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Oculocutaneous albinism (OCA) describes a group of autosomal recessive disorders characterised by reduced or absent pigmentation of the eye, skin, and hair as a result of a congenital reduction in melanin synthesis. Additional findings in the eye include decreased visual acuity, nystagmus, iris transillumination, hypopigmentation of the uveal tract and retinal pigment epithelium, foveal hypoplasia, and abnormal decussation of the optic nerve fibres at the optic chiasm leading to a lack of binocular vision.1,2 Type I OCA results from mutations in the tyrosinase gene and leads to either total absence of tyrosinase activity (OCA Ia) associated with absence of pigmentation (“tyrosinase negative”), or a marked reduction in tyrosine activity (OCA Ib) associated with reduced pigmentation (“tyrosinase positive” or “yellow albinism”). We report a new case of the rare variant temperature sensitive albinism and our identification of missense mutations in the tyrosinase gene, not previously found in this form of albinism.
The patient, a 31 year old woman, was referred to us for genetic advice. She had originally presented at 6 weeks old with nystagmus and white hair; her parents both have dark hair and olive skin. The diagnosis of oculocutaneous albinism was made at 9 months. As she grew older the hair of her head darkened and, particularly in her teens, the hair on her lower legs and forearms darkened. As an adult she has light blonde hair, darker eye lashes and eyebrows, white axillary and pubic hair, but strongly pigmented hair on forearms and lower legs (fig 1). When examined in the clinic she had reduced visual acuity (6/36 bilaterally), marked iris translucency, and an albinotic retina with foveal hypolasia bilaterally. Visually evoked potential revealed crossed asymmetry consistent with oculocutaneous albinism. We made a diagnosis of temperature sensitive albinism and searched for mutations in the tyrosinase gene. Blood was taken, with informed consent, from the patient and her parents and DNA extracted using standard techniques. Using polymerase chain reaction we amplified each of her tyrosinase gene exons3 and sequenced the entire coding region and intron-exon boundaries. Our patient did not have the R422Q mutation previously reported in patients with this phenotype and also did not have two other mutations known to be temperature sensitive.4 We did identify two missense mutations: R217Q and A355P, in exons 1 and 3 respectively (fig 2). The exon 1 mutation had been inherited from her mother and the exon 3 mutation from her father. R217Q has been previously reported in OCA1,5 and A355P in OCA1b in a patient with “little apparent pigmentation” but with no description of the distribution of the pigmentation.6 Neither has previously been associated with a temperature sensitive phenotype.
Temperature sensitive albinism is a rare variant, first described in 19911 and subsequently associated with a particular missense mutation in the tyrosinase gene.1 The mutation, R422Q, results in a temperature sensitive trafficking defect preventing the translocation of the mutant tyrosinase into melanosomes.4 Thus, at 37°C mutant R422Q tyrosinase is retained in the endoplasmic reticulum and degraded by proteasomes and no pigment is produced. At lower temperatures (31°C) the enzyme can be successfully translocated into the melanosomes and can produce pigment. This leads to a phenotype reminiscent of the Siamese cat with no pigment centrally but pigmentation develops in the peripheries (lower legs and forearms).
Our patient is heterozygous for missense mutations in the tyrosinase gene that have both previously been reported in OCA1 but neither with a temperature sensitive phenotype. We are not aware of other patients with this particular combination of mutations. It has been shown that co-expression of wild type tyrosinase can correct the mutant conformation in temperature sensitive alleles such that exit from the endoplasmic reticulum and complex carbohydrate processing in the Golgi is promoted even at the non-permissive temperature.7 It may be that one of the mutant alleles identified in our patient modulates the expression of the other, revealing its temperature sensitive nature whereas coexpression with a different allele may give no residual activity. Alternatively, this phenotype may be much commoner than previously thought. To date there have been no studies of function or response to temperature variation of these particular mutant forms of tyrosinase. In light of the phenotype we describe here these studies would be valuable. Furthermore, it is not unusual for patients with albinism to report development of some pigmentation with age and it would be interesting to review other patients with these mutations. Unless patients with albinism are reviewed later in life this developing phenotype will not be noted.