A Double-Deletion Mutation in the Pitx3 Gene Causes Arrested Lens Development in Aphakia Mice

doi:10.1006/geno.2000.6464

Genomics

Volume 72, Issue 1, 15 February 2001, Pages 61-72

https://doi.org/10.1006/geno.2000.6464 Get rights and content

Abstract

The recessive aphakia (ak) mouse mutant is characterized by bilateral microphthalmia due to a failure of lens morphogenesis. We fine-mapped the ak locus to the interval between D19Umi1 and D19Mit9, developed new polymorphic markers, and mapped candidate genes by construction of a BAC contig. The Pitx3 gene, known to be expressed in lens primordia, shows zero recombination with the ak mutation on our intersubspecific intercross panel representing 1170 meioses. A recent report described a deletion in the intergenic region between Gbf1 and Pitx3 as the possible ak mutation. Our results differ in that we find not only the distant intergenic deletion, but also a much larger deletion directly in the Pitx3 gene, eliminating exon 1 and extending into intron 1 and the promoter region. Pitx3 transcript levels are severely reduced in ak/ak mice from E11.5 to newborn (5 ± 1% of the wildtype levels at E13.5), while an involvement of the flanking Gbf1 and Cig30 genes in the aberrant lens development is highly unlikely based on expression analysis. We conclude that the ak mutation consists of two deletions, the larger of which removes part of Pitx3, indicating a crucial role of this gene in early lens development.

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Citation Excerpt :
In the mouse, mutations affecting the Pitx3 gene are responsible for the aphakia (gene symbol ak) (Varnum and Stevens, 1968; Semina et al., 2000; Rieger et al., 2001), eyeless (gene symbol eyl) (Rosemann et al., 2010) and microphthalmia/aphakia (gene symbiol miak) phenotypes (Wada et al., 2014); all three mutations are of spontaneous origin and demonstrate a recessive mode of inheritance. The ak-mouse was one of the most famous eye mutants in the pre-genomic area; the molecular analysis demonstrated 2 deletions in the promotor area including the untranslated 1st exon, which leads to a loss of Pitx3 expression in the developing eye (Semina et al., 2000; Rieger et al., 2001). In the eyl-mutants, a point mutation (416insG) leads to a frame shift and therefore, to an inactive hybrid protein (Rosemann et al., 2010).
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^☆: Sequence data from this article have been deposited with the EMBL/GenBank Data Libraries under Accession No. AF306315.

¹: To whom correspondence should be addressed. Telephone: (617) 432-2088. Fax: (617) 432-0638. E-mail: [email protected].

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Regular ArticleA Double-Deletion Mutation in the Pitx3 Gene Causes Arrested Lens Development in Aphakia Mice☆

Abstract

Mech. Dev.

Lancet

Trends Genet.

Mech. Dev.

Genomics

Genomics

Blood

Trends Neurosci.

Mech. Dev.

J. Biol. Chem.

J. Biol. Chem.

Dev. Biol.

Gapped BLAST and PSI-BLAST: A new generation of protein database search programs

Nucleic Acids Res.

Lens aplasia: A new mutation producing lens abnormality in the mouse

Lab. Anim. Sci.

Apoptosis in the lens anlage of the heritable lens aplastic mouse (lap mouse)

Teratology

A family of LIM domain-associated cofactors confer transcriptional synergism between LIM and Otx homeodomain proteins

Genes Dev.

The NF-κB and IκB proteins: New discoveries and insights

Annu. Rev. Immunol.

A forkhead gene, FoxE3, is essential for lens epithelial proliferation and closure of the lens vesicle

Genes Dev.

Forkhead foxe3 maps to the dysgenetic lens locus and is critical in lens development and differentiation

Genesis

New insights into the role of nuclear factor-κB, a ubiquitous transcription factor in the initiation of diseases

Clin. Chem.

GBF1: A novel Golgi-associated BFA-resistant guanine nucleotide exchange factor that displays specificity for ADP-ribosylation factor 5

J. Cell Biol.

Genome maps IV 1993. [Wall chart]

Science

A comprehensive genetic map of the mouse genome

Nature

A genetic map of the mouse with 4,006 simple sequence length polymorphisms

Nat. Genet.

Revised nomenclature for strain 129 mice

Mamm. Genome

Abnormal eye development associated with Cat4a, a dominant mouse cataract mutation on chromosome 8

Invest. Ophthalmol. Vis. Sci.

Aphakia (ak), a mouse mutation affecting early eye development: Fine mapping, consideration of candidate genes and altered Pax6 and Six3 gene expression pattern

Dev. Genet.

A comprehensive large-insert yeast artificial chromosome library for physical mapping of the mouse genome

Mamm. Genome

Restoration of half the normal dystrophin sequence in a double-deletion Duchenne muscular dystrophy family

Am. J. Med. Genet.

Regular Article
A Double-Deletion Mutation in the Pitx3 Gene Causes Arrested Lens Development in Aphakia Mice☆