Genetic defects affecting melanin pathway causes albinism disordersThe pigment melanin is formed in the melanocytes present in the skin, hair follicles and pigment cells of the eye. The production of melanin involves a series of enzymatic reactions converting the amino acid tyrosine into two types of melanin, namely black-brown eumelanin and red-blond pheomelanin. Genetic mutations affecting proteins and enzymes involved in melanin production pathway cause non-production or reduced production of melanin. Tyrosinase enzyme has a major role in converting tyrosine to DOPA. DOPA is then converted to dopaquinone and then to eumelanin or pheomelanin. Tyrosinase-related protein 1 and tyrosinase-related protein 2 are also involved in formation of eumelanin. P protein (a melanosomal membrane protein) is involved in the transport of tyrosine for mealnin synthesis. Any genetic mutation affecting these enzymes and proteins can cause albinism disorder.
Genetics and causes of oculocutaneous albinism (OCA)In oculocutaneous type of albinism disorder eyes (ocular), skin (cutaneous) and hair are involved. One of the four mutated genes causes this albinism disorder. Oculocutaneous albinism has four sub types OCA1, OCA2, OCA3 and OCA4 caused by mutated genes TYR, OCA2, TYRP1, and SLC45A2 respectively.
Oculocutaneous albinism type 1 (OCA1) is Tyrosinase-Related OCA and is caused by mutated TYR gene on the chromosome 11. There is a genetic defect in the tyrosinase enzyme which is responsible for the metabolism of amino acid tyrosine into Melanin pigment. Oculocutaneous albinism type 1 is transmitted by autosomal recessive inheritance. The characteristics of OCA1 type are deficient melanin synthesis in the skin, hair and eyes, nystagmus, reduced visual acuity and iris translucency. At birth the affected children with this type of albinism disorder usually have white skin, white hair and blue eyes. Later on some of them may produce some pigment to have a slight tan and blond hair.
Oculocutaneous albinism 1A (OCA1A) is Tyrosinase-Negative OCA. The genetic defect in the tyrosinase enzyme makes it inactive and melanin is not produced. Individuals having oculocutaneous albinism type 1A have white hair and skin. The skin does not tan and the iris remain translucent and does not darken with age. It causes reduced visual acuity.
Oculocutaneous albinism 1B (OCA1B) is Yellow OCA. The genetic defect in the tyrosinase enzyme makes it minimally active and a small amount of melanin pigment is produced. Individuals with oculocutaneous albinism type 1B have white or light yellow hair and white skin at birth. The hair may darken with age. The skin may develop light pigment and tan. The blue iris at birth may turn hazel/green/brown with age. Individuals having OCA1B type disorder have better visual acuity when compared to OCA1A type individuals.
Temperature-sensitive albinism is a sub-type of oculocutaneous albinism type 1B. In this genetic disorder there is mutation in tyrosinase gene and causes temperature-sensitive tyrosinase enzyme to be produced. Temperature-sensitive tyrosinase enzyme has reduced activity than normal tyrosinase enzyme at normal temperatures (37*C). Its activity improves with lower temperatures. Parts of the body with normal temperature like scalp hair and axillary hair have minimal pigment while cooler areas of the body like arms and legs are greatly pigmented.
Oculocutaneous albinism type 2 (OCA2) is caused by OCA2 gene mutation on the chromosome 15. In OCA TYpe 2 disorder there is a genetic defect in P protein which helps in the function of tyrosinase enzyme. Oculocutaneous albinism type 2 disorder is transmitted by autosomal recessive inheritance. OCA2 is characterized by reduced pigmentation of the skin, hair and iris. This type of disorder causes ocular defects, including nystagmus, iris translucency and reduced visual acuity. Skin pigmentation may vary from minimal to near-normal. Newborns have pigmented hair ranging from very light yellow to brown. There is a variant of OCA2 disorder identified in Africans and African Americans which causes light brown skin and hair.
Oculocutaneous albinism type 3 (OCA3) is caused by mutation of TyRP1 gene on the chromosome 9. OCA type 3 disorder is transmitted by autosomal recessive inheritance. This is a very rare type of disorder caused by genetic defect in TYRP1, a protein related to tyrosinase enzyme. There is substantial pigmentation in people with OCA3.
Oculocutaneous albinism type 4 (OCA4) is caused by mutated SLC45A2 gene on the chromosome 5. This disorder is caused by defect in the SLC45A2 protein that helps the function of tyrosinase enzyme. OCA4 is transmitted by autosomal recessive inheritance. OCA4 is characterized by reduced pigmentation of the skin, hair and iris. Ocular defects include nystagmus, iris translucency and reduced visual acuity. Skin pigmentation may vary from minimal to near-normal. Newborns have some pigmentation in hair ranging from silvery white to light yellow. OCA4 is rarer except in people of Japanese origin.
Genetic causes of ocular albinismOcular albinism (OA1) is caused by mutation of GPR143 gene on X chromosome. It is passed on to sons by carrier-mother (50% chances). For the daughters to inherit OA1, father must have OA1 and mother should be either a OA1 (100% chances) or carrier (50% chances). Ocular albinism disorder affects only eyes and causes minimal pigment in them. Reduced visual acuity, nystagmus, and difficulty controlling eye movements are caused in persons with ocular albinism.
Hermansky-Pudlak Syndrome (HPS)
HPS is a rare type of albinism and is autosomal recessive. This disorder is more common in Puerto Rico.
HPS can be caused by mutations in several genes: HPS1, HPS3, HPS4, HPS5, HPS6 and HPS7. HPS shows all the characteristics of oculocutaneous albinism. HPS also has bleeding problems due to a platelet abnormality in lacking dense bodies and storage of an abnormal fat-protein compound. This disorder may also involve lung and bowl malfunctions.
Chediak-Higashi Syndrome (CHS)
CHS is a rare autosomal recessive disorder caused by the mutation of LYST gene. Individuals with CHS show characteristics of oculocutaneous albinism, having light skin and silvery hair. They are also afflicted by solar sensitivity, photophobia, frequent infections and neuropathy. A defect in the granules present in skin pigment cells and white blood cells causes this type of albinism associated with immunodeficiency. Albinism disorder is typically partial, and some individuals may also have peripheral neuropathy.
Griscelli syndrome is a rare autosomal recessive disorder, characterized by albinism with immunodeficiency and neurological problems. It usually causes death in early childhood.
To sum up there are various genetic causes giving rise to various types of albinism disorders requiring further research and social efforts to alleviate the problems of the affected people.
Causes of chronic hives
Richard A King, MD, PhD, FACMG and William S Oetting, PhD., Oculocutaneous Albinism Type 2, University of Minnesota Health Center, Minneapolis, PMID: 20301410.