ClinVar Genomic variation as it relates to human health

Hutton and Spritz (2008) noted that the rs1126809 variant encodes a tyrosinase enzyme with an arg402-to-gln (R402Q) substitution, resulting in a tyrosinase peptide that is thermolabile and subject to endoplasmic reticulum retention, yielding only 25% of the catalytic activity of the wildtype enzyme at 37 degrees C. The SNP is quite common among Caucasians, with an allele frequency of approximately 0.278. Oetting et al. (2009) noted that the allele frequency is much lower in African Americans (0.05) and absent in the Asian population. Oculocutaneous Albinism Type IB Fukai et al. (1995) showed that a mild form of oculocutaneous albinism 1B (OCA1B; 606952) with only ocular albinism can result from compound heterozygosity for a mutant allele of TYR and the polymorphic R402Q allele. This polymorphic allele encodes a form of tyrosinase with reduced catalytic activity. Chiang et al. (2008) reported a Hispanic family in which 2 sibs had variable manifestations of OCA1B. A 6-year-old boy had nystagmus, decreased vision, light hair, light skin color, and foveal hypoplasia. His sister had exotropia, blonde hair, light skin color, and brown irides with no history of nystagmus, foveal hypoplasia or decreased vision. Genetic analysis identified compound heterozygosity for 2 variants in the TYR gene: G47D (606933.0024) and the hypomorphic allele R402Q. Each unaffected parent was heterozygous for 1 of the variants. Chiang et al. (2008) postulated that the clinical spectrum of OCA depends on a pigmentation threshold of the affected individual, and that OCA is a quantitative trait disorder with phenotypic variation in individuals of different ethnic backgrounds. In 36 unrelated Caucasian patients with a clinical diagnosis of autosomal recessive ocular albinism (AROA), Hutton and Spritz (2008) identified 20 patients who were compound heterozygous for the R402Q variant on 1 allele and for various severe OCA1 mutations on the other allele. The authors noted that this genotypic combination should occur in approximately 1 per 280 Caucasian individuals; however, the prevalence of AROA, while unknown, is certainly lower than that, indicating that the penetrance of the AROA phenotype must be very low, given a susceptible genotype. After excluding black and Asian OCA1 patients, Chiang et al. (2009) identified 23 OCA patients in their database with 1 or 2 TYR mutations. The authors found that 10 of the 11 patients with only 1 TYR mutation were heterozygous for the R402Q allele, whereas among the 12 patients with 2 mutations in TYR, 2 were heterozygous and 1 homozygous for R402Q, and 9 did not carry the R402Q allele. Chiang et al. (2009) concluded that the R402Q allele is strongly associated with albinism patients who have only 1 mutation in TYR. Oetting et al. (2009) analyzed the segregation of the Q402 allele in 12 families with oculocutaneous albinism type I in which all parents were unaffected with normal visual acuity. In 9 families, 1 parent in each sibship had a pathologic mutation on 1 allele and the Q402 allele in trans, yet none had hypopigmentation or the presence of abnormal visual acuity and fovial hypoplasia. In the remaining 3 families, 2 of which were previously studied by Hutton and Spritz (2008), the maternal mutation was not identified: in 1 family, the unaffected mother was homozygous for Q402 and also presumably carried an unidentified pathologic mutation; in another, the normal father had a pathologic mutation on 1 allele and Q402 in trans; and in the last family, the unaffected mother carried R402 on the allele presumably containing an unidentified mutation that was passed to her child, and Q402 in trans on the untransmitted allele. Oetting et al. (2009) concluded that the R402Q variant of TYR is not associated with autosomal recessive ocular albinism (AROA) but suggested that a causative variant may be in genetic disequilibrium with the R402Q variant. In 31 Caucasian patients with 1 or 2 mutations in the TYR gene, Simeonov et al. (2013) found that the R402Q allele was more frequent in the group with 1 mutation (50%) compared to the group with 2 mutations (10%). In 5 patients with no mutation in TYR who did not have paired trans-mutation in another OCA gene, they found that 40% of alleles had R402Q. Morell et al. (1997) found that the family reported by Bard (1978) with a combination of congenital deafness and ocular albinism had a syndrome apparently due to digenic inheritance. Affected individuals had features consistent with Waardenburg syndrome type 2 (WS2A; 193510) and ocular albinism; they were heterozygous for a 1-bp deletion in the MITF gene (156845.0005) and homozygous or heterozygous for the R402Q mutation. The transcription factor MITF regulates the expression of the TYR gene. Temperature-Sensitive Oculocutaneous Albinism In an unusual subset of oculocutaneous albinism type I, designated OCA1-TS (see 606952), mutations in the TYR gene render tyrosinase temperature-sensitive (ts). Consequently, melanin synthesis occurs only in cooler areas of the body, such as the arms and legs. The resultant pattern of peripheral pigmentation is analogous to that of the Siamese cat and the Himalayan mouse. Both the R402Q variant and the similar but less prevalent R422Q variant (606933.0012) are temperature-sensitive. The R402Q variant represents approximately 15% of the gene pool among Caucasians (King et al., 1991). Berson et al. (2000) analyzed the localization and processing of the R402Q variant and showed that the ts phenotype is due to a defect in protein folding that prevents exit from the endoplasmic reticulum (ER). The partial ts phenotype of a wildtype allelic form of tyrosinase and the lack of an apparent significant increase in ER-associated degradation of the R402Q variant suggested that it exaggerates an inefficient folding process inherent in human tyrosinase when expressed in nonmelanogenic cells. Variation in Skin/Hair/Eye Pigmentation In a genomewide association study using Icelandic and Dutch population samples, Sulem et al. (2007) found an association of the TYR SNP rs1042602 (S192Y; 606933.0008) with freckling (SHEP3; 601800). They also found strong correlation (r(2) = 0.86) of the TYR SNP rs1393350 with the TYR SNP rs1126809 (R402Q). Sulem et al. (2008) presented results from a genomewide association study for variants associated with human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals. The rs1126809 R402Q variant showed genomewide significance for association with skin sensitivity to sun (p = 7.1 x 10(-13)) and blue versus green eye color (p = 4.6 x 10(-21)). Susceptibility to Cutaneous Malignant Melanoma In a study of the effect of pigmentation-associated genetic sequence variants on risk of cutaneous melanoma (see 601800) and basal cell carcinoma, Gudbjartsson et al. (2008) found that the R402Q variant of TYR, previously shown to affect eye color and tanning response, conferred risk of cutaneous melanoma (odds ratio = 1.21, p = 2.8 x 10(-7)) and basal cell carcinoma (odds ratio = 1.14, p = 6.1 x 10(-4)). (less)

Hutton and Spritz (2008) noted that the rs1126809 variant encodes a tyrosinase enzyme with an arg402-to-gln (R402Q) substitution, resulting in a tyrosinase peptide that is thermolabile and subject to endoplasmic reticulum retention, yielding only 25% of the catalytic activity of the wildtype enzyme at 37 degrees C. The SNP is quite common among Caucasians, with an allele frequency of approximately 0.278. Oetting et al. (2009) noted that the allele frequency is much lower in African Americans (0.05) and absent in the Asian population. Oculocutaneous Albinism Type IB Fukai et al. (1995) showed that a mild form of oculocutaneous albinism 1B (OCA1B; 606952) with only ocular albinism can result from compound heterozygosity for a mutant allele of TYR and the polymorphic R402Q allele. This polymorphic allele encodes a form of tyrosinase with reduced catalytic activity. Chiang et al. (2008) reported a Hispanic family in which 2 sibs had variable manifestations of OCA1B. A 6-year-old boy had nystagmus, decreased vision, light hair, light skin color, and foveal hypoplasia. His sister had exotropia, blonde hair, light skin color, and brown irides with no history of nystagmus, foveal hypoplasia or decreased vision. Genetic analysis identified compound heterozygosity for 2 variants in the TYR gene: G47D (606933.0024) and the hypomorphic allele R402Q. Each unaffected parent was heterozygous for 1 of the variants. Chiang et al. (2008) postulated that the clinical spectrum of OCA depends on a pigmentation threshold of the affected individual, and that OCA is a quantitative trait disorder with phenotypic variation in individuals of different ethnic backgrounds. In 36 unrelated Caucasian patients with a clinical diagnosis of autosomal recessive ocular albinism (AROA), Hutton and Spritz (2008) identified 20 patients who were compound heterozygous for the R402Q variant on 1 allele and for various severe OCA1 mutations on the other allele. The authors noted that this genotypic combination should occur in approximately 1 per 280 Caucasian individuals; however, the prevalence of AROA, while unknown, is certainly lower than that, indicating that the penetrance of the AROA phenotype must be very low, given a susceptible genotype. After excluding black and Asian OCA1 patients, Chiang et al. (2009) identified 23 OCA patients in their database with 1 or 2 TYR mutations. The authors found that 10 of the 11 patients with only 1 TYR mutation were heterozygous for the R402Q allele, whereas among the 12 patients with 2 mutations in TYR, 2 were heterozygous and 1 homozygous for R402Q, and 9 did not carry the R402Q allele. Chiang et al. (2009) concluded that the R402Q allele is strongly associated with albinism patients who have only 1 mutation in TYR. Oetting et al. (2009) analyzed the segregation of the Q402 allele in 12 families with oculocutaneous albinism type I in which all parents were unaffected with normal visual acuity. In 9 families, 1 parent in each sibship had a pathologic mutation on 1 allele and the Q402 allele in trans, yet none had hypopigmentation or the presence of abnormal visual acuity and fovial hypoplasia. In the remaining 3 families, 2 of which were previously studied by Hutton and Spritz (2008), the maternal mutation was not identified: in 1 family, the unaffected mother was homozygous for Q402 and also presumably carried an unidentified pathologic mutation; in another, the normal father had a pathologic mutation on 1 allele and Q402 in trans; and in the last family, the unaffected mother carried R402 on the allele presumably containing an unidentified mutation that was passed to her child, and Q402 in trans on the untransmitted allele. Oetting et al. (2009) concluded that the R402Q variant of TYR is not associated with autosomal recessive ocular albinism (AROA) but suggested that a causative variant may be in genetic disequilibrium with the R402Q variant. In 31 Caucasian patients with 1 or 2 mutations in the TYR gene, Simeonov et al. (2013) found that the R402Q allele was more frequent in the group with 1 mutation (50%) compared to the group with 2 mutations (10%). In 5 patients with no mutation in TYR who did not have paired trans-mutation in another OCA gene, they found that 40% of alleles had R402Q. Morell et al. (1997) found that the family reported by Bard (1978) with a combination of congenital deafness and ocular albinism had a syndrome apparently due to digenic inheritance. Affected individuals had features consistent with Waardenburg syndrome type 2 (WS2A; 193510) and ocular albinism; they were heterozygous for a 1-bp deletion in the MITF gene (156845.0005) and homozygous or heterozygous for the R402Q mutation. The transcription factor MITF regulates the expression of the TYR gene. Temperature-Sensitive Oculocutaneous Albinism In an unusual subset of oculocutaneous albinism type I, designated OCA1-TS (see 606952), mutations in the TYR gene render tyrosinase temperature-sensitive (ts). Consequently, melanin synthesis occurs only in cooler areas of the body, such as the arms and legs. The resultant pattern of peripheral pigmentation is analogous to that of the Siamese cat and the Himalayan mouse. Both the R402Q variant and the similar but less prevalent R422Q variant (606933.0012) are temperature-sensitive. The R402Q variant represents approximately 15% of the gene pool among Caucasians (King et al., 1991). Berson et al. (2000) analyzed the localization and processing of the R402Q variant and showed that the ts phenotype is due to a defect in protein folding that prevents exit from the endoplasmic reticulum (ER). The partial ts phenotype of a wildtype allelic form of tyrosinase and the lack of an apparent significant increase in ER-associated degradation of the R402Q variant suggested that it exaggerates an inefficient folding process inherent in human tyrosinase when expressed in nonmelanogenic cells. Variation in Skin/Hair/Eye Pigmentation In a genomewide association study using Icelandic and Dutch population samples, Sulem et al. (2007) found an association of the TYR SNP rs1042602 (S192Y; 606933.0008) with freckling (SHEP3; 601800). They also found strong correlation (r(2) = 0.86) of the TYR SNP rs1393350 with the TYR SNP rs1126809 (R402Q). Sulem et al. (2008) presented results from a genomewide association study for variants associated with human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals. The rs1126809 R402Q variant showed genomewide significance for association with skin sensitivity to sun (p = 7.1 x 10(-13)) and blue versus green eye color (p = 4.6 x 10(-21)). Susceptibility to Cutaneous Malignant Melanoma In a study of the effect of pigmentation-associated genetic sequence variants on risk of cutaneous melanoma (see 601800) and basal cell carcinoma, Gudbjartsson et al. (2008) found that the R402Q variant of TYR, previously shown to affect eye color and tanning response, conferred risk of cutaneous melanoma (odds ratio = 1.21, p = 2.8 x 10(-7)) and basal cell carcinoma (odds ratio = 1.14, p = 6.1 x 10(-4)). (less)

Hutton and Spritz (2008) noted that the rs1126809 variant encodes a tyrosinase enzyme with an arg402-to-gln (R402Q) substitution, resulting in a tyrosinase peptide that is thermolabile and subject to endoplasmic reticulum retention, yielding only 25% of the catalytic activity of the wildtype enzyme at 37 degrees C. The SNP is quite common among Caucasians, with an allele frequency of approximately 0.278. Oetting et al. (2009) noted that the allele frequency is much lower in African Americans (0.05) and absent in the Asian population. Oculocutaneous Albinism Type IB Fukai et al. (1995) showed that a mild form of oculocutaneous albinism 1B (OCA1B; 606952) with only ocular albinism can result from compound heterozygosity for a mutant allele of TYR and the polymorphic R402Q allele. This polymorphic allele encodes a form of tyrosinase with reduced catalytic activity. Chiang et al. (2008) reported a Hispanic family in which 2 sibs had variable manifestations of OCA1B. A 6-year-old boy had nystagmus, decreased vision, light hair, light skin color, and foveal hypoplasia. His sister had exotropia, blonde hair, light skin color, and brown irides with no history of nystagmus, foveal hypoplasia or decreased vision. Genetic analysis identified compound heterozygosity for 2 variants in the TYR gene: G47D (606933.0024) and the hypomorphic allele R402Q. Each unaffected parent was heterozygous for 1 of the variants. Chiang et al. (2008) postulated that the clinical spectrum of OCA depends on a pigmentation threshold of the affected individual, and that OCA is a quantitative trait disorder with phenotypic variation in individuals of different ethnic backgrounds. In 36 unrelated Caucasian patients with a clinical diagnosis of autosomal recessive ocular albinism (AROA), Hutton and Spritz (2008) identified 20 patients who were compound heterozygous for the R402Q variant on 1 allele and for various severe OCA1 mutations on the other allele. The authors noted that this genotypic combination should occur in approximately 1 per 280 Caucasian individuals; however, the prevalence of AROA, while unknown, is certainly lower than that, indicating that the penetrance of the AROA phenotype must be very low, given a susceptible genotype. After excluding black and Asian OCA1 patients, Chiang et al. (2009) identified 23 OCA patients in their database with 1 or 2 TYR mutations. The authors found that 10 of the 11 patients with only 1 TYR mutation were heterozygous for the R402Q allele, whereas among the 12 patients with 2 mutations in TYR, 2 were heterozygous and 1 homozygous for R402Q, and 9 did not carry the R402Q allele. Chiang et al. (2009) concluded that the R402Q allele is strongly associated with albinism patients who have only 1 mutation in TYR. Oetting et al. (2009) analyzed the segregation of the Q402 allele in 12 families with oculocutaneous albinism type I in which all parents were unaffected with normal visual acuity. In 9 families, 1 parent in each sibship had a pathologic mutation on 1 allele and the Q402 allele in trans, yet none had hypopigmentation or the presence of abnormal visual acuity and fovial hypoplasia. In the remaining 3 families, 2 of which were previously studied by Hutton and Spritz (2008), the maternal mutation was not identified: in 1 family, the unaffected mother was homozygous for Q402 and also presumably carried an unidentified pathologic mutation; in another, the normal father had a pathologic mutation on 1 allele and Q402 in trans; and in the last family, the unaffected mother carried R402 on the allele presumably containing an unidentified mutation that was passed to her child, and Q402 in trans on the untransmitted allele. Oetting et al. (2009) concluded that the R402Q variant of TYR is not associated with autosomal recessive ocular albinism (AROA) but suggested that a causative variant may be in genetic disequilibrium with the R402Q variant. In 31 Caucasian patients with 1 or 2 mutations in the TYR gene, Simeonov et al. (2013) found that the R402Q allele was more frequent in the group with 1 mutation (50%) compared to the group with 2 mutations (10%). In 5 patients with no mutation in TYR who did not have paired trans-mutation in another OCA gene, they found that 40% of alleles had R402Q. Morell et al. (1997) found that the family reported by Bard (1978) with a combination of congenital deafness and ocular albinism had a syndrome apparently due to digenic inheritance. Affected individuals had features consistent with Waardenburg syndrome type 2 (WS2A; 193510) and ocular albinism; they were heterozygous for a 1-bp deletion in the MITF gene (156845.0005) and homozygous or heterozygous for the R402Q mutation. The transcription factor MITF regulates the expression of the TYR gene. Temperature-Sensitive Oculocutaneous Albinism In an unusual subset of oculocutaneous albinism type I, designated OCA1-TS (see 606952), mutations in the TYR gene render tyrosinase temperature-sensitive (ts). Consequently, melanin synthesis occurs only in cooler areas of the body, such as the arms and legs. The resultant pattern of peripheral pigmentation is analogous to that of the Siamese cat and the Himalayan mouse. Both the R402Q variant and the similar but less prevalent R422Q variant (606933.0012) are temperature-sensitive. The R402Q variant represents approximately 15% of the gene pool among Caucasians (King et al., 1991). Berson et al. (2000) analyzed the localization and processing of the R402Q variant and showed that the ts phenotype is due to a defect in protein folding that prevents exit from the endoplasmic reticulum (ER). The partial ts phenotype of a wildtype allelic form of tyrosinase and the lack of an apparent significant increase in ER-associated degradation of the R402Q variant suggested that it exaggerates an inefficient folding process inherent in human tyrosinase when expressed in nonmelanogenic cells. Variation in Skin/Hair/Eye Pigmentation In a genomewide association study using Icelandic and Dutch population samples, Sulem et al. (2007) found an association of the TYR SNP rs1042602 (S192Y; 606933.0008) with freckling (SHEP3; 601800). They also found strong correlation (r(2) = 0.86) of the TYR SNP rs1393350 with the TYR SNP rs1126809 (R402Q). Sulem et al. (2008) presented results from a genomewide association study for variants associated with human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals. The rs1126809 R402Q variant showed genomewide significance for association with skin sensitivity to sun (p = 7.1 x 10(-13)) and blue versus green eye color (p = 4.6 x 10(-21)). Susceptibility to Cutaneous Malignant Melanoma In a study of the effect of pigmentation-associated genetic sequence variants on risk of cutaneous melanoma (see 601800) and basal cell carcinoma, Gudbjartsson et al. (2008) found that the R402Q variant of TYR, previously shown to affect eye color and tanning response, conferred risk of cutaneous melanoma (odds ratio = 1.21, p = 2.8 x 10(-7)) and basal cell carcinoma (odds ratio = 1.14, p = 6.1 x 10(-4)). (less)

Hutton and Spritz (2008) noted that the rs1126809 variant encodes a tyrosinase enzyme with an arg402-to-gln (R402Q) substitution, resulting in a tyrosinase peptide that is thermolabile and subject to endoplasmic reticulum retention, yielding only 25% of the catalytic activity of the wildtype enzyme at 37 degrees C. The SNP is quite common among Caucasians, with an allele frequency of approximately 0.278. Oetting et al. (2009) noted that the allele frequency is much lower in African Americans (0.05) and absent in the Asian population. Oculocutaneous Albinism Type IB Fukai et al. (1995) showed that a mild form of oculocutaneous albinism 1B (OCA1B; 606952) with only ocular albinism can result from compound heterozygosity for a mutant allele of TYR and the polymorphic R402Q allele. This polymorphic allele encodes a form of tyrosinase with reduced catalytic activity. Chiang et al. (2008) reported a Hispanic family in which 2 sibs had variable manifestations of OCA1B. A 6-year-old boy had nystagmus, decreased vision, light hair, light skin color, and foveal hypoplasia. His sister had exotropia, blonde hair, light skin color, and brown irides with no history of nystagmus, foveal hypoplasia or decreased vision. Genetic analysis identified compound heterozygosity for 2 variants in the TYR gene: G47D (606933.0024) and the hypomorphic allele R402Q. Each unaffected parent was heterozygous for 1 of the variants. Chiang et al. (2008) postulated that the clinical spectrum of OCA depends on a pigmentation threshold of the affected individual, and that OCA is a quantitative trait disorder with phenotypic variation in individuals of different ethnic backgrounds. In 36 unrelated Caucasian patients with a clinical diagnosis of autosomal recessive ocular albinism (AROA), Hutton and Spritz (2008) identified 20 patients who were compound heterozygous for the R402Q variant on 1 allele and for various severe OCA1 mutations on the other allele. The authors noted that this genotypic combination should occur in approximately 1 per 280 Caucasian individuals; however, the prevalence of AROA, while unknown, is certainly lower than that, indicating that the penetrance of the AROA phenotype must be very low, given a susceptible genotype. After excluding black and Asian OCA1 patients, Chiang et al. (2009) identified 23 OCA patients in their database with 1 or 2 TYR mutations. The authors found that 10 of the 11 patients with only 1 TYR mutation were heterozygous for the R402Q allele, whereas among the 12 patients with 2 mutations in TYR, 2 were heterozygous and 1 homozygous for R402Q, and 9 did not carry the R402Q allele. Chiang et al. (2009) concluded that the R402Q allele is strongly associated with albinism patients who have only 1 mutation in TYR. Oetting et al. (2009) analyzed the segregation of the Q402 allele in 12 families with oculocutaneous albinism type I in which all parents were unaffected with normal visual acuity. In 9 families, 1 parent in each sibship had a pathologic mutation on 1 allele and the Q402 allele in trans, yet none had hypopigmentation or the presence of abnormal visual acuity and fovial hypoplasia. In the remaining 3 families, 2 of which were previously studied by Hutton and Spritz (2008), the maternal mutation was not identified: in 1 family, the unaffected mother was homozygous for Q402 and also presumably carried an unidentified pathologic mutation; in another, the normal father had a pathologic mutation on 1 allele and Q402 in trans; and in the last family, the unaffected mother carried R402 on the allele presumably containing an unidentified mutation that was passed to her child, and Q402 in trans on the untransmitted allele. Oetting et al. (2009) concluded that the R402Q variant of TYR is not associated with autosomal recessive ocular albinism (AROA) but suggested that a causative variant may be in genetic disequilibrium with the R402Q variant. In 31 Caucasian patients with 1 or 2 mutations in the TYR gene, Simeonov et al. (2013) found that the R402Q allele was more frequent in the group with 1 mutation (50%) compared to the group with 2 mutations (10%). In 5 patients with no mutation in TYR who did not have paired trans-mutation in another OCA gene, they found that 40% of alleles had R402Q. Morell et al. (1997) found that the family reported by Bard (1978) with a combination of congenital deafness and ocular albinism had a syndrome apparently due to digenic inheritance. Affected individuals had features consistent with Waardenburg syndrome type 2 (WS2A; 193510) and ocular albinism; they were heterozygous for a 1-bp deletion in the MITF gene (156845.0005) and homozygous or heterozygous for the R402Q mutation. The transcription factor MITF regulates the expression of the TYR gene. Temperature-Sensitive Oculocutaneous Albinism In an unusual subset of oculocutaneous albinism type I, designated OCA1-TS (see 606952), mutations in the TYR gene render tyrosinase temperature-sensitive (ts). Consequently, melanin synthesis occurs only in cooler areas of the body, such as the arms and legs. The resultant pattern of peripheral pigmentation is analogous to that of the Siamese cat and the Himalayan mouse. Both the R402Q variant and the similar but less prevalent R422Q variant (606933.0012) are temperature-sensitive. The R402Q variant represents approximately 15% of the gene pool among Caucasians (King et al., 1991). Berson et al. (2000) analyzed the localization and processing of the R402Q variant and showed that the ts phenotype is due to a defect in protein folding that prevents exit from the endoplasmic reticulum (ER). The partial ts phenotype of a wildtype allelic form of tyrosinase and the lack of an apparent significant increase in ER-associated degradation of the R402Q variant suggested that it exaggerates an inefficient folding process inherent in human tyrosinase when expressed in nonmelanogenic cells. Variation in Skin/Hair/Eye Pigmentation In a genomewide association study using Icelandic and Dutch population samples, Sulem et al. (2007) found an association of the TYR SNP rs1042602 (S192Y; 606933.0008) with freckling (SHEP3; 601800). They also found strong correlation (r(2) = 0.86) of the TYR SNP rs1393350 with the TYR SNP rs1126809 (R402Q). Sulem et al. (2008) presented results from a genomewide association study for variants associated with human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals. The rs1126809 R402Q variant showed genomewide significance for association with skin sensitivity to sun (p = 7.1 x 10(-13)) and blue versus green eye color (p = 4.6 x 10(-21)). Susceptibility to Cutaneous Malignant Melanoma In a study of the effect of pigmentation-associated genetic sequence variants on risk of cutaneous melanoma (see 601800) and basal cell carcinoma, Gudbjartsson et al. (2008) found that the R402Q variant of TYR, previously shown to affect eye color and tanning response, conferred risk of cutaneous melanoma (odds ratio = 1.21, p = 2.8 x 10(-7)) and basal cell carcinoma (odds ratio = 1.14, p = 6.1 x 10(-4)). (less)

Hutton and Spritz (2008) noted that the rs1126809 variant encodes a tyrosinase enzyme with an arg402-to-gln (R402Q) substitution, resulting in a tyrosinase peptide that is thermolabile and subject to endoplasmic reticulum retention, yielding only 25% of the catalytic activity of the wildtype enzyme at 37 degrees C. The SNP is quite common among Caucasians, with an allele frequency of approximately 0.278. Oetting et al. (2009) noted that the allele frequency is much lower in African Americans (0.05) and absent in the Asian population. Oculocutaneous Albinism Type IB Fukai et al. (1995) showed that a mild form of oculocutaneous albinism 1B (OCA1B; 606952) with only ocular albinism can result from compound heterozygosity for a mutant allele of TYR and the polymorphic R402Q allele. This polymorphic allele encodes a form of tyrosinase with reduced catalytic activity. Chiang et al. (2008) reported a Hispanic family in which 2 sibs had variable manifestations of OCA1B. A 6-year-old boy had nystagmus, decreased vision, light hair, light skin color, and foveal hypoplasia. His sister had exotropia, blonde hair, light skin color, and brown irides with no history of nystagmus, foveal hypoplasia or decreased vision. Genetic analysis identified compound heterozygosity for 2 variants in the TYR gene: G47D (606933.0024) and the hypomorphic allele R402Q. Each unaffected parent was heterozygous for 1 of the variants. Chiang et al. (2008) postulated that the clinical spectrum of OCA depends on a pigmentation threshold of the affected individual, and that OCA is a quantitative trait disorder with phenotypic variation in individuals of different ethnic backgrounds. In 36 unrelated Caucasian patients with a clinical diagnosis of autosomal recessive ocular albinism (AROA), Hutton and Spritz (2008) identified 20 patients who were compound heterozygous for the R402Q variant on 1 allele and for various severe OCA1 mutations on the other allele. The authors noted that this genotypic combination should occur in approximately 1 per 280 Caucasian individuals; however, the prevalence of AROA, while unknown, is certainly lower than that, indicating that the penetrance of the AROA phenotype must be very low, given a susceptible genotype. After excluding black and Asian OCA1 patients, Chiang et al. (2009) identified 23 OCA patients in their database with 1 or 2 TYR mutations. The authors found that 10 of the 11 patients with only 1 TYR mutation were heterozygous for the R402Q allele, whereas among the 12 patients with 2 mutations in TYR, 2 were heterozygous and 1 homozygous for R402Q, and 9 did not carry the R402Q allele. Chiang et al. (2009) concluded that the R402Q allele is strongly associated with albinism patients who have only 1 mutation in TYR. Oetting et al. (2009) analyzed the segregation of the Q402 allele in 12 families with oculocutaneous albinism type I in which all parents were unaffected with normal visual acuity. In 9 families, 1 parent in each sibship had a pathologic mutation on 1 allele and the Q402 allele in trans, yet none had hypopigmentation or the presence of abnormal visual acuity and fovial hypoplasia. In the remaining 3 families, 2 of which were previously studied by Hutton and Spritz (2008), the maternal mutation was not identified: in 1 family, the unaffected mother was homozygous for Q402 and also presumably carried an unidentified pathologic mutation; in another, the normal father had a pathologic mutation on 1 allele and Q402 in trans; and in the last family, the unaffected mother carried R402 on the allele presumably containing an unidentified mutation that was passed to her child, and Q402 in trans on the untransmitted allele. Oetting et al. (2009) concluded that the R402Q variant of TYR is not associated with autosomal recessive ocular albinism (AROA) but suggested that a causative variant may be in genetic disequilibrium with the R402Q variant. In 31 Caucasian patients with 1 or 2 mutations in the TYR gene, Simeonov et al. (2013) found that the R402Q allele was more frequent in the group with 1 mutation (50%) compared to the group with 2 mutations (10%). In 5 patients with no mutation in TYR who did not have paired trans-mutation in another OCA gene, they found that 40% of alleles had R402Q. Morell et al. (1997) found that the family reported by Bard (1978) with a combination of congenital deafness and ocular albinism had a syndrome apparently due to digenic inheritance. Affected individuals had features consistent with Waardenburg syndrome type 2 (WS2A; 193510) and ocular albinism; they were heterozygous for a 1-bp deletion in the MITF gene (156845.0005) and homozygous or heterozygous for the R402Q mutation. The transcription factor MITF regulates the expression of the TYR gene. Temperature-Sensitive Oculocutaneous Albinism In an unusual subset of oculocutaneous albinism type I, designated OCA1-TS (see 606952), mutations in the TYR gene render tyrosinase temperature-sensitive (ts). Consequently, melanin synthesis occurs only in cooler areas of the body, such as the arms and legs. The resultant pattern of peripheral pigmentation is analogous to that of the Siamese cat and the Himalayan mouse. Both the R402Q variant and the similar but less prevalent R422Q variant (606933.0012) are temperature-sensitive. The R402Q variant represents approximately 15% of the gene pool among Caucasians (King et al., 1991). Berson et al. (2000) analyzed the localization and processing of the R402Q variant and showed that the ts phenotype is due to a defect in protein folding that prevents exit from the endoplasmic reticulum (ER). The partial ts phenotype of a wildtype allelic form of tyrosinase and the lack of an apparent significant increase in ER-associated degradation of the R402Q variant suggested that it exaggerates an inefficient folding process inherent in human tyrosinase when expressed in nonmelanogenic cells. Variation in Skin/Hair/Eye Pigmentation In a genomewide association study using Icelandic and Dutch population samples, Sulem et al. (2007) found an association of the TYR SNP rs1042602 (S192Y; 606933.0008) with freckling (SHEP3; 601800). They also found strong correlation (r(2) = 0.86) of the TYR SNP rs1393350 with the TYR SNP rs1126809 (R402Q). Sulem et al. (2008) presented results from a genomewide association study for variants associated with human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals. The rs1126809 R402Q variant showed genomewide significance for association with skin sensitivity to sun (p = 7.1 x 10(-13)) and blue versus green eye color (p = 4.6 x 10(-21)). Susceptibility to Cutaneous Malignant Melanoma In a study of the effect of pigmentation-associated genetic sequence variants on risk of cutaneous melanoma (see 601800) and basal cell carcinoma, Gudbjartsson et al. (2008) found that the R402Q variant of TYR, previously shown to affect eye color and tanning response, conferred risk of cutaneous melanoma (odds ratio = 1.21, p = 2.8 x 10(-7)) and basal cell carcinoma (odds ratio = 1.14, p = 6.1 x 10(-4)). (less)