Melanogenesis and melanocytic disorders Flashcards
1
Q
What gene mutations have been associated with piebaldism?
A
c-kit/CD117
steel factor
1
Q
What genes are mutated in Waardenburg-Klein syndrome?
A
EDNRB
MITF
SOX10
PAX3
2
Q
What is the inheritance pattern of Waardenburg-Klein syndrome?
A
Autosomal dominant
3
Q
What is the inheritance pattern of lentiginosis profusa?
A
Autosomal dominant
4
Q
What breed is predisposed to lentiginosis profusa?
A
Pugs
5
Q
What is the inheritance pattern of piebaldism?
A
Autosomal dominant
6
Q
What breed of cat is affected by Chediak-Higashi syndrome?
A
Persian (blue smoke color only)
7
Q
What is the inheritance pattern of Chediak-Higashi syndrome in cats?
A
Autosomal recessive
8
Q
What gene is mutated in Chediak-Higashi syndrome in cats?
A
LYST
9
Q
What is the inheritance pattern of color dilution alopecia?
A
Autosomal recessive
10
Q
What gene is mutated in color dilution alopecia?
A
MLPH
11
Q
What is the inheritance pattern of vitiligo?
A
Autosomal recessive
12
Q
What gene is mutated in vitiligo?
A
FOXD3
13
Q
What is the inheritance pattern of feline acromelanism?
A
Autosomal recessive
14
Q
What gene is mutated in feline acromelanism?
A
tyrosinase OCA1B
15
Q
From what structure are melanocytes derived?
A
Neural crest
16
Q
Besides the skin, where else are melanocytes found?
A
Meninges
Cochlea (stria vascularis)
Eyes
17
Q
What determines color in amphibians, fish, reptiles, and crustaceans?
A
Chromatophores
18
Q
What determines color in mammals and birds?
A
Melanin
19
Q
How many melanocytes comprise an epidermal melanin unit in dogs?
A
1 melanocyte per 10-20 KCs
20
Q
What IHC markers are used for melanocytes?
A
Vimentin
S-100 protein
21
Q
What type of melanin is red-yellow?
A
Pheomelanin
22
Q
What type of melanin is brown-black?
A
Eumelanin
23
Q
What type of melanin has spherical melanosomes?
A
Pheomelanin
24
What type of melanin has elliptical melanosomes?
Eumelanin
25
What type of melanin is low in cysteine?
Eumelanin
26
What type of melanin is high in cysteine?
Pheomelanin
27
What type of melanin is produced in high levels of tyrosinase?
Eumelanin
28
What type of melanin is produced in low levels of tyrosinase?
Pheomelanin
29
What type of melanin is high in sulfur?
Pheomelanin
30
What enzyme converts tyrosine to DOPA?
tyrosinase
31
What serves as a critical co-factor in melanogenesis?
copper
32
What is the rate limiting step in melanogenesis?
Conversion of tyrosine to DOPA via tyrosinase
33
What protein serves as a specific marker for melanocytes?
Tyrosinase
34
What hormone is the main driver of melanogenesis?
alpha-MSH (melanocyte stimulating hormone)
35
What receptor does alpha-MSH act on to activate melanogenesis?
MC1-R
36
What cytokine does alpha-MSH antagonize?
IL-1
37
What protein inhibits the differentiation of neural crest cells into melanocytes?
BMP-4
38
What cytokines act as inhibitors of melanogenesis?
TNF-a
IL-1
IL-6
39
During which phase of the hair cycle are melanosomes transferred to hair shafts?
Anagen only
40
What is the mutation in Waardenburg syndrome type IV?
EDNRB
41
What is the mutation in lethal white foal syndrome and what is the mode of inheritance?
EDNRB
Autosomal recessive
42
What condition is responsible for the "blaze" pattern and deafness seen in many pet store ferrets?
Waardenburg syndrome
43
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)
44
What breed is affected by lethal lavender foal syndrome?
Arabians of Egyptian descent
45
What gene is mutated in lethal lavender foal syndrome?
MYO5A (affects melanosome transfer to KCs)
46
What breeds are predisposed to color dilution alopecia?
Great Danes
Dobermans
Dachshunds
Whippets
Italian Greyhounds
47
What is the most common type of acquired hyperpigmentation?
Post-inflammatory hyperpigmentation
48
At which temperature does tyrosinase OCA1B become inactive?
above 35degC
49
Inhibition of the MC1R gene would result in production of which melanin?
Pheomelanin
50
Activation of the MC1R gene would result in production of which melanin?
Eumelanin
51
What controls the shade of eumelanin that is produced?
TYRP1
52
Why does piebaldism tend to affect midline areas (forehead, chest, abdomen)?
These areas are the furthest for melanocytes to migrate
53
True or false: deafness and hypopigmented irises are clinical features of piebaldism in dogs
False
54
What is mutated in short-horned and Belgian blue cattle to cause the roan coat color?
KIT-ligand (aka stem cell factor)
55
What condition is characterized by white coat color and congenital sensorineural deafness?
Waardenburg syndrome type 2
56
What genes have been associated with mutations causing Waardenburg syndrome type 2 in dogs?
MITF
SILV
57
What genes have been associated with mutations causing Waardenburg syndrome type 2 in cats?
KIT
58
What genes have been associated with mutations causing Waardenburg syndrome type 2 in cattle?
MITF
59
What genes have been associated with mutations causing Waardenburg syndrome type 2 in pigs?
MITF
60
What genes have been associated with mutations causing Waardenburg syndrome type 2 in horses?
EDNRB
PAX3
MITF
61
What breed of horse has a mutation in EDNRB that causes Waardenburg syndrome type 2?
Paint
62
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
63
What interaction between melanocytes and KCs controls migration of melanocytes to the anagen hair bulb?
KIT and KIT-ligand (Steel factor)
64
What signals are responsible for keeping melanocyte stem cells inactive during telogen?
TGF-B
Notch
65
Why does Palladia result in hair graying?
It is a KIT inhibitor --> melanocyte stem cells do not migrate to anagen hair bulb
66
What is the inheritance pattern of the gray horse phenotype?
Autosomal dominant
67
What gene is mutated in the gray horse phenotype?
STX17
68
What stages of melanosome formation involve melanin?
Stages III and IV (stages I+II melanin-free)
69
What gene is mutated in Gray Collie Syndrome?
AP3B1
70
What is Gray Collie syndrome also known as?
Canine cyclical hematopoiesis
71
What coat phenotype is associated with Germansky-Pudlak syndrome type 3 in Frenchies?
Cocoa coat
72
Besides coat color, what abnormality is seen in Frenchies with Hemansky-Pudlak syndrome type 3?
Decreased platelet dense granules (though normal bleeding)
73
A silver-coated cat is presented with large granules within the cytoplasm of neutrophils. What gene is affected?
LYST (Chediak-Higashi syndrome)
74
What gene mutation is associated with the merle coat phenotype in dogs?
SILV
75
What gene is mutated in the Harlequin phenotype in Great Danes?
PSMB7
76
What are the two components of eumelanin?
DHI (5,6-dihydroxyindole)
DHICA (5,6-dihydroxyindole-2-carboxylic acid)
77
What is pheomelanin composed of?
Benzothiazine units
78
How is L-tyrosine obtained?
From the diet
From conversion of phenylalanine
79
Describe the melanogenesis pathway that is shared between eumelanin and pheomelanin
L-tyrosine--> L-dopa--> dopaquinone
80
How is dopaquinone converted into dopachrome?
It is converted spontaneously
81
What enzyme is responsible for the conversion of dopachrome into DHICA and what type of melanin is subsequently produced?
dopachrome tautomerase/TYRP2
Eumelanin produced
82
What is dopachrome converted into?
5,6-dihydroxyindole (DHI) and DHICA
83
What needs to be present in sufficient amounts in order for pheomelanin to be produced?
Cysteine or glutathione
84
What are the 3 enzymes involved in the production of eumelanin from L-tyrosine?
Tyrosinase
TYRP1
TYRP2
85
What is dopaquinone converted to in the presence of cysteine or glutathione?
cysteinylDOPA
86
What is the role of tyrosinase or TYRP1 late in the eumelanin pathway?
It converts DHICA into eumelanin
87
What is the pathogenesis of oculocutaneous albinism?
Lack of melanin synthesis in melanosomes
88
Are animals with oculocutaneous albinism deaf?
No--melanocytes are present but there is a lack of melanin synthesis (present melanocytes=unaffected hearing)
89
What types of oculocutaneous albinism are present in animals?
Types I-IV
90
What gene is mutated in oculocutaneous albinism type IV?
SCL45A2
91
What gene mutation is associated with cream and white coat colors in dogs and horses?
SLC45A2 (analogous to oculocutaneous albinism type IV)
92
What gene mutation causes a dilution in pheomelanin but not eumelanin?
MFSD12
93
What amino acids are likely lacking in the diet in a black cat whose coat turns red-brown?
Tyrosine or phenylalanine
94
What dietary deficiency would lead to graying of the coat?
Copper
95
What is the pigmentary synapse?
melanosome transfer to KCs at the tips of melanocyte dendrites
96
Which proteins present at the tips of melanocyte dendrites facilitate melanosome transfer?
Rab27a
Melanophilin
Myosin-5a
97
Where are the primary locations of melanocytes in the skin?
Epidermis
Hair follicle
98
What layer of the skin houses the most melanocytes?
Basal layer of epidermis
99
What serves as the prime mediator of adhesion between melanocytes and keratinocytes?
E-cadherin
100
What special stain would highligh melanocytes?
Fontana-Masson
101
What is the key intermediate in the melanin synthesis pathway?
Dopaquinone
102
What transcription factor serves as the primary regulator of melanogenesis?
MITF
103
What is the role of Wnt in melanogenesis?
Promotes differentiation of melanoblasts into melanocytes
104
What protein serves as a precursor for alpha-MSH and where is the precursor protein produced?
POMC
Produced by pituitary gland
105
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
106
What is the effect of nitric oxide on melanogenesis?
Stimulatory
107
What is the effect of ACTH on melanogensis?
Stimulatory
108
What is the effect of steel factor on melanogensis?
Stimulatory
109
What is the effect of PGE2 on melanogenesis?
Stimulatory
110
What is the effect of histamine on melanogensis?
Stimulatory
111
What is the effect of TNF-a on melanogenesis?
Inhibitory
111
What is the effect of IL-1 on melanogenesis?
Inhibitory
112
What is the effect of IL-6 on melanogenesis?
Inhibitory
113
What is the role of BMP-4 in melanogenesis?
Inhibits differentiation of neural crest cells into melanocytes
114
What family of peptides is important for the migration of melanoblasts from dermis to basal layer of epidermis?
Endothelin family
115
What receptor is present on melanoblasts and interacts with endothelin-3 to allow for normal proliferation and migration of melanoblasts?
endothelin receptor B (EDNRB)
116
Besides resulting in abnormal melanocyte formation, what else will fail to form if there is a faulty interaction between EDNRB and ET3?
Enteric nerves
117
What proteins help transport melanosomes along the dendrites of melanocytes?
Dyneins
Kinesins
118
What protein plays a role in actin binding and melanosome transfer once the melanosome has reached the tip of the dendrite?
Myosin-5a
119
Are melanosomes larger in follicular melanocytes or in epidermal melanosomes?
Follicular
120
Are follicular or epidermal melanocytes larger?
Follicular
121
In what part of the follicle are melanocytes located during anagen?
Proximal hair bulb
122
What happens to melanocytes during catagen?
Apoptosis
123
What form of Waardenburg syndrome (WS) does lethal white foal syndrome most closely resemble?
WS type IV
124
What might you see on a trichogram from a cat with Chediak Higashi syndrome?
Macromelanosomes
125
Is melanin production necessary for normal hearing?
No
126
What is the mutation causing oculocutaneous albinism type I?
Tyrosinase
127
In which dog breed have they demonstrated the presence of anti-melanocyte antibodies in vitiligo cases?
Belgian Tervurens
128
What tissues are targeted by uveodermatologic syndrome?
Any melanin-containing tissue (eyes, skin, meninges, cochlea)
129
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
130
What color iris would you expect in a dog with albinism?
Blue
131
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)
132
What dog breed is predisposed to primary acanthosis nigricans?
Dachshunds
133
What clinical feature helps differentiate Snow Nose from Dudley Nose?
Snow Nose usually incomplete depigmentation
Dudley Nose is complete depigmentation
134
Name 3 drugs that have been associated with acquired hypopigmentation
Vitamin E
Ketoconazole
Procainamide
135
What dog breeds are predisposed to vitiligo?
Rottweilers
Dobermans
Collies
136
What cat breed is predisposed to vitiligo?
Siamese
137
What are the autoantibody targets in vitiligo?
Tyrosinase
TYRP1
TYRP2
Melan-
138
What are the targets of uveodermatologic yndrome?
tyrosinase
gp100
139
What allele is increased in Akitas with uveodermatologic syndrome?
DLA-DQA1
