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Sarah DeBehnke, Brett Deml, Linda Reis, Robyn Jamieson, Elena Semina; An exploration of the role of MAB21l1 in MAC-Spectrum Anomalies. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5259.
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© ARVO (1962-2015); The Authors (2016-present)
Microphthalmia, anophthalmia and coloboma (MAC spectrum) are structural ocular disorders that are sources of childhood blindness. These disorders are highly genetically heterogeneous; however, many cases remain without genetic diagnoses. Mutations in MAB21L2 have been previously associated with MAC phenotypes in human patients and confirmed in zebrafish model. This study tested the hypothesis that MAB21L family member, MAB21L1, may also participate in ocular development and contribute to disorders.
We examined 276 human patients with developmental ocular conditions, including MAC spectrum anomalies. Samples were screened by Sanger Sequencing of full-length MAB21L1 coding region. To further study MAB21L1, we utilized zebrafish model to analyze expression and function in development. To do so, we carried out in situ hybridization of 18-72 hpf wild-type embryos using a mab21l1 probe. We also generated mab21l1-deficient lines using TALENs.
Human samples revealed one patient with a c.184C<T, p.(Arg62Cys) variant who exhibited unilateral colobomatous microphthalmia in one eye and congenital cataracts in the other. ExAC shows the variant present at low levels of the population (6/121,398 alleles). A second variant, c.658G>C, p.(G220R), was identified in a patient displaying MAC anomalies; this variant is novel and not listed in ExAC.Zebrafish expression data showed mab21l1 transcript early in the optic cup and throughout the central nervous system (CNS). As development continues, expression remains in the CNS but becomes restricted to the inner nuclear and ganglion cell layer of the retina and the ciliary marginal zone. For TALEN-generated mab21l1-deficient lines, mosaic founders were bred to generate progeny with the following germline mutations: p.(Cys35_Val37del), p.(Lys36Argfs*7), and p.(Cys35Alafs*5). Heterozygotes were bred to generate homozygous mutants/compound heterozygotes that were observed for phenotypes at embryonic and adult stages. While embryos showed no gross morphological changes, adults had reduced survival and features of microphthalmia, misshapen pupils, coloboma and corneal defects.
Our human and zebrafish data support a role for MAB21L1 in ocular development. However, protein function is currently unknown. Further functional studies are in progress, including identification of binding partners of wild-type and mutant MAB21L1 protein. This data will be presented at the conference.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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