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A locus for autosomal recessive congenital microphthalmia maps to chromosome 14q32
D A Bessant1, S Khaliq, A Hameed
1Department of Molecular Genetics, Institute of Ophthalmology, University College, London, United Kingdom.
Abstract:
Congenital microphthalmia (CMIC) (OMIM 309700) may occur in isolation or in association with a variety of systemic malformations. Isolated CMIC may be inherited as an autosomal dominant, an autosomal recessive, or an X-linked trait. On the basis of a whole-genome linkage analysis, we have mapped the first locus for isolated CMIC, in a five-generation consanguineous family with autosomal recessive inheritance, to chromosome 14q32. All affected individuals in this family have bilateral CMIC. Linkage analysis gave a maximum two-point LOD score of 3.55 for the marker D14S65. Surrounding this marker is a region of homozygosity of 7.3 cM, between the markers D14S987 and D14S267, within which the disease gene is predicted to lie. The genes for several eye-specific transcription factors are located on human chromosome 14q and in the syntenic region of mouse chromosome 12. However, both CHX10 (14q24.3), mutations of which give rise to CMIC in mouse models, and OTX2 (14q21-22) can be excluded as candidates for autosomal recessive congenital microphthalmia (arCMIC), since they map outside the critical disease region defined by recombination events. This suggests that arCMIC is caused by defects in a novel developmental gene that may be important or even essential in eye development.
Insights
Congenital microphthalmia (CMIC) is a rare eye condition. Researchers identified a new gene locus on chromosome 14q32 responsible for autosomal recessive CMIC, crucial for eye development.
Area of Science:
- Genetics
- Ophthalmology
- Developmental Biology
Background:
- Congenital microphthalmia (CMIC) is a spectrum of ocular malformations that can occur in isolation or with systemic abnormalities.
- Isolated CMIC exhibits diverse inheritance patterns, including autosomal dominant, autosomal recessive, and X-linked traits.
- Previous genetic mapping efforts had not identified specific loci for isolated autosomal recessive CMIC.
Purpose of the Study:
- To identify the genetic locus responsible for isolated autosomal recessive congenital microphthalmia (arCMIC) in a large consanguineous family.
- To investigate the chromosomal location of the arCMIC disease gene.
- To exclude known candidate genes within the mapped region.
Main Methods:
- Whole-genome linkage analysis was performed in a five-generation family with autosomal recessive inheritance of bilateral CMIC.
- Genetic markers, including D14S65, D14S987, and D14S267, were used to analyze linkage and define the critical region.
- Candidate gene analysis was conducted for genes located on chromosome 14q, such as CHX10 and OTX2.
Main Results:
- The first locus for isolated CMIC was mapped to chromosome 14q32, with a maximum two-point LOD score of 3.55 for marker D14S65.
- A critical region of homozygosity of 7.3 cM was defined between markers D14S987 and D14S267.
- Candidate genes CHX10 and OTX2 were excluded as they map outside the critical disease region.
Conclusions:
- Autosomal recessive congenital microphthalmia in this family is caused by a defect in a novel developmental gene located on chromosome 14q32.
- This novel gene is likely essential for normal eye development.
- The identification of this locus provides a foundation for further molecular characterization of arCMIC.