Human oculocutaneous albinism caused by single base insertion in the tyrosinase gene

doi:10.1016/0006-291X(89)91767-1

Biochemical and Biophysical Research Communications

Volume 164, Issue 3, 15 November 1989, Pages 990-996

https://doi.org/10.1016/0006-291X(89)91767-1 Get rights and content

Abstract

Tyrosinase-negative oculocutaneous albinism (OCA) is an inborn error of metabolism, characterized by a complete lack of melanin pigments in the eyes and skin. We have isolated and characterized the tyrosinase gene of one affected child (S.S.) with tyrosinase-negative OCA. Sequence analysis reveals a single-base insertion in the exon 2 that shifts the reading frame and introduces a premature termination signal (TGA codon) after the amino acid residue 298. Functional analysis of the mutated gene indicates that such a truncated tyrosinase lacking one potential copper-binding region is catalytically inactive. We therefore conclude that the albino phenotype of the patient S.S. is a consequence of the inactive tyrosinase caused by the nonsense mutation in the tyrosinase gene.

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Albinism is a pigment disorder affecting eye, skin and/or hair. Patients usually have decreased melanin in affected tissues and suffer from severe visual abnormalities, including foveal hypoplasia and chiasmal misrouting. Combining our data with those of the literature, we propose a single functional genetic retinal signalling pathway that includes all 22 currently known human albinism disease genes. We hypothesise that defects affecting the genesis or function of different intra-cellular organelles, including melanosomes, cause syndromic forms of albinism (Hermansky-Pudlak (HPS) and Chediak-Higashi syndrome (CHS)). We put forward that specific melanosome impairments cause different forms of oculocutaneous albinism (OCA1-8). Further, we incorporate GPR143 that has been implicated in ocular albinism (OA1), characterised by a phenotype limited to the eye. Finally, we include the SLC38A8-associated disorder FHONDA that causes an even more restricted “albinism-related” ocular phenotype with foveal hypoplasia and chiasmal misrouting but without pigmentation defects. We propose the following retinal pigmentation pathway, with increasingly specific genetic and cellular defects causing an increasingly specific ocular phenotype: (HPS1-11/CHS: syndromic forms of albinism)-(OCA1-8: OCA)-(GPR143: OA1)-(SLC38A8: FHONDA). Beyond disease genes involvement, we also evaluate a range of (candidate) regulatory and signalling mechanisms affecting the activity of the pathway in retinal development, retinal pigmentation and albinism. We further suggest that the proposed pigmentation pathway is also involved in other retinal disorders, such as age-related macular degeneration. The hypotheses put forward in this report provide a framework for further systematic studies in albinism and melanin pigmentation disorders.
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Citation Excerpt :
According to these results, tyr and tyrp1 as tyrosine metabolism-related genes are regard as key genes which play an important role in pigment metabolic process. In human, oculocutaneous albinism (OCA) is commonly subdivided into four types based on the genes that are mutated: TYR, OCA2, TYRP1, and SLC45A2 (Tomita, Takeda, Okinaga, Tagami, & Shibahara, 1989; Rinchik et al., 1993; Boissy et al., 1996; Newton et al., 2001). In the present study, these four genes were all significantly up-regulated in both ocular-side normal skin and blind-side hypermelanotic skin, while their expression in blind-side normal skin was very low (Supplementary Fig 2; Supplementary Table 5).
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Human oculocutaneous albinism caused by single base insertion in the tyrosinase gene

Abstract

J. Biol. Chem

Biochem. Biophys. Res. Commun

Methods Enzymol

J. Biol. Chem

Am. J. Hum. Genet

Cancer Res