Gene & Signaling Pathway

Gene Expression in Melanin Synthesis Normal Variant vs. Albinism

Genes Involved in Melanin Regulation and Synthesis

SLC45A2 Gene (OCA4) : In non-albino individuals this gene codes for a membrane associated transporter protein (MATP) which transports ions across the cell membrane's lipid phospho-lipid bilayer utilizing a proton gradient 23. When functional it helps maintain a slightly alkaline melanasome , leading to increased tyrosinase activity and more melanin production 23. This gene's dysfunction is associated with OCA4 albinism 23. The more inhibited this gene is the less melanin produced, this is why this gene even if functional is largely responsible for the lighter skin seen in non-African populations 23.

TYR Gene: TYR encodes the tyrosinase enzyme which moves tyrosine through melanosomes during melanin production 24. The tyrosinase enzyme is glycosylated and folded in the endoplasmic reticulum where it is then directed to melanosomes (organelles in melanocytes) 24. It is made up of three domains: the inner melanosomal catalytic domain, short melanosomal transmembrane domain, and the cytoplasmic domain 24. In melanin production tyrosinase is the rate-limiting enzyme in melanin biosynthesis 24. The conversion of tyrosine to L-dihydroxyphenylalanine is catalyzed by this enzyme 24. This is a precursor to melanin 24.

OCA2 Gene: OCA2 encodes the pink-eyed dilution protein (P-protein) 25. The function of P protein is not entirely clear, although it is proposed to help regulate pH in melanosomes similar to how MATP does 25. It is also proposed to help sort tyrosinase to melanosomes, tyrosinase processing, and other functions 25. Studies have shown that when OCA2 is inhibited melanin production goes down 25.

With MATP activity altered, the cell's acidity increases making the inactive tyrosinase unable to bind copper and become active 23.

Mutations

TYR: There are multiple mutations in this gene that can impair its function and lead to OCA1 albinism 27. One of the best studied mutations is the R299H mutation which leads to impaired ability for copper binding in tyrosinase, leading to less activity of it 27.

SLC45A2: There are more than 20 mutations responsible for OCA4 28. The most common mutation seen in Japanese people is a switch at position 157 from an aspartate to an asparagine 28. This mutation greatly reduces the function of SLC45A2 28.

These are only some of the mutations associated with oculocutaneous albinism. The University of Minnesota maintains a database of hundreds of mutations linked to the development of various types of albinism.

Albinism Database

Signaling Pathways

MITF: MITF ( Melanocyte Inducing Transcription Factor/Microphthalmia-associated transcription factor) is a transcription factor that plays a crucial role in regulating melanocyte development as well as the differentiation of melanocytes 26. The MITF gene contains multiple promoters and nine promoter-exon units that help in expression of the gene 26. MITF is regulated at the transcriptional level by PAX3, CREB, SOX9, and SOX10 amongst other factors 26. It is also regulated at the post-transcriptional level 26. MITF regulates the expression at the transcriptional level of three pigmentation enzymes: TYR, TYRP1 and TYRP2 26. TYR is implicated in OCA1, therefore dysregulation or mutations of MITF can lead to downstream dysregulation of TYR and albinism 26.

Wnt: Wnt1 and Wnt3a are proteins which signal to the neural crest cells to differentiate into melanocytes 26. Wnt1 signals to increase the number of melanocytes and Wnt3a as well as B-catenin signal the differentiation of neural crest cells into melanocytes 26.

Protein Kinase C: This pathway also regulates melanogenesis 26. There are subclasses of this family that are categorized by their requirements for activation 26. In the case of cells irradiated by UV light, diacylglycerol is present and activates protein kinase B which phosphorylates tyrosinase leading to an increase of its activity and melanin production, i.e. tanning 26.

Sox Family: SOX 10 helps to control the transcription of MITF and therefore the regulation of TYR 26. Without SOX10, MITF cannot induce the expression of tyrosinase, leading to minimal melanin production 26. In the dorsal neural tube SOX10 is upregulated alongside SOX9 26. The loss of SOX10 leads to an absence of neural crest cells along the pigment cell migratory pathway 26. The expression of SOX proteins continues after embryogenesis into adulthood where during melanocyte differentiation in adults SOX9 behaves the same as SOX10 would in embryogenesis 26. The ectopic expression of SOX9 is enough to stimulate the differentiation of melanocytes 26.

PAX3: Help to regulate the development of the neural crest including derivatives of neural crest cells such as melanocyte progenitors 26.

Diagram detailing the regulatory and signaling pathways that impact melanin synthesis 26.

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