Melanogenesis and melanocytic disorders Flashcards
What gene mutations have been associated with piebaldism?
c-kit/CD117
steel factor
What genes are mutated in Waardenburg-Klein syndrome?
EDNRB
MITF
SOX10
PAX3
What is the inheritance pattern of Waardenburg-Klein syndrome?
Autosomal dominant
What is the inheritance pattern of lentiginosis profusa?
Autosomal dominant
What breed is predisposed to lentiginosis profusa?
Pugs
What is the inheritance pattern of piebaldism?
Autosomal dominant
What breed of cat is affected by Chediak-Higashi syndrome?
Persian (blue smoke color only)
What is the inheritance pattern of Chediak-Higashi syndrome in cats?
Autosomal recessive
What gene is mutated in Chediak-Higashi syndrome in cats?
LYST
What is the inheritance pattern of color dilution alopecia?
Autosomal recessive
What gene is mutated in color dilution alopecia?
MLPH
What is the inheritance pattern of vitiligo?
Autosomal recessive
What gene is mutated in vitiligo?
FOXD3
What is the inheritance pattern of feline acromelanism?
Autosomal recessive
What gene is mutated in feline acromelanism?
tyrosinase OCA1B
From what structure are melanocytes derived?
Neural crest
Besides the skin, where else are melanocytes found?
Meninges
Cochlea (stria vascularis)
Eyes
What determines color in amphibians, fish, reptiles, and crustaceans?
Chromatophores
What determines color in mammals and birds?
Melanin
How many melanocytes comprise an epidermal melanin unit in dogs?
1 melanocyte per 10-20 KCs
What IHC markers are used for melanocytes?
Vimentin
S-100 protein
What type of melanin is red-yellow?
Pheomelanin
What type of melanin is brown-black?
Eumelanin
What type of melanin has spherical melanosomes?
Pheomelanin
What type of melanin has elliptical melanosomes?
Eumelanin
What type of melanin is low in cysteine?
Eumelanin
What type of melanin is high in cysteine?
Pheomelanin
What type of melanin is produced in high levels of tyrosinase?
Eumelanin
What type of melanin is produced in low levels of tyrosinase?
Pheomelanin
What type of melanin is high in sulfur?
Pheomelanin
What enzyme converts tyrosine to DOPA?
tyrosinase
What serves as a critical co-factor in melanogenesis?
copper
What is the rate limiting step in melanogenesis?
Conversion of tyrosine to DOPA via tyrosinase
What protein serves as a specific marker for melanocytes?
Tyrosinase
What hormone is the main driver of melanogenesis?
alpha-MSH (melanocyte stimulating hormone)
What receptor does alpha-MSH act on to activate melanogenesis?
MC1-R
What cytokine does alpha-MSH antagonize?
IL-1
What protein inhibits the differentiation of neural crest cells into melanocytes?
BMP-4
What cytokines act as inhibitors of melanogenesis?
TNF-a
IL-1
IL-6
During which phase of the hair cycle are melanosomes transferred to hair shafts?
Anagen only
What is the mutation in Waardenburg syndrome type IV?
EDNRB
What is the mutation in lethal white foal syndrome and what is the mode of inheritance?
EDNRB
Autosomal recessive
What condition is responsible for the “blaze” pattern and deafness seen in many pet store ferrets?
Waardenburg syndrome
A gray-blue Persian is presented with yellow eyes and a red light reflection on fundic exam. What mutation is responsible for this?
LYST gene mutation (causing Chediak-Higashi syndrome)
What breed is affected by lethal lavender foal syndrome?
Arabians of Egyptian descent
What gene is mutated in lethal lavender foal syndrome?
MYO5A (affects melanosome transfer to KCs)
What breeds are predisposed to color dilution alopecia?
Great Danes
Dobermans
Dachshunds
Whippets
Italian Greyhounds
What is the most common type of acquired hyperpigmentation?
Post-inflammatory hyperpigmentation
At which temperature does tyrosinase OCA1B become inactive?
above 35degC
Inhibition of the MC1R gene would result in production of which melanin?
Pheomelanin
Activation of the MC1R gene would result in production of which melanin?
Eumelanin
What controls the shade of eumelanin that is produced?
TYRP1
Why does piebaldism tend to affect midline areas (forehead, chest, abdomen)?
These areas are the furthest for melanocytes to migrate
True or false: deafness and hypopigmented irises are clinical features of piebaldism in dogs
False
What is mutated in short-horned and Belgian blue cattle to cause the roan coat color?
KIT-ligand (aka stem cell factor)
What condition is characterized by white coat color and congenital sensorineural deafness?
Waardenburg syndrome type 2
What genes have been associated with mutations causing Waardenburg syndrome type 2 in dogs?
MITF
SILV
What genes have been associated with mutations causing Waardenburg syndrome type 2 in cats?
KIT
What genes have been associated with mutations causing Waardenburg syndrome type 2 in cattle?
MITF
What genes have been associated with mutations causing Waardenburg syndrome type 2 in pigs?
MITF
What genes have been associated with mutations causing Waardenburg syndrome type 2 in horses?
EDNRB
PAX3
MITF
What breed of horse has a mutation in EDNRB that causes Waardenburg syndrome type 2?
Paint
Why are animals with Waardenburg syndrome also usually deaf?
Failure of melanocytes to migrate normally to stria vascularis –> hypoplastic cochlea –> failure to recycle K+ for action potential –> less endolymph production
What interaction between melanocytes and KCs controls migration of melanocytes to the anagen hair bulb?
KIT and KIT-ligand (Steel factor)
What signals are responsible for keeping melanocyte stem cells inactive during telogen?
TGF-B
Notch
Why does Palladia result in hair graying?
It is a KIT inhibitor –> melanocyte stem cells do not migrate to anagen hair bulb
What is the inheritance pattern of the gray horse phenotype?
Autosomal dominant
What gene is mutated in the gray horse phenotype?
STX17
What stages of melanosome formation involve melanin?
Stages III and IV (stages I+II melanin-free)
What gene is mutated in Gray Collie Syndrome?
AP3B1
What is Gray Collie syndrome also known as?
Canine cyclical hematopoiesis
What coat phenotype is associated with Germansky-Pudlak syndrome type 3 in Frenchies?
Cocoa coat
Besides coat color, what abnormality is seen in Frenchies with Hemansky-Pudlak syndrome type 3?
Decreased platelet dense granules (though normal bleeding)
A silver-coated cat is presented with large granules within the cytoplasm of neutrophils. What gene is affected?
LYST (Chediak-Higashi syndrome)
What gene mutation is associated with the merle coat phenotype in dogs?
SILV
What gene is mutated in the Harlequin phenotype in Great Danes?
PSMB7
What are the two components of eumelanin?
DHI (5,6-dihydroxyindole)
DHICA (5,6-dihydroxyindole-2-carboxylic acid)
What is pheomelanin composed of?
Benzothiazine units
How is L-tyrosine obtained?
From the diet
From conversion of phenylalanine
Describe the melanogenesis pathway that is shared between eumelanin and pheomelanin
L-tyrosine–> L-dopa–> dopaquinone
How is dopaquinone converted into dopachrome?
It is converted spontaneously
What enzyme is responsible for the conversion of dopachrome into DHICA and what type of melanin is subsequently produced?
dopachrome tautomerase/TYRP2
Eumelanin produced
What is dopachrome converted into?
5,6-dihydroxyindole (DHI) and DHICA
What needs to be present in sufficient amounts in order for pheomelanin to be produced?
Cysteine or glutathione
What are the 3 enzymes involved in the production of eumelanin from L-tyrosine?
Tyrosinase
TYRP1
TYRP2
What is dopaquinone converted to in the presence of cysteine or glutathione?
cysteinylDOPA
What is the role of tyrosinase or TYRP1 late in the eumelanin pathway?
It converts DHICA into eumelanin
What is the pathogenesis of oculocutaneous albinism?
Lack of melanin synthesis in melanosomes
Are animals with oculocutaneous albinism deaf?
No–melanocytes are present but there is a lack of melanin synthesis (present melanocytes=unaffected hearing)
What types of oculocutaneous albinism are present in animals?
Types I-IV
What gene is mutated in oculocutaneous albinism type IV?
SCL45A2
What gene mutation is associated with cream and white coat colors in dogs and horses?
SLC45A2 (analogous to oculocutaneous albinism type IV)
What gene mutation causes a dilution in pheomelanin but not eumelanin?
MFSD12
What amino acids are likely lacking in the diet in a black cat whose coat turns red-brown?
Tyrosine or phenylalanine
What dietary deficiency would lead to graying of the coat?
Copper
What is the pigmentary synapse?
melanosome transfer to KCs at the tips of melanocyte dendrites
Which proteins present at the tips of melanocyte dendrites facilitate melanosome transfer?
Rab27a
Melanophilin
Myosin-5a
Where are the primary locations of melanocytes in the skin?
Epidermis
Hair follicle
What layer of the skin houses the most melanocytes?
Basal layer of epidermis
What serves as the prime mediator of adhesion between melanocytes and keratinocytes?
E-cadherin
What special stain would highligh melanocytes?
Fontana-Masson
What is the key intermediate in the melanin synthesis pathway?
Dopaquinone
What transcription factor serves as the primary regulator of melanogenesis?
MITF
What is the role of Wnt in melanogenesis?
Promotes differentiation of melanoblasts into melanocytes
What protein serves as a precursor for alpha-MSH and where is the precursor protein produced?
POMC
Produced by pituitary gland
How does UVR increase skin pigmentation?
Increases POMC gene expression –> cleaved into alpha-MSH –> alpha-MSH binds to MC1R –> increased cAMP –> increased MITF –> increased melanogenesis
What is the effect of nitric oxide on melanogenesis?
Stimulatory
What is the effect of ACTH on melanogensis?
Stimulatory
What is the effect of steel factor on melanogensis?
Stimulatory
What is the effect of PGE2 on melanogenesis?
Stimulatory
What is the effect of histamine on melanogensis?
Stimulatory
What is the effect of TNF-a on melanogenesis?
Inhibitory
What is the effect of IL-1 on melanogenesis?
Inhibitory
What is the effect of IL-6 on melanogenesis?
Inhibitory
What is the role of BMP-4 in melanogenesis?
Inhibits differentiation of neural crest cells into melanocytes
What family of peptides is important for the migration of melanoblasts from dermis to basal layer of epidermis?
Endothelin family
What receptor is present on melanoblasts and interacts with endothelin-3 to allow for normal proliferation and migration of melanoblasts?
endothelin receptor B (EDNRB)
Besides resulting in abnormal melanocyte formation, what else will fail to form if there is a faulty interaction between EDNRB and ET3?
Enteric nerves
What proteins help transport melanosomes along the dendrites of melanocytes?
Dyneins
Kinesins
What protein plays a role in actin binding and melanosome transfer once the melanosome has reached the tip of the dendrite?
Myosin-5a
Are melanosomes larger in follicular melanocytes or in epidermal melanosomes?
Follicular
Are follicular or epidermal melanocytes larger?
Follicular
In what part of the follicle are melanocytes located during anagen?
Proximal hair bulb
What happens to melanocytes during catagen?
Apoptosis
What form of Waardenburg syndrome (WS) does lethal white foal syndrome most closely resemble?
WS type IV
What might you see on a trichogram from a cat with Chediak Higashi syndrome?
Macromelanosomes
Is melanin production necessary for normal hearing?
No
What is the mutation causing oculocutaneous albinism type I?
Tyrosinase
In which dog breed have they demonstrated the presence of anti-melanocyte antibodies in vitiligo cases?
Belgian Tervurens
What tissues are targeted by uveodermatologic syndrome?
Any melanin-containing tissue (eyes, skin, meninges, cochlea)
What is the explanation for dark hair regrowth in a Siamese cat who has been shaved?
acromelanism – tyrosinase is only active at low temperatures. Shaving will lower the temperature in the area and tyrosinase will be active, resulting in melanin synthesis
What color iris would you expect in a dog with albinism?
Blue
A young collie is presented with a light-colored nose. Labs reveal thrombocytopenia and neutropenia though labs 2 weeks prior revealed a neutrophilia. The dog is smaller and weaker than his littermates. What gene is likely mutated?
AP3B1 (gray collie syndrome)
What dog breed is predisposed to primary acanthosis nigricans?
Dachshunds
What clinical feature helps differentiate Snow Nose from Dudley Nose?
Snow Nose usually incomplete depigmentation
Dudley Nose is complete depigmentation
Name 3 drugs that have been associated with acquired hypopigmentation
Vitamin E
Ketoconazole
Procainamide
What dog breeds are predisposed to vitiligo?
Rottweilers
Dobermans
Collies
What cat breed is predisposed to vitiligo?
Siamese
What are the autoantibody targets in vitiligo?
Tyrosinase
TYRP1
TYRP2
Melan-
What are the targets of uveodermatologic yndrome?
tyrosinase
gp100
What allele is increased in Akitas with uveodermatologic syndrome?
DLA-DQA1
