Among the 121 non-Hispanic/Latino Caucasian OCA patients studied here, 69% had OCA1, 18% had OCA2, none had OCA3, 6% had OCA4, and 7% had no identifiable pathologic mutations in any of the genes studied. No patients had undiagnosed HPS1 or HPS4, and none had mutations of SILV
, a candidate OCA gene. These findings thus indicate that, contrary to long-standing clinical lore (King et al., 2001
; King and Oetting, 2006
), among Caucasian patients with OCA, the great majority has OCA1. Virtually none have OCA3.
Among patients with OCA1, about half of the patients genotypically have “tyrosinase-negative” OCA1A and about half have OCA1B, associated with low residual tyrosinase catalytic activity. Clinical distinction between these two diagnostic subcategories may be difficult in Caucasian patients, especially in patients from families with fair complexion, and indeed accuracy of these a priori clinical diagnoses was only 71%. Accuracy of clinical diagnoses was especially low among very young patients, in whom progressive pigmentation of OCA1B may not yet be evident, and among older patients, in whom age-related lightening of hair pigmentation may obscure the correct diagnosis.
We observed a diversity of pathologic mutations in each gene. Nevertheless, among the patients with OCA1, 13 mutations accounted for 62% of total alleles. T373K is most frequent overall (13.7%), which together with P81L, V275F, G446S, and IVS2-7T>A account for 41% of total mutant TYR
alleles among Caucasian patients. Similarly, among the patients with OCA2, 3 mutations accounted for most of the total, and two, V443I and G27R, accounted for half. It remains problematic that, in 17% of the OCA1 patients, 41% of the OCA2 patients, and 43% of the OCA4 patients, we were able to find only one pathologic mutation. These patients most likely are compound heterozygotes for TYR
alleles carrying occult mutations deep within the intervening sequences or regulatory elements distant from the respective structural genes that were not sequenced. Alternatively, some of these patients may have partial gene deletions not detected by PCR-based DNA sequencing, although heterozygosity patterns of common intragenic SNPs suggested that such deletions are not frequent. Interestingly, 7 of the 14 nondiagnostic TYR
alleles carried the common (q
= 0.278 among Caucasians) R402Q polymorphism, which results in a thermolabile tyrosinase polypeptide that has reduced catalytic activity at 37°C (Tripathi et al., 1991
) and which is very highly associated with TYR
-related AROA (Fukai et al., 1995
; Hutton and Spritz, 2008
). The elevated frequency (P
= 0.05) of the R402Q variant among “nondiagnostic” OCA1 alleles suggests that the R402Q variant (or an occult mutation with which it is in linkage disequilibrium) might also contribute to a more severe OCA1 phenotype in some patients.
The findings of this study are generally similar to those of a parallel study we have carried out of USA/Canada non-Hispanic/Latino Caucasian patients with AROA (Hutton and Spritz, 2008
), a disorder that represents clinically mild presentations of OCA. In a series of 37 AROA patients, 60% had pathological mutations of TYR
, 14% had mutations of OCA2
, and possibly 5% had mutations of TYRP1
, although it is not certain that these last were pathologic. Among the patients with TYR
-related AROA, 95% were compound heterozygotes for a severe OCA1-mutant allele (again, most commonly T373K) and the common R402Q polymorphic variant.
Tomita et al. (2000)
have reported a similar analysis of a series of 80 patients with the clinical diagnosis of OCA from Japan. These investigators found that, among those 80 patients, 47% had OCA1, 7.5% had OCA2 (Suzuki et al., 2003
), 24% had OCA4 (Inagaki et al., 2004
), and 12.5% had HPS1 (Ito et al., 2005
). Although superficially similar, this prevalence distribution in Japanese patients is in fact significantly different from that reported here for non-Hispanic/Latino Caucasian OCA patients (P
= 2.3E-7). Nevertheless, in both Japanese and Caucasian patients, the most prevalent form of OCA is OCA1, whereas OCA2 and OCA4 are much less frequent and OCA3 is virtually non-existent.
Our findings thus demonstrate that, among non-Hispanic/Latino Caucasian patients with either classical OCA or AROA, the great majority has OCA1, with lower percentages having other types of OCA and a few remaining diagnostically indeterminate. Furthermore, although both OCA and AROA result from a diversity of different gene mutations, for both disease presentations a relatively limited number of mutations account for the majority of mutant alleles. These findings have important implications for molecular diagnostic strategies aimed at efficient detection of mutations among Caucasian OCA patients.