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James A. Poulter, Alice E. Davidson, Manir Ali, Helen A. Mintz-Hittner, Louise M. Downey, Panagiotis I. Sergouniotis, Anthony T. Moore, Andrew R. Webster, Chris F. Inglehearn, Carmel Toomes; Mutational Load In TSPAN12 Influences The Severity Of FEVR. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5370.
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FEVR is an inherited blinding disorder caused by defects in the development of the retinal vasculature. The phenotypic severity seen in FEVR patients varies greatly, even between members of the same family. This has led to speculation that FEVR is not a simple Mendelian disorder and that additional genetic or environmental factors contribute to the disease severity. We have recently identified mutations in TSPAN12 as a cause of dominant FEVR. The purpose of this study was to determine the mutation spectrum in TSPAN12.
PCR products were generated from genomic DNA with primers designed to amplify the coding and flanking intronic sequences of TSPAN12. The PCR products were screened for mutations by direct sequencing.
TSPAN12 screening in a large dominant FEVR family unexpectedly led to the identification of homozygous mutations in severely affected family members, whereas mildly affected family members were heterozygous. Further screening in a cohort of ten retinal dysplasia/severe FEVR patients identified an additional three cases with recessive TSPAN12 mutations. In all examined cases, single mutation carriers were mildly affected compared to patients harbouring two TSPAN12 mutations.
Here we describe, for the first time, recessive mutations in TSPAN12, and show that patients with two mutant alleles have a severe form of FEVR more akin to retinal dysplasia, whereas heterozygous family members have milder disease phenotypes. This shows that the FEVR phenotype is sensitive to the dosage of TSPAN12 and raises the possibility that patients with severe FEVR may actually harbour two mutant alleles, derived either from the same gene or potentially from other genes encoding components of the Norrin-β-catenin signaling pathway. Correspondence: email@example.com.
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