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 T. Lamb, Nicole Maphis, Jürgen K. Naggert, Patsy M. Nishina, Neal S. Peachey

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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
Issue number6
StatePublished - Jun 2010
Externally publishedYes

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience


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