressing An Early Stop Mutation In CLCN2

AU - Edwards, Malia M.

AU - de Evsikova, Caralina Marín

AU - Collin, Gayle B.

AU - Gifford, Elaine

AU - Wu, Jiang

AU - Hicks, Wanda L.

AU - Whiting, Carrie

AU - Varvel, Nicholas H.

AU - Lamb, Bruce

AU - Maphis, Nicole

AU - Naggert, Jürgen K.

AU - Nishina, Patsy M.

AU - Peachey, Neal S.

PY - 2010/6

Y1 - 2010/6

N2 - Purpose. To determine the molecular basis and the pathologic consequences of a chemically induced mutation in a mouse model of photoreceptor degeneration, nmf240.Methods. Mice from a G3 N-ethyl-N-nitrosourea mutagenesis program were screened by indirect ophthalmoscopy for abnormal fundi. A chromosomal position for the recessive nmf240 mutatiaon was determined by a genome-wide linkage analysis by use of simple sequence length polymorphic markers in an F2 intercross. The critical region was refined, and candidate genes were screened by direct sequencing. The nmf240 phe-notype was characterized by histologic analysis of the retina, brain, and male reproductive organs and by electroretinogram (ERG)-based studies of the retina and retinal pigment epithelium (RPE).Results. Clinically, homozygous nmf240 mutants exhibit a grainy retina that progresses to panretinal patches of depig-mentation. The mutation was localized to a region on chromosome 16 containing Clcn2, a gene associated with retinal degeneration. Sequencing identified a missense C-T mutation at nucleotide 1063 in Clcn2 that converts a glutamine to a stop codon. Mice homozygous for the Clcn2nmf240 mutation experience a severe loss of photoreceptor cells at 14 days of age that is preceded by an elongation of RPE apical microvilli. Homozygous mutants also experience leukoencephalopathy in multiple brain areas and male sterility. Despite a normal retinal histology in nmf240 heterozygotes, the ERG light peak, generated by the RPE, is reduced.Conclusions. The nmf240 phenotype closely resembles that reported for Clcn2 knockout mice. The observation that heterozygous nmf240 mice present with a reduced ERG lightpeak component suggests that CLCN2 is necessary for the generation of this response component.

AB - Purpose. To determine the molecular basis and the pathologic consequences of a chemically induced mutation in a mouse model of photoreceptor degeneration, nmf240.Methods. Mice from a G3 N-ethyl-N-nitrosourea mutagenesis program were screened by indirect ophthalmoscopy for abnormal fundi. A chromosomal position for the recessive nmf240 mutatiaon was determined by a genome-wide linkage analysis by use of simple sequence length polymorphic markers in an F2 intercross. The critical region was refined, and candidate genes were screened by direct sequencing. The nmf240 phe-notype was characterized by histologic analysis of the retina, brain, and male reproductive organs and by electroretinogram (ERG)-based studies of the retina and retinal pigment epithelium (RPE).Results. Clinically, homozygous nmf240 mutants exhibit a grainy retina that progresses to panretinal patches of depig-mentation. The mutation was localized to a region on chromosome 16 containing Clcn2, a gene associated with retinal degeneration. Sequencing identified a missense C-T mutation at nucleotide 1063 in Clcn2 that converts a glutamine to a stop codon. Mice homozygous for the Clcn2nmf240 mutation experience a severe loss of photoreceptor cells at 14 days of age that is preceded by an elongation of RPE apical microvilli. Homozygous mutants also experience leukoencephalopathy in multiple brain areas and male sterility. Despite a normal retinal histology in nmf240 heterozygotes, the ERG light peak, generated by the RPE, is reduced.Conclusions. The nmf240 phenotype closely resembles that reported for Clcn2 knockout mice. The observation that heterozygous nmf240 mice present with a reduced ERG lightpeak component suggests that CLCN2 is necessary for the generation of this response component.

UR - http://www.scopus.com/inward/record.url?scp=77953262151&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953262151&partnerID=8YFLogxK

U2 - 10.1167/iovs.09-4887

DO - 10.1167/iovs.09-4887

M3 - Article

C2 - 20071672

AN - SCOPUS:77953262151

VL - 51

SP - 3264

EP - 3272

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 6

ER -