65 Melanocyte Biology

Question 1

diffuse pigmentary dilution disorders

Answer 1

1) oculocutaneous albinism; types 1-7
2) Hermansky-Pudlak syndrome; types 1-10
3) Chediak-Hagashi syndrome
4) Griscelli syndrome; types 1-3

Question 2

oculocutaneous albinism; affected proteins:

Answer 2

• tyrosinase in types 1
• P protein [OCA2, a melanosomal TM protein which helps regulate processing/trafficking of tyrosinase] in type 2
• tyrosinase-related protein 1 [TYRP1, stabilizes tyrosinase] in type 3
• solute carrier family 45 member (Asians) in type 4
• types 5-7

Question 3

Hermansky-Pudlak syndrome; affected proteins:

Answer 3

• HPS1 [BLOC-3 subunit 1, defective trafficking protein in melanosomes, lysosomes, and cytoplasmic granules e.g. in platelets and cytotoxic T cells) in type 1; a/w pulm fibrosis and granulomatous colitis
• adaptor related protein complex 3 beta-1 subunit [AP3B1, recognizes sorting signals within cargo molecules; trafficking of proteins from Golgi apparatus to appropriate organelles] in type 2
• above a/w pulm fibrosis
• types 3-10

Question 4

Chediak-Hagashi syndrome, affected protein:

Answer 4

-lysosomal trafficking regulator [abnormal vesicle trafficking and fission/fusion –> giant organelles esp melanosomes, neutrophil granules, and platelet dense granules]

Question 5

Griscelli syndrome, affected proteins:

Answer 5

• all have silvery hair
• myosin Va [attaches melanosomes to actin filaments, melanosomes are retained in the melanocyte rather than trafficking to the tips of dendrites; also expressed in neurons –> neurologic abnormalities] in type 1
• RAB27A [melanosomal membrane GTPase that binds melanophilin; also expressed in hematopoietic cells –> defective release of granules contents from cytotoxic T cells leading to recurrent infections and hemophagocytic syndrome] in type 2
• MLPH [melanophilin, links myosin Va and RAB27A, only melanocytes are affected so only pigmentary dilution in this disorder] in type 3
• also myosin Va F-exon deletion in type 3.

Question 6

melanocyte origin and function

Answer 6

• neural crest derived
• melanoblasts migrate along dorsolateral then ventral pathway via mesenchyme to reach the epidermis and fair follicles
• also arise from neural crest-drives Schwann cell precursor
• other sites of migration: uveal tract, leptomeninges, and inner ear (may play a role in hearing); think Vogt-Koyanagi Harada syndrome, Waardenburg syndrome, Hirschsprung disease
• migration dependent on interactions between specific receptors and ligands: KIT ligand binds KIT receptor on melanocytes/blasts and this aids in their normal chemotactic migration, think piebladism; endothelia proteins [EDNRB and EDN3] involved in migration and mutation thereof seen in Waardenburg syndrome plus aganglionic megacolon
• also TFs that are essential in embryogenesis are affected: PAX3 and SOX10 control expression of MITF; MITF = master regulator of melanocyte development and function

Question 7

Vogt-Koyanagi Harada syndrome

Answer 7

death of melanocytes at sites of migration leading to aseptic meningitis, auditory sxs, and areas of vitiligo

Question 8

Waardenburg syndrome

Answer 8

congenital deafness, heterochromia irides, and patches of leukoderma