The long term goals of this project are to uncover the molecular basis of a subset of strabismic disorders known as the congenital fibrosis syndromes and, in the process, to study the molecular basis of cranial nerve development. The congenital fibrosis syndromes are characterized by restrictive ophthalmoplegia with or without ptosis, and each disorder varies in the fixed position of the globes and in the specifically affected cranial nerves and extraocular muscles. The neuropathologic basis of the two more common fibrosis syndromes have been described; Duane syndrome, which results from absence of the abducens nerve and nucleus, and CFEOM l, which the investigator has established results from an absence of the superior division of the oculomotor nerve and corresponding oculomotor subnuclei. Clinical, radiological, surgical, and pathological data support the hypothesis that the disorders defined as CFEOM2 and CFEOM3 are also fibrosis syndromes and result from distinct, but analogous developmental defects. By linkage analysis of affected families, the investigator has mapped disease genes for CFEOM1, CFEOM2, and CFEOM3. This grant proposes to identify the CFEOM2 disease gene, as this gene is currently the most accessible of the three to positional cloning. CFEOM2 is an autosomal recessive disorder that has been identified in several consanguineous families. The gene maps to a 2.5 cM region of human chromosome 11q13, corresponding to a 1300 kb physical region, and appears to have a founder mutation.
The specific aims of this proposal are: l) to refine the genetic boundaries of the CFEOM2 disease gene by developing additional markers for linkage analysis and linkage disequilibrium studies; 2) to construct a BAC contig of the refined critical region; 3) to identify transcripts encoded within this region by exon trapping and mapping of expressed sequences, and to construct specialized fetal and embryonic tissue Northern blots to analyze and prioritize these transcripts; and 4) to identify the CFEOM2 disease gene by searching for mutations in candidate genes. Lastly, 5) functional characterization of the CFEOM2 RNA and protein product will be initiated. By cloning the CFEOM2 disease gene, the investigator hopes to define the genetic basis of this strabismic disorder, develop a handle with which to study its molecular basis and to search for related fibrosis genes, and gain important new insights into brainstem cranial nerve development.
|Di Gioia, Silvio Alessandro; Shaaban, Sherin; Tüysüz, Beyhan et al. (2018) Recessive MYF5 Mutations Cause External Ophthalmoplegia, Rib, and Vertebral Anomalies. Am J Hum Genet 103:115-124|
|Grant, P Ellen; Im, Kiho; Ahtam, Banu et al. (2018) Altered White Matter Organization in the TUBB3 E410K Syndrome. Cereb Cortex :|
|Jamuar, Saumya S; Schmitz-Abe, Klaus; D'Gama, Alissa M et al. (2017) Biallelic mutations in human DCC cause developmental split-brain syndrome. Nat Genet 49:606-612|
|Whitman, Mary C; Engle, Elizabeth C (2017) Ocular congenital cranial dysinnervation disorders (CCDDs): insights into axon growth and guidance. Hum Mol Genet 26:R37-R44|
|Whitman, Mary C; Andrews, Caroline; Chan, Wai-Man et al. (2016) Two unique TUBB3 mutations cause both CFEOM3 and malformations of cortical development. Am J Med Genet A 170A:297-305|
|Park, Jong G; Tischfield, Max A; Nugent, Alicia A et al. (2016) Loss of MAFB Function in Humans and Mice Causes Duane Syndrome, Aberrant Extraocular Muscle Innervation, and Inner-Ear Defects. Am J Hum Genet 98:1220-1227|
|Khan, Arif O; Almutlaq, Mohammed; Oystreck, Darren T et al. (2016) Retinal Dysfunction in Patients with Congenital Fibrosis of the Extraocular Muscles Type 2. Ophthalmic Genet 37:130-6|
|Balasubramanian, Ravikumar; Chew, Sheena; MacKinnon, Sarah E et al. (2015) Expanding the phenotypic spectrum and variability of endocrine abnormalities associated with TUBB3 E410K syndrome. J Clin Endocrinol Metab 100:E473-7|
|MacKinnon, Sarah; Oystreck, Darren T; Andrews, Caroline et al. (2014) Diagnostic distinctions and genetic analysis of patients diagnosed with moebius syndrome. Ophthalmology 121:1461-8|
|Thomas, Shery; Thomas, Mervyn G; Andrews, Caroline et al. (2014) Autosomal-dominant nystagmus, foveal hypoplasia and presenile cataract associated with a novel PAX6 mutation. Eur J Hum Genet 22:344-9|
Showing the most recent 10 out of 40 publications