Domain disruption and mutation of the bZIP transcription factor, MAF, associated with cataract, ocular anterior segment dysgenesis and coloboma

Autor: Rahat Perveen, Martin Carette, Robyn V. Jamieson, Graeme C.M. Black, Di Donnai, Francis L. Munier, Bronwyn Kerr, Veronica van Heyningen, Jill Yardley, M. Gabriela Wirth, Elise Heon
Předmět:
Male
DNA Mutational Analysis
Molecular Sequence Data
Biology
Microphthalmia
Cataract
Dysgenesis
Anterior Eye Segment
Proto-Oncogene Proteins
Lens
Crystalline
Genetics
medicine
Humans
Amino Acid Sequence
Molecular Biology
Genetics (clinical)
Amino Acid Sequence Anterior Eye Segment/*abnormalities/embryology Base Sequence Basic-Leucine Zipper Transcription Factors Cataract/congenital/*genetics Chromosomes
Human
Pair 16/genetics Coloboma/*genetics DNA/chemistry/genetics DNA Mutational Analysis DNA-Binding Proteins/*genetics Female G-Box Binding Factors Humans Karyotyping Lens
Crystalline/growth & development/metabolism/pathology Leucine Zippers/*genetics Male Molecular Sequence Data *Mutation Pedigree Proto-Oncogene Proteins/*genetics Proto-Oncogene Proteins c-maf Sequence Homology
Amino Acid Transcription Factors/*genetics
Leucine Zippers
Coloboma
Base Sequence
Sequence Homology
Amino Acid
Chromosomal fragile site
DNA
General Medicine
Transcription Factor Maf
medicine.disease
eye diseases
Pedigree
DNA-Binding Proteins
Basic-Leucine Zipper Transcription Factors
G-Box Binding Factors
medicine.anatomical_structure
Karyotyping
Proto-Oncogene Proteins c-maf
Lens (anatomy)
Mutation
Congenital cataracts
Female
sense organs
Chromosomes
Human
Pair 16
Transcription Factors
Zdroj: Scopus-Elsevier
Human Molecular Genetics, vol. 11, no. 1, pp. 33-42
Popis: Human congenital cataract and ocular anterior segment dysgenesis both demonstrate extensive genetic and phenotypic heterogeneity. We identified a family where ocular developmental abnormalities (cataract, anterior segment dysgenesis and microphthalmia) co-segregated with a translocation, t(5;16)(p15.3;q23.2), in both balanced and unbalanced forms. We hypothesized that this altered the expression of a gene of developmental significance in the human lens and ocular anterior segment. Cloning the 16q23.2 breakpoint demonstrated that it transected the genomic-control domain of MAF, a basic region leucine zipper (bZIP) transcription factor, first identified as an oncogene, which is expressed in vertebrate lens development and regulates the expression of the eye lens crystallins. The homozygous null mutant Maf mouse embryo demonstrates defective lens formation and microphthalmia. Through mutation screening of a panel of patients with hereditary congenital cataract we identified a mutation in MAF in a three-generation family with cataract, microcornea and iris coloboma. The mutation results in the substitution of an evolutionarily highly conserved arginine with a proline at residue 288 (R288P) in the basic region of the DNA-binding domain of MAF. Our findings further implicate MAF/Maf in mammalian lens development and highlight the role of the lens in anterior segment development. The 16q23.2 breakpoint transects the common fragile site, FRA16D, providing a molecular demonstration of a germline break in a common fragile site.
Databáze: OpenAIRE
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