RESUMO
Familial macular degeneration is a clinically and genetically heterogeneous group of disorders characterized by progressive central vision loss. Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of autosomal-dominant macular degeneration. In transgenic mice expressing R373C mutant human PROM1, both mutant and endogenous PROM1 were found throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments, where PROM1 is normally localized. Moreover, the outer segment disk membranes were greatly overgrown and misoriented, indicating defective disk morphogenesis. Immunoprecipitation studies showed that PROM1 interacted with protocadherin 21 (PCDH21), a photoreceptor-specific cadherin, and with actin filaments, both of which play critical roles in disk membrane morphogenesis. Collectively, our results identify what we believe to be a novel complex involved in photoreceptor disk morphogenesis and indicate a possible role for PROM1 and PCDH21 in macular degeneration.
Assuntos
Antígenos CD/genética , Glicoproteínas/genética , Degeneração Macular/genética , Mutação de Sentido Incorreto , Peptídeos/genética , Células Fotorreceptoras de Vertebrados/metabolismo , Antígeno AC133 , Citoesqueleto de Actina/metabolismo , Animais , Antígenos CD/metabolismo , Proteínas Relacionadas a Caderinas , Caderinas/metabolismo , Eletrorretinografia , Glicoproteínas/metabolismo , Humanos , Degeneração Macular/fisiopatologia , Camundongos , Camundongos Transgênicos , Morfogênese , Proteínas do Tecido Nervoso/metabolismo , Peptídeos/metabolismo , Células Fotorreceptoras de Vertebrados/ultraestruturaRESUMO
INTRODUCTION: In this paper, we report a novel VMD2 gene mutation in a Chinese family with Best vitelliform macular dystrophy. MATERIALS AND METHODS: Ophthalmologic examination and optical coherence tomography (OCT) were performed in 2 members of this family. Mutational screening was performed by single-strand conformation polymorphism (SSCP) and direct sequencing of PCR-amplified DNA fragments, corresponding to the 11 exons of the gene. RESULTS: Sequence analysis identified a previously unreported C to G change, predicting a Phe-113-Leu substitution. Both the proband and his sister harboured this novel mutation. Each had bilateral vitelliform lesions. CONCLUSIONS: A novel mutation in the VMD2 gene (C427G) was found in Chinese patients with Best vitelliform macular dystrophy.