The authors report that this Gln variant has some heat instability, with 25% enzyme activity when expressed in HeLa cells at 37C compared to 31C, while the Arg variant did not show temperature sensitivity.
These authors report the variant, along with other TYR mutants, mislocalizing to endoplasmic reticulum in COS7 cells at 37C. According to earlier publications, tyrosinase is expressed by transfection in non-pigment cells (like COS7) it is sorted to lysosomes, which is what they observed for the wildtype variant here at 37C. The variant had wildtype localization pattern at 31C.
In a study of 36 Caucasian patients with autosomal recessive ocular albinism, this variant was seen compound heterozygously with more severe variants in TYR. The authors note that 95% (20 of 21) of cases with mutations in TYR were compound heterozygous with R402Q. Out of 36 cases in total: 402Q/Q: 1, 402Q/R: 26, 402R/R: 9. The authors state that this variant has an allele frequency of ~0.278 based on dbSNP data.
Assuming that frequency is correct, their results have a significance of p = 0.0012. However, ideally the controls against which we would compare would’ve been selected by the authors to be ethnically matched — there may be some variation in allele frequency within different caucasian subpopulations.
If the incidence of ocular albinism is 1 in 1000 (0.1%), we estimate carrying this variant may have an increased attributable risk of 0.056% (total risk of 0.156%).
GWAS study, confirming and extending similar observations by Sulem et al. 2007 for this variant association with pigmentation.
Blue vs. green eyes, average odds ratio of 1.5, p=4.6e-21.
Blonde vs. brown hair, average odds ratio of 1.33, p=2.7e-5
Skin sensitivity to sun, average odds ratio of 1.25, p=7.1e-13
p < 1.5e-7 was required for genome-wide significance, so the hair pigmentation finding was not significant.
After excluding black & asian cases, they examine 23 cases with 1 or 2 mutations in this gene. 10/11 cases with just one mutation are heterozygous for this variant, the other being wildtype. The 12 that already had 2 mutations, 9 were wildtype, 2 were heterozygous, and 1 was homozygous. Grouping hets & homs together, this is case1+: 10, case1-: 1, case2+: 3, case2-: 9. This is p=0.003.
Unclear whether these represent “oculocutaneous albinism” or “ocular albinism”.