DiagnosisClinical DiagnosisThe diagnosis of oculocutaneous albinism type 1 (OCA1) [Creel et al 1990] is established by the presence of the following:Hypopigmentation of the skin and hair (including brows and lashes) on physical examinationInfantile nystagmus (usually noticed between ages 3 and 12 weeks)Markedly reduced iris pigment with iris transilluminationReduced retinal (pigment epithelial) pigmentation with visualization of the choroidal blood vessels on ophthalmoscopic examination Foveal hypoplasia associated with substantial reduction in visual acuityMisrouting of the optic nerve fiber projections at the optic chiasm frequently associated with strabismus (that may not develop until later in infancy), reduced stereoscopic vision, and altered visually evoked potentials (VEP)
Note: The VEP is performed with a technique specifically designed to demonstrate selective misrouting; thus, a conventional simultaneous binocular VEP will not demonstrate this anomaly. Normal routing of the optic nerves, demonstrated with a selective VEP, excludes the diagnosis of albinism/OCA. The VEP is not necessary for the diagnosis of albinism because misrouting is implied by the observation of strabismus and reduced stereoscopic vision. In some persons with mild hypopigmentation (a few with OCA1B) and foveal hypoplasia and no obvious nystagmus, a VEP may be a useful adjunct to demonstrate misrouting of the retinal to occipital projections [Creel et al 1990, Pott et al 2003]. MRI studies may demonstrate misrouting but this approach is not validated sufficiently to replace VEP [Schmitz et al 2003]. Molecular Genetic TestingGene. TYR is the only gene in which mutations are known to cause oculocutaneous albinism type 1 [Jeffery et al 1997, Simeonov et al 2013]. Most individuals with OCA1 are compound heterozygotes with different paternal and maternal TYR mutations. No mutations in the proximal promoter of the gene have been identified. Evidence that additional undetected mutations are responsible for OCA1 comes from individuals with the OCA1A phenotype with only a single identifiable mutation, but who are likely to be compound heterozygotes with a second, as-yet unidentified, mutation. Table 1. Summary of Molecular Genetic Testing Used in OCA1View in own windowGene ^{1Test Method Mutations Detected 2PhenotypeMutation Detection Frequency by Test Method 3Test Availability2 mutations1 mutationTYRSequence analysisSequence variants 4, 5OCA1A75%-90% 610%-20%ClinicalOCA1B37% 63% 7Deletion/duplication analysis 8Exonic or whole-gene deletions 9Both forms9Unknown1. See Table A. Genes and Databases for chromosome locus and protein name. 2. See Molecular Genetics for information on allelic variants. 3. These data are only estimates based on clinical, assumed diagnoses. In early life, often before age one year, it is difficult to distinguish OCA1A from OCA1B. Other forms of OCA2-4 may result in light pigmentation that may be difficult to distinguish from OCA1, especially OCA1B. Mild forms of albinism are underdiagnosed and confused with other forms of early-onset, infantile nystagmus. 4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 5. In some populations, laboratories may only sequence select exons or specific targeted mutations6. Hutton & Spritz [2008], Rooryck et al [2008], Gronskov et al [2009], Wei et al [2010] 7. This estimate includes individuals who may have milder forms of oculocutaneous albinism (caused by mutations in genes other than TYR) and who, incidentally, also carry one TYR mutation.8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. 9. Large deletions are quite rare (Albinism Database). Testing Strategy To confirm/establish the diagnosis in a proband. The diagnosis of OCA1 is usually based on clinical findings, especially for OCA1A. Molecular genetic testing is rarely necessary for diagnosis except in those individuals who develop some cutaneous, hair, and ocular pigment after the first year of life, particularly if the light pigmentation is confused with the clinical appearance of infants and children with OCA2.}

Natural HistoryIndividuals with all variations of OCA1 have white or nearly white scalp hair, brows, and lashes; white skin; and blue irides with extensive transillumination at birth. The presence of white scalp hair at birth should not be the exclusive clinical criterion for OCA1 because some persons with OCA2 may seem exceedingly fair in the first six to twelve months of life as well. The claim of "white" scalp hair is not universally understood in some infants because of sparse, short hair, and because of the discoloration that occurs with some yellow-tinted shampoos. Parents may describe hair that is light yellow/blond as "white“. In families with darker constitutional pigmentation, the white hair and skin are an immediate indication of hypopigmentation, and the diagnosis of OCA1 may be suspected at birth. In families with lighter constitutional pigmentation, the presence of a "tow-headed" child may not seem unusual and the diagnosis of oculocutaneous albinism may be suspected only after the ocular findings of nystagmus, photodysphoria, and reduced visual function are noted. Indeed, the initial diagnosis of oculocutaneous albinism may be delayed into adolescence until confirmed by an ophthalmologist aware of the spectrum of its clinical features.Rarely, children with albinism have been reported to have nystagmus at birth; however, most children with albinism develop nystagmus between ages three weeks and three months. The nystagmus can be very rapid in early life but its speed and amplitude generally slow with time; however, nearly all individuals with albinism have nystagmus throughout their lives. Nystagmus is more noticeable when an individual is tired, ill, or anxious, and less marked when s/he is well rested.Many years of unprotected exposure to solar radiation of lightly pigmented skin may result in coarse, rough, thickened skin (pachydermia), solar keratoses (premalignant lesions), and skin cancer, both basal cell carcinoma and squamous cell carcinoma. Melanoma is rare in individuals with OCA, but may occur because dermal melanocytes are present. Skin cancer is unusual in individuals with OCA1 in the US because of the availability of sun screens, the social acceptability of wearing clothes that cover most of the exposed skin, and the reality that individuals with albinism can be educated to minimize unprotected solar exposure. In regions of the planet where solar exposure is extensive and sunscreen difficult to obtain, the malignant cutaneous manifestations of oculocutaneous albinism are life-shortening.OCA1 is divided into two categories: OCA1A, associated with no melanin synthesis in any tissue, and OCA1B, associated with minimal amounts of melanin synthesis in the hair, skin, and eyes. The ocular features of OCA1A and OCA1B are identical except for the amount of iris pigment. OCA1A. Affected individuals have white hair, brows, and lashes, and white skin at birth. The skin stays white throughout life in all ethnic groups and invariably burns but does not tan. Skin lesions such as nevi are pink and unpigmented. The irides are blue and fully translucent at birth and remain so throughout life. Nystagmus continues and the retinal pigment epithelium does not develop melanin pigment. Best correctable visual acuity ranges between 20/100 and 20/400, unless strabismic amblyopia adds to the deficit. OCA1B. Affected individuals typically have white or very light off-white (minimally yellow) hair at birth and develop observable light yellow hair color by age one to three years. The development of pigment in scalp hair is progressive and hair color usually goes through the stages of light yellow to light blond to golden blond to dark blond to light brown, but may stop at any color. The color of eyebrow hair is similar to that of the scalp hair, but the eyelash hair often turns mildly darker than the scalp hair.
The skin color remains white and burns in prolonged solar exposure but may develop some generalized tan. Lightly pigmented nevi and freckles appear with time.
Iris color may remain blue or change slowly in adolescence to a green/hazel or light tan color. Fine granular pigment may develop in the retina. The evolution of pigment in the iris and/or retina does not affect the nystagmus, which persists throughout life but does tend to dampen in speed and amplitude with age. Best corrected visual acuity is usually between 20/100 and 20/200, and tends to improve slowly until the late teens. Some affected individuals report modest improvements in visual acuity over time; however, part of the response may be improved understanding of the ophthalmic acuity tests with maturation of the child. No longitudinal data have been published to firmly assess the frequency or extent of visual “improvement” over time. It is critically important that all parents of affected children realize that, although visually impaired, children with albinism never lose the visual acuity that they achieve, unless an intervening event such as amblyopia occurs.

Genotype-Phenotype CorrelationsOCA1A is caused by null mutations of TYR that produce a completely inactive or an incomplete tyrosinase enzyme polypeptide [Gronskov et al 2007, Simeonov et al 2013]. The total lack of tyrosinase enzyme function blocks the first step of the melanin biosynthetic pathway and, thus, no melanin forms in any melanocyte. OCA1B is caused by mutations of TYR that produce a partially active or hypomorphic tyrosinase enzyme [Gronskov et al 2007, Simeonov et al 2013]. Affected individuals may be homozygous for a single hypomorphic mutation, compound heterozygous for two different hypomorphic mutations, or compound heterozygous for a hypomorphic and a null or inactivating mutation.

Differential DiagnosisTable 2: Oculocutaneous Albinism: OMIM Phenotypic SeriesView in own windowPhenotypePhenotype
MIM numberGene/LocusGene/Locus
MIM numberAlbinism, oculocutaneous, type IA 203100 TYR, SHEP3, CMM8 606933 Albinism, oculocutaneous, type IB 606952 TYR, SHEP3, CMM8 606933 Albinism, oculocutaneous, type II 203200 OCA2, P, PED, D15S12, BOCA, EYCL3, HCL3, SHEP1 611409 {Oculocutaneous albinism, type II, modifier of} 203200 MC1R, SHEP2, CMM5 155555 Albinism, oculocutaneous, type III 203290 TYRP1, CAS2, GP75 115501 Oculocutaneous albinism, type IV 606574 SLC45A2, MATP, AIM1, SHEP5 606202 Albinism, brown oculocutaneous 203200 OCA2, P, PED, D15S12, BOCA, EYCL3, HCL3, SHEP1 611409 Data from Online Mendelian Inheritance in ManAlbinism. The ocular features of all types of oculocutaneous albinism (OCA) and X-linked ocular albinism are similar, and the terms "OCA" and "albinism" can be used interchangeably for these ocular manifestations. Biallelic null mutations of TYR are the only known cause of oculocutaneous albinism with white hair, white skin, and “blue” eyes (OCA1A). As noted in the Clinical Description, the identification of white hair may be difficult because of the sparsity of scalp hair, brows, and lashes in a young child and the different perceptions by family members to describe what qualifies as "white" hair. The differential diagnosis for individuals with albinism who have pigment in the skin and hair (OCA1B) includes OCA2, OCA3, OCA4, Hermansky-Pudlak syndromes 1-7, and X-linked (Nettleship-Falls) ocular albinism (OA1). Previous studies suggested the existence of autosomal recessive ocular albinism, presenting with reportedly normal skin and hair pigment in males and females in a sibship; however, this interpretation seems to have been incorrect, and individuals with this apparent phenotype are now recognized to be part of the spectrum of OCA1B and OCA2. Recently another form of oculocutaneous albinism has been associated with mutations in C10orf11, a melanocyte-differentiation gene [Gronskov et al 2013], and others remain to be discovered.Oculocutaneous albinism type 2 (OCA2) is characterized by hypopigmentation of the skin and hair and the characteristic ocular changes found in all types of albinism, including nystagmus; reduced iris pigment with iris translucency; reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination; foveal hypoplasia associated with reduction in visual acuity; and misrouting of the optic nerves at the chiasm associated with strabismus, reduced stereoscopic vision, and altered visual evoked potentials (VEP). Vision is stable to slowly improving after early childhood until mid- to late teens, and no major change or loss of established visual acuity occurs related to the albinism. The amount of cutaneous pigmentation in OCA2 ranges from minimal to near-normal. Newborns with OCA2 almost always have lightly pigmented hair, brows, and lashes, with color ranging from light yellow to blond to brown. Hair color may darken with age but does not vary substantially from adolescence to adulthood. Brown OCA, initially identified in Africans and African Americans with light brown hair and skin, is part of the spectrum of OCA2. The diagnosis of OCA2 is based on clinical findings. OCA2 is inherited in an autosomal recessive manner. OCA2 (previously called P) is the only gene in which mutations are known to cause OCA2. OCA3 is caused by mutations in TYRP1, encoding tyrosinase-related protein 1, which stabilizes TYR in large molecular complexes and without which TYR is degraded rapidly [Kobayashi & Hearing 2007]. Since the gene product is necessary to synthesize the black/brown eumelanin but not the reddish pheomelanin, the phenotype for OCA3 is a milder OCA in which affected individuals accumulate reddish pigment in their hair and skin, particularly noticeable in families of African ancestry. OCA3 is also inherited in an autosomal recessive manner.Oculocutaneous albinism type 4 (OCA4) is characterized by hypopigmentation of the skin and hair plus the ocular characteristics of all other types of albinism. Vision is likely to be stable after early childhood. The amount of cutaneous pigmentation in OCA4 ranges from minimal to near-normal. Newborns with OCA4 usually have some pigment in their hair, the color ranging from silvery white to light yellow. Hair color may darken with time but does not vary significantly from childhood to adulthood. This form of albinism is rarer than OCA2, except in the Japanese population. SLC45A2 (previously called MATP and AIM1) is the only gene in which mutation is known to cause OCA4. SLC45A2 encodes membrane-associated transporter protein, the human ortholog to the mouse gene Underwhite [Newton et al 2001]. OCA4 was identified initially in one male of Turkish origin. Studies now suggest that this is the second most common type of OCA in Japanese individuals [Inagaki et al 2004]. Because OCA2 and OCA4 are phenotypically similar, it is not possible to diagnose OCA4 accurately only on clinical findings. OCA4 is inherited in an autosomal recessive manner. Hermansky-Pudlak syndromes (HPS) are nine multi-system disorders characterized by oculocutaneous albinism, a bleeding diathesis resulting from a platelet storage pool deficiency, and, in some cases, pulmonary fibrosis or granulomatous colitis evolving with age. The albinism is characterized by: hypopigmentation of the skin and hair; and ocular findings of reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in easy bruising, frequent epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and progresses to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. The diagnosis of HPS is established by clinical findings of hypopigmentation of the skin and hair, characteristic eye findings, and demonstration of absent dense bodies on whole mount electron microscopy of platelets. Biallelic mutations in HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, or BLOC1S6 are known to be associated with HPS. HPS is inherited in an autosomal recessive manner. X-linked ocular albinism (OA1) is a disorder of melanosome biogenesis leading to minor skin manifestations and congenital and persistent visual impairment in affected males. OA1 is characterized by infantile nystagmus, reduced visual acuity, hypopigmentation of the iris pigment epithelium and the ocular fundus, and foveal hypoplasia in affected males. Significant refractive errors, reduced or absent binocular functions, photoaversion, and strabismus are common. OA1 is a non-progressive disorder and the visual acuity remains stable throughout life, often slowly improving into the mid-teens. A diagnosis of ocular albinism (OA) is probable in the presence of infantile nystagmus, iris translucency, substantial hypopigmentation of the ocular fundus periphery in males with mildly hypopigmented skin (most notably when compared to unaffected siblings), foveal hypoplasia, reduced visual acuity, and aberrant optic pathway projection as demonstrated by crossed asymmetry of the cortical responses on visual evoked potential testing (VEP).OA1 is caused by mutations in GPR143 (formerly OA1). X-linked inheritance is documented by either a family history consistent with X-linked inheritance or the presence of typical carrier signs (irregular retinal pigmentation and partial iris transillumination) in an obligate carrier female. Chediak-Higashi syndrome (CHS) is characterized by partial oculocutaneous albinism (OCA), immunodeficiency, and a mild bleeding tendency. Approximately 85% of affected individuals develop an accelerated phase, a lymphoproliferative infiltration of the bone marrow and reticuloendothelial system. Adolescents and adults with atypical CHS and children with classic CHS who have successfully undergone allogenic hematopoietic stem cell transplantation (HSCT) develop neurologic findings during early adulthood.Ophthalmologic findings, history of recurrent or severe infections, and abnormal platelet aggregation studies should prompt evaluation for CHS. Diagnosis is based on identification of abnormal WBC granules on blood smear. Biallelic LYST mutations are causative. Inheritance is autosomal recessive.Congenital motor nystagmus. Congenital motor nystagmus is a phenotype that presents as infantile nystagmus associated with reduced visual acuity. Some individuals with congenital motor nystagmus have been reported to have retinal hypopigmentation and foveal abnormalities; however, the studies were done before the molecular analysis of the different types of OCA was available, implying that the populations may have included individuals with OCA who were diagnosed incorrectly with infantile nystagmus. The visually evoked potential (VEP) analysis to evaluate misrouting of the nerve fibers from the optic nerves is normal in congenital motor nystagmus. A single gene, FRMD7, for congenital infantile nystagmus has been reported.FRMD7-related infantile nystagmus (FIN) is an X-linked disorder characterized by either the onset of horizontal, conjugate, gaze-dependent nystagmus in the first six months of life or periodic alternating nystagmus (with cyclical changes of nystagmus direction) of infantile onset. Binocular vision and color vision are normal and visual acuity is typically better than 6/12. An abnormal head posture is seen in approximately 15% of affected individuals. The eyes are structurally normal and electrophysiologic studies, such as visual evoked potential (VEP) and electroretinogram (ERG), are normal. Affected females report slightly better visual acuity than affected males; however, no differences between males and females in the amplitude, frequency, and waveform of nystagmus are observed. The diagnosis is based on clinical findings and the presence of a hemizygous FRMD7 mutation in males and a heterozygous FRMD7 mutation in females.Other considerations. Additional confusion may occur among infants with blue cone monochromacy (males, X-linked) or rod monochromacy (both genders, autosomal recessive) in which nystagmus begins early in life, the foveas are underdeveloped, and myopia is common, leading to an exaggerated impression of underpigmented retinas. The severe loss of color perception clinically and the electroretinographic responses of abnormal cone and rod signals should separate these two entities from the albinisms. Hypopigmentation of hair, skin, and fundus and iris transillumination are not features. Many other ocular disorders present with infantile nystagmus; that differential diagnosis is beyond the scope of this review.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs of an individual diagnosed oculocutaneous albinism type 1 (OCA1), the following evaluations are recommended: Complete ophthalmologic evaluation, including assessment for the presence of nystagmus, ocular alignment and strabismus, iris pigmentation and transillumination, dilated retinal examination assessing retinal pigment epithelial hypopigmentation and foveal hypoplasia, and best corrected visual acuity (with cycloplegic refraction);Evaluation of the pigmentation status of the skin, especially the solar-exposed skin, and the adnexa (brows, lashes, and when appropriate extremity hair and pubic hair), linked to a (pediatric) dermatologic consultation for sun-protective clothing, lotions, and future self-care;Medical genetics consultation to review natural history, pattern of inheritance and recurrence risks, and to clarify genotype.Parents should be assured repeatedly that the visual disability with OCA1 does not deteriorate over time, that changes in acuity are usually refractive in nature, that the nystagmus tends to dampen with age (but never disappears), that many children with OCA1B manifest slow improvement in acuity and some plateau by their teen years, and that intellectual disabilities are not a component of this group of disorders.Treatment of ManifestationsOphthalmologic care. Correction with spectacles or (when age-appropriate) contact lenses of the refractive errors of either hyperopia or myopia and astigmatism found in most individuals with albinism can optimize visual acuity. Notably, visual acuity is never correctable to normal, but parents should be advised that the achievable acuity never deteriorates.Strabismus surgery is usually not mandatory but may be performed if the strabismus is marked. Surgery may improve peripheral binocularity or appearance. When an anomalous null point creates a substantial face turn or head tilt, strabismus surgery may reposition the null point to a more central, straight-ahead location to allow more socially acceptable head position. Nystagmus surgery remains highly controversial; no comparative clinical trial has compared the surgical reduction of amplitude of nystagmus to the outcomes of the natural history of dampened nystagmus with age among those forms of albinism in which increasing pigment occurs normally over time.Photodysphoria (discomfort in bright light; as distinct from ‘photophobia’, which is painful aversion of light associated with intraocular inflammation) is common among all individuals with OCA; however, the severity of discomfort varies and is not completely concordant with the amount of pigment present in the iris or the skin.Dark glasses or transition lenses may be helpful, but many individuals with albinism prefer to go without the tint because of the reduction in acuity from the dark lenses. Note: Going without dark glasses does not harm vision.Darkly tinted contact lenses do not improve visual function substantively because the reduction of transmission of the thin contact lens is no match for the density of a tinted spectacle lens.Most children with albinism should remain in mainstream classrooms, as long as the school attends to their special needs resulting from visual limitation. Preschoool evaluations allow teachers and parents to develop an Individual Education Plan (IEP). Neither Braille nor ‘white cane” mobility training is needed in the overwhelming majority of children with albinism.Additional classroom aids may include:High contrast reading materials (black on white);Large font texts or xerographically enlarged worksheets;Preferential seating near the front of the class and work boards;Selective optical devices, especially mobile ones such as stand magnifiers and monocular telescopes, and closed circuit chip-camera televisions; andComputers and tablets with zoom-magnification text software.A hat with a brim (such as a baseball hat with a visor) is helpful to reduce overhead glare, to reduce some photodysphoria, and to provide some sun protection to the face.Prevention of Primary ManifestationsSkin care in individuals with OCA1 is guided by the amount of pigment in the skin and the cutaneous response to sunlight. For individuals with OCA1A, the white skin is completely devoid of melanin and needs to be protected whenever exposed to the sun. Sun exposure as short as five to ten minutes can be substantial in very sensitive individuals, and exposure of 30 minutes or more is usually substantial in less sensitive individuals. Prolonged periods in the sun require skin protection with clothing (hats with brims, long sleeves, pants, and socks) and sun screens with a high SPF value (blocks with SPF 45-50+). Even early in life, a (pediatric) dermatologic consultation is warranted to teach parents about the use of sun-protective clothing and interpretation of the often confusing validity of numerical values and contents of sun-protective lotions and formulas.For individuals with OCA1B, the amount of skin pigmentation varies and the use of sun screen should correlate with skin pigmentation and the ability to tan. Skin that burns with sun exposure needs protection. An early (pediatric) dermatologic consultation is warranted.Surveillance The following are appropriate:During the first few years of life, annual ophthalmologic examination, including assessment of refractive error and strabismusIn adults, dermatologic surveillance of unusual skin thickening, hyperkeratosis, and erosive lesions that may be harbingers of skin cancerAgents/Circumstances to AvoidOther than the avoidance of prolonged solar exposure because of the enhanced damage to the skin and increasing cumulative risk of cutaneous neoplasms, no special precautions are needed.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementIn classic OCA1 of either type, an affected mother who is pregnant needs no exceptional consideration. Similarly, a pregnancy affected with OCA1 requires no exceptional prenatal care.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Oculocutaneous Albinism Type 1: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTYR11q14​.3TyrosinaseAlbinism Database Mutations of the tyrosinase gene
Retina International Mutations of the Tyrosinase GeneTYRData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Oculocutaneous Albinism Type 1 (View All in OMIM) View in own window 203100ALBINISM, OCULOCUTANEOUS, TYPE IA; OCA1A 606933TYROSINASE; TYR 606952ALBINISM, OCULOCUTANEOUS, TYPE IB; OCA1BNormal allelic variants. The reference transcript NM_000372.4 has five exons. Normal variants of TYR are known. The normal variants c.575C>A (p.Ser192Tyr) and c.1205G>A (p.Arg402Gln) result in amino acid substitutions. The c.575C>A (p.Ser192Tyr) variant has not been associated with any pigmentation phenotype. The c.1205G>A (p.Arg402Gln) variant has been associated with an OCA1B phenotype in persons who are compound heterozygous for a pathogenic mutation on the other allele; however, this association has not been shown to occur in the homozygous state in unaffected individuals.Pathologic allelic variants. Hundreds of TYR pathologic alleles have been reported [Simeonov et al 2013]. Several have been found to be common to multiple families, while the majority have been identified in only a few families. Normal gene product. Tyrosinase is the key enzyme, catalyzing several steps in melanin synthesis, including the essential first and second steps: the hydroxylation of tyrosine to L-DOPA and the oxidation of L-DOPA to DOPA quinone. This is a copper-containing enzyme with activity limited to the melanosome within the melanocyte. Abnormal gene product. Most mutations of TYR are missense mutations that produce enzyme with no catalytic activity (TYR null mutations or predicted to be subject to nonsense-mediated decay) associated with the OCA1A phenotype or small amounts of residual catalytic activity (TYR hypomorphic mutations) associated with the OCA1B phenotype. The mechanism for partial activity is currently being explored [Chiang et al 2009, Simeonov et al 2013].