Oculocutaneous albinism type 4

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The oculocutaneous albinism type 4 (OCA 4) is a form of albinism , which leads to brightened skin and hair color due to a mutation in the MATP gene. Other names of the gene are: underwhite (uw), dominant brown (Dbr), B / AIM-1-like protein, Aim1, Aim-1, blanc-sale (bls), 1A1 and solute carrier family 45, member 2 (SLC45A2 ) and membrane associated transporter protein (MATP).

Appearance

Albinism

Pigmented spots on the skin occur both with the European OCA4 mutation, which leads to white skin color, and with some other mutations of this gene location

The appearance of OCA4 was examined in Japanese people, who normally have light skin, black hair, and brown eyes. The hair color of the affected people varied from completely white to dark blonde, depending on the mutation. The eye color from blue to reddish brown. In those people in whom OCA4 was most pronounced, no more melanin production was found, as is also the case with OCA1A . Correspondingly, in these cases the nystagmus (eye tremors) and the visual impairment are pronounced with a visual acuity of 10% as in OCA1A. In addition, OCA4 also have people who have pigmented spots on their skin.

Contribution of the locus to normal variation in skin color

The light skin color of Europeans and Asians is due to OCA4 variants

While mutations of the OCA4 locus are rare in black Africans, they are quite common in Asians. Japanese and New Guinea residents often have the 272K allele. Well over 90% of Europeans have the same allele of the gene called 374F, which is responsible for the pale skin color here. The variations in hair and eye color in Europeans are largely explained by mutations in the OCA2 gene . While in Africa dark skin has considerable health benefits as protection against skin cancer through UV radiation, in northern countries the advantage of light skin, which enables improved vitamin D production with the help of the weaker UV radiation, predominates.

genetics

Oculocutaneous albinism type 4 (OCA 4) was only described as a new form of OCA in 2001. Based on the observation that mutations in the underwhite gene or hypopigmentation occur in mice, it was assumed that the corresponding gene in humans was related to OCA. In addition to MATP, the gene is also called Slc45a2 (solute carrier family 45, member 2), Aim-1, Aim1, blanc-sale, bls, Dbr and dominant brown.

In humans, the MATP gene is located on chromosome 5 (5p13.3) and consists of 7 exons and five introns. Its transcription is modulated by MITF . The gene encodes a protein consisting of 530 amino acids. In 2006, 18 disease-causing mutations and 8 non-pathological variations of the gene were known.

The protein has a structure and sequence similarity to plant sucrose transporters.

physiology

The physiology of OCA4 was studied in mice with the Underwhite (uw) mutation, which is a variant of OCA4 in mice.

Melanocytes from underwhite mice have considerably more cell processes than normal melanocytes and are also significantly larger than these. The melanosomes contain only a small amount of melanin, have an irregular shape and their matrix proteins form irregularly arranged fibers.

Like the P protein, which is responsible for oculocutaneous albinism type 2 (OCA2), MATP has 12 transmembrane domains. MATP obviously only functions as a transporter for melanocyte-specific proteins and its mutations therefore have no other negative effects on health besides albinism.

Both the P protein and MATP are necessary for the transport of tyrosinase, but while with OCA2 the tyrosinase is excreted from the cell instead of being transported into the melanosomes, the Underwhite mutation has been found to be too early in the Melanosomes is transported. The synthesis of tyrosinase in the endoplasmic reticulum and Golgi apparatus proceeds normally. A significant amount of tyrosinase is transported into immature melanosomes and vesicles for excretion rather than being transported into mature melanosomes where it could be used for melanin synthesis. In addition to tyrosinase, Tyrp1 - and to a lesser extent Dct - also does not reach the melanosomes.

The production of tyrosinase proceeds in the same way and in almost the same amount in ruddy mice as in mice with the underwhite mutation, but while almost 100% of the tyrosinase produced can still be found in the melanocytes of the ruddy mice after 24 hours, remains in the underwhite- Mice received very little tyrosinase.

frequency

OCA4 occurs in 5–8% of German patients with albinism, but is responsible for 18% of Japanese albinism cases.

OCA4 in animals: MATP gene

Palomino, quarter horse

Mammals

horse

Complete albinism is not known in horses. The cream gene (Cr) leads to incomplete albinism (OCA4), which is responsible for the horse colors Buckskin, Palomino, Cremello and Perlino, among others. The cream gene is therefore listed as a dilute gene .

mouse

In the mouse, MATP is responsible for several mutations, most of which have the term "underwhite" in their names, since the undercoat of the affected animals is more lighter than the top coat or is white. The coat, skin and eyes are lightened to different degrees depending on the mutation. The eyes are light at birth, but darken in the course of life.

Birds: domestic chicken

In chickens, the gene location is called the silver locus and lies on the sex chromosome, which is called Z. There are three known variants of the gene: Silver, wild type / gold and sex-linked imperfect albinism.

fishes

An orange-red variant of the Japanese rice fish ( Oryzias latipes ), which belongs to the rice fish (Adrianichthyidae), has a mutation of a gene locus that is called the b locus in this fish, the gene itself was called AIM1 when it was discovered. It has been proven that this is the Oryzias latipes homolog of the MATP gene.

Fruit flies

In fruit flies ( Drosophila ) the homologous gene is called CG4484. A connection with the color is not known here.

Individual evidence

  1. ↑ NCBI: Slc45a2 solute carrier family 45, member 2 (Mus musculus). GeneID: 22293. As of April 6, 2007.
  2. ↑ Katsuhiko Inagaki, Tamio Suzuki, Hiroshi Shimizu, Norihisa Ishii, Yoshinori Umezawa, Joji Tada, Noriaki Kikuchi, Minoru Takata, Kenji Takamori, Mari Kishibe, Michi Tanaka, Yoshinori Miyamura, Shiro Ito, Yasushi Tomita: Oculocut 4 Isaneous Isaneous the Most Common Types of Albinism in Japan . In: The American Journal of Human Genetics . tape 74 , no. 3 , March 2004, p. 466-471 , doi : 10.1086 / 382195 , PMID 14961451 , PMC 1182260 (free full text).
  3. ↑ M. Sengupta, M. Chaki, N. Arti, K. Ray: SLC45A2 variations in Indian oculocutaneous albinism patients . In: Molecular Vision . tape 13 , 10 August 2007, ISSN  1090-0535 , p. 1406-1411 , PMID 17768386 .
  4. ↑ M. Soejima, H. Tachida, T. Ishida, A. Sano, Y. Koda: Evidence for recent positive selection at the human AIM1 locus in a European population . In: Molecular Biology and Evolution . tape 23 , no. 1 , January 2006, p. 179-188 , doi : 10.1093 / molbev / msj018 , PMID 16162863 .
  5. ↑ David L. Duffy, Grant W. Montgomery, Wei Chen, Zhen Zhen Zhao, Lien Le, Michael R. James, Nicholas K. Hayward, Nicholas G. Martin, Richard A. Sturm: A Three-Single-Nucleotide Polymorphism Haplotype in Intron 1 of OCA2 Explains Most Human Eye-Color Variation . In: The American Journal of Human Genetics . tape 80 , no. 2 , February 2007, ISSN  0002-9297 , p. 241-252 , PMID 17236130 , PMC 1785344 (free full text).
  6. ↑ SN Shekar, DL Duffy, T. Frudakis, RA Sturm, ZZ Zhao, GW Montgomery, NG Martin: Linkage and association analysis of spectrophotometrically quantified hair color in Australian adolescents: the effect of OCA2 and HERC2 . In: The Journal of Investigative Dermatology . tape 128 , no. 12 , 2008, ISSN  1523-1747 , p. 2807-2814 , doi : 10.1038 / jid.2008.147 , PMID 18528436 .
  7. ↑ a b J. M. Newton, O. Cohen-Barak, N. Hagiwara, JM Gardner, MT Davisson, RA King, MH Brilliant: Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4 . In: The American Journal of Human Genetics . tape 69 , no. 5 , November 2001, pp. 981-988 , doi : 10.1086 / 324340 , PMID 11574907 , PMC 1274374 (free full text).
  8. ↑ a b Mouse Genome Informatics: Slc45a2 Gene Detail. Retrieved: 9:10 p.m., Jun 20, 2009 (CEST).
  9. ^ HY Li, HL Duan, H. Zheng: A new form of Oculocutaneous albinism, OCA4 . In: Yi Chuan = Hereditas . tape 28 , no. 9 , September 2006, ISSN  0253-9772 , p. 1149-1152 , PMID 16963427 .
  10. ↑ a b S. Fukamachi, A. Shimada, A. Shima: Mutations in the gene encoding B, a novel transporter protein, reduce melanin content in medaka . In: Nature Genetics . tape 28 , no. 4 , 2001, ISSN  1061-4036 , p. 381-385 , doi : 10.1038 / ng584 , PMID 11479596 .
  11. ↑ a b c d e G. E. Costin, JC Valencia, WD Vieira, ML Lamoreux, VJ Hearing: Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4 . In: Journal of Cell Science . tape 116 , Pt. 15, 2003, ISSN  0021-9533 , p. 3203-3212 , doi : 10.1242 / jcs.00598 , PMID 12829739 .
  12. ↑ K. Grønskov, J. Ek, K. Brondum-Nielsen: Oculocutaneous albinism . In: Orphanet Journal of Rare Diseases . tape 2 , 2007, ISSN  1750-1172 , p. 43 , doi : 10.1186 / 1750-1172-2-43 , PMID 17980020 , PMC 2211462 (free full text).
  13. ↑ Denis Mariat, Sead Taourit, Gérard Guérin: A mutation in the MATP gene causes the cream coat color in the horse . In: Genetics, selection, evolution: GSE . tape 35 , no. 1 , 2003, ISSN  0999-193X , p. 119–133 , doi : 10.1051 / gse: 2002039 , PMID 12605854 , PMC 2732686 (free full text).
  14. ↑ Ulrika Gunnarsson, Anders R. Hellström, Michele Tixier-Boichard, Francis Minvielle, Bertrand Bed'hom, Shin'ichi Ito, Per Jensen, Annemieke Rattink, Addie Vereijken, Leif Andersson: Mutations in SLC45A2 cause plumage color variation in chicken and Japanese quail . In: Genetics . tape 175 , no. 2 , February 2007, ISSN  0016-6731 , p. 867-877 , doi : 10.1534 / genetics.106.063107 , PMID 17151254 , PMC 1800597 (free full text).
  15. ↑ Shoji Fukamachi et al: Gene encoding b protein. Application number: 10 / 168,017, Publication number: US 2003/0175962 A1, Filing date: 18 Jun 2002. ( google.de ).