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A. Garguilo, S. Montefusco, E. M. Surace; Molecular Genetics in the Italian Albino Population and Adeno-Associated Viral Vector-Based Treatment of Tyrosinase Deficient Albino Mice. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1982.
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Albinism is a recessive disorder affecting the skin, hair and eyes (Oculocutaneous albinism or OCA) or primarily the retinal pigment epithelium (RPE) of the eye (Ocular albinism or OA). Four different genes have been described as responsible for OCA: the tyrosinase (TYR) gene (OCA type 1), the P gene (OCA2), tyrosinase-related protein 1 (TYRP-1) gene (OCA3) and membrane-associated-transporter-protein (MATP) gene (OCA4); and one for the X-linked form OA: the OA1 gene (OA1). This study is aimed at determining the molecular genetics of albinism in a cohort of Italian albino patients. In parallel we are seeking whether morphological and functional abnormalities of mice carrying a lack of function mutation in the tyrosinase gene (Tyrc-2j) is reversible following AAV mediated gene transfer of the Tyr gene.
In order to identify novel and recurrent mutations present in the Italian population we carried out a direct sequencing analysis on all five genes on 22 Italian patients with a clinical diagnosis of albinism. The complete coding sequences of these genes, including the exon-intron boundaries, were amplified by PCR and sequenced. In addition in order to correct the electrophysiological anomalies and the pigmentation defect present in Tyrc-2j mice we performed a subretinal injection of adeno-associated viral vectors (AAV) harboring the human TYR gene, AAV2/1-CMV-TYR.
We identified 11 known mutations, 9 in the TYR and 2 in the P gene. Five novel nucleotide variations were found in the TYR gene, two in the P gene and one in the TYRP1 gene. We are currently assessing whether these are present in control chromosomes. In addition in 9 cases was possible to study the segregation of sequence variants in relatives. On the other hand, subretinal injection of human Tyr gene via AAV to newborn and 1 month old Tyrc-2j mouse retina resulted in melanin production in the RPE.
We identified 16 different mutations in TYR, P, and TYRP-1 genes in 90.9% of patients screened, 9 of which unknown. Subretinal injection of AAV2/1-CMV-hTYR in newborn and adult retina results in de-novo synthesis of melanin in the RPE. We are currently performing functional tests to assess whether the gene replacement in Tyrc-2j retina results also in a functional rescue.
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