Study Group 4

Pathological analysis of oculocutaneous albinism and research toward treatment

Team leader: Kazuyoshi Fukai

There are several types of oculocutaneous albinism (OCA). OCA1A, which is caused by mutations in the tyrosinase gene, is known for the lack of melanin synthesis, making the hair white and vision impairment severe. In tyrosinase missense mutations, tyrosinase proteins undergo misfolding. Normal tyrosinase proteins are transported from the endoplasmic reticulum (ER) to the Golgi apparatus and on to the melanosome, whereas misfolded tyrosinase proteins are retained in the ER. Various missense mutations, including R77Q, P431L, R239W, D383N, and R295S, are known to occur in Japanese OCA1 patients.

In my research I have shown that tyrosinase gene polymorphism is responsible for autosomal recessive ocular albinism (Nature Genet 1995), and have performed analysis of mutations in OCA1 (Human Mutation 1997). I have also published studies on OCA2, for which the P gene is responsible (Genomics 1995, Am J Hum Genet 1995, Human Mutation 1997, J Med Genet 2000, Am J Med Genet 2001, J Dermatol Sci 2003, Am J Med Genet A 2003, Am J Med Genet A 2004). In further research I have carried out pathological analysis of OCA4 (Br J Dermatol 2005, Pigment Cell Res 2005), Hermansky–Pudlak syndrome (Hum Mol Genet 1995, Nature Genet 1996, J Invest Dermatol 1997, Br J Dermatol 2000), and Chediak–Higashi syndrome (J Dermatol 1993, Am J Hum Genet 1996, Am J Med Genet 2002). However, it has proved very difficult to treat albinism; even with gene therapy or treatment using iPS cells, it is extremely hard to find ways to distribute the cells to the skin over the entire body and to the eyes.

Recently, a treatment known as pharmacologic chaperone therapy has been tried for lysosomal storage diseases such as Gaucher’s disease. Pharmacologic chaperones are small compounds that enable misfolded mutant proteins in the ER to be folded like normal proteins. The ER has a neutral environment and the lysosome an acidic environment, and misfolded proteins can take their normal folded form in an acidic environment. Since melanosomes are intracellular organelles derived from lysosomes and their interior is known to be acidic, it is thought that pharmacologic chaperone therapy will be as effective in OCA1 as in Gaucher’s disease.

Compounds that are structurally similar to tyrosine, the substrate for tyrosinase, and that can bind to tyrosinase “loosely” are expected to function as pharmacologic chaperones. We are performing basic experiments to find out whether these candidate compounds show pharmacologic chaperone effects and help restore melanin synthesis. We believe that the time will come when OCA1 can be treated with an oral drug.

Treatment of albinism with pharmacologic chaperones

In OCA1, which is caused by mutations in the tyrosinase gene, tyrosinase proteins resulting from missense mutation build up in the ER. When pharmacologic chaperones are added, they bind to mutant tyrosinase proteins, enabling these proteins to be folded normally and sent through the Golgi apparatus and on to the melanosome. The ER has a neutral environment, whereas the melanosome has an acidic environment. In this acidic environment, mutant tyrosinase proteins are expected to take on the normal folded structure, show enzyme activity, and produce melanin within the melanosome. In this way, we believe that albinism can be treated with oral drugs.

Revised from: FEBS Journal 274(2007)4944-4950