Melanogenesis Flashcards
What cells can have giant granules with Chediak-Higashi syndrome?
melanocytes, eosinophils, mast cells, lymphocytes, neutrophils, etc.
Which are red-yellow in color: eumelanin or phenomelanin?
pheomelanin
T/F: Homozygous mutation in PSMB7 (Harlequin locus) is embryonic lethal.
TRUE
What breeds of dogs are over-represented with color dilution alopecia?
Dobermans (esp. blue and fawn), Dachshunds, Great Danes, Whippets, Italian Greyhounds
What role do melanocytes play in the cochlea?
they are intermediate cells of the stria vascularis; maintain the endocochlear potential in endolymph –> allows hearing to take place
What is the rate limiting step in melanin synthesis?
conversion of L-tyrosine to L-DOPA (by tyrosinase OR tyrosine hydroxylase-1)
What is facultative pigment?
pigmentation that occurs in response to stimuli (such as UV light)
What changes in coat color can be seen with copper deficiency? Why?
Copper is a cofactor for Tyrosinase –> absence of copper –> graying of the hair coat
T/F: Leukoderma without leukotrichia is common.
False - usually accompanied by leukotrichia
T/F: With good supportive care, collies affected by Gray Collie Syndrome can have a normal life expectancy.
False - even with supportive care, are prone to anemia, arthritis, amyloidosis, glomerulonephritis, and lymphoid exhaustion
What is the function of Myosin 5A? What disease results from a mutation in the gene that encodes for it?
Myosin 5A is a motor protein involved in shuttling intracellular proteins; mutations in this protein lead to faulty melanosome transfer (among others) –> lavendar foal syndrome
Where are epidermal melanocytes located?
basal layer
T/F: Oculocutaneous albinism type 1 and type 3 primarily affect eumelanin synthesis.
TRUE
T/F: Leukotrichia without leukoderma is common.
TRUE
T/F: In piebaldism, the mutation is in the gene for KIT and results in absence of melanocytes in the affected area.
TRUE
Does steel (stem cell) factor stimulate or inhibit melanogenesis?
stimulate
What defect in neutrophils occurs with Gray Collie Syndrome?
lack neutrophil elastase (difficulty in making the neutrophil granules)
What cell type is targed in uveodermatologic syndrome?
melanocytes
Which is produced with ASP (agonist stimulating protein = agouti) binds to MC1R: eumelanin or pheomelanin?
pheomelanin
Does UV radiation stimulate or inhibit melanogenesis
stimulate
What breeds of dogs are over-represented with vitiligo?
Belgian Tervuren dogs, Rottweilers, Old English Sheepdogs
What cell type is targeted in cutaneous lupus erythematosus?
basal keratinocytes
T/F: Animals with oculocutaneous albinism have congenital deafness.
False - even though they have hypopigmentation, the melanocytes are still present - they just don’t produce pigment due to lack of tyrosinase
Lethal White Foal Syndrome is associated with a mutation in what gene? What are the clinical features?
Endothelin receptor type-B (EDNR-B); white hair coat, hypopigmented blue eyes, congenital sensorineural deafness, colonic aganglionosis
Which are larger: follicular or epidermal melanocytes?
follicular - they also are more dendritic and produce larger melanosomes
Does endothelin-1 stimulate or inhibit melanogenesis?
stimulate
What does ultraviolet radiation upregulate that can stimulate melanogenesis and produce increased pigmentation?
POMC gene expression –> POMC –> alpha-MSH & ACTH –> bind to MC1R –> increases activity of MITF
Does BMP-4 (bone morphogenetic protein-4) stimulate or inhibit melanogenesis?
inhibit
What is the function of the silver protein (premelanosome protein 17)? Mutations in this gene result in what clinical phenotype?
adds internal protein fibrils that hold melanin and give the ellipsoid melanosome shape; Mutations result in the Merle phenotype
What is the mode of inheritance in the Harlequin locus in Great Danes? In what gene is the mutation?
Autosomal dominant mutation in PSMB7 = beta-2 catalytic subunit of the proteasome
Does IL-1 stimulate or inhibit melanogenesis?
inhibit
Age-related graying is thought to be a disorder of what cell type?
stem cells (either melanocyte stem cells or hair follicle stem cells) – thought to be related to oxidative injury to these cells
What gene induces transcription of tyrosinase, TyRP-1, DOPA, and TyRP-2?
microphthalmia-associated transcription factor (MITF)
Neural crest cells that utilize the ventral track can differentiate into what cell types?
neural cells, glial cells, melanocytes
T/F: Animals with piebaldism may also be deaf due to aberrant melanocyte migration.
False - no other phenotypic abnormalities are present
T/F: Collies affected by Gray Collie Syndrome lack melanocytes.
False - they have melanocytes, the defect is in melanosome formation – can only may a stage 3 melanosome (reason color is dilute instead of albino)
Does ACTH stimulate or inhibit melanogenesis?
stimulate
If an animal has a defect in melanosome formation, what other organelles may be affected?
platelet dense granules, lymphocyte lytic granules
Mode of inheritance of gray horse phenotype? In what gene in the mutation?
Autosomal dominant mutation in STX17
Does TNF-alpha stimulate or inhibit melanogenesis?
inhibit
Mode of inheritance of Oculocutaneous albinism-Type 1TS seen in Siamese and Burmese cats?
Autosomal recessive
What is constitutive pigment?
pigmentation that is genetically determined in the absence of external influences
Which has more structure to the melanosome: eumelanin or pheomelanin?
eumelanin
Mode of inheritance of Chediak-Higashi Syndrome?
Autosomal recessive
T/F: Horses with a gray phenotype lose pigment in the skin and hair follicles.
False - just the hair follicles –> predisposes them to cutaneous melanomas
What is the mode of inheritance of Gray Collie Syndrome? What are the clinical signs associated with the disease?
Autosomal recessive; Cyclical hematopoiesis (congenital neutropenia); infections, gingivitis; fever, diarrhea, arthralgia; Gonadal hypoplasia
What is the clinical presentation of animals affected with Chediak-Higashi syndrome?
hypopigmentatoin of the skin, hair coat, and eyes – silver-colored hair
Mode of inheritance of lavendar foal syndrome? In what gene/protein is the mutation?
Autosomal recessive, homozygous lethal mutation in MYO5A – Myosin 5A
Does nitric oxide stimulate or inhibit melanogenesis?
stimulate
Which are black-brown in color: eumelanin or pheomelanin?
eumelanin
T/F: Homozygous mutation in SILV (PMEL17) = Merle locus is embryonic lethal.
False - has a higher incidence of deafness
What abnormalities results from a mutation in KIT? Mode of inheritance?
Piebaldism; autosomal dominant
T/F: The hair of animals with color dilution alopecia contains more melanin than non-dilute counterparts.
True - they appear lighter in color due to the clumping and abnormal melanosomes
Which is high in cysteine or glutathione: eumelanin or pheomelanin?
pheomelanin
Do leukotrienes (LTB4, LTC4) and prostaglandins (PGE2, PGF2alpha) stimulate or inhibit melanogenesis
stimulate
What is the role of KIT and its ligand SCF in melanogenesis?
involved in melanocyte migration to epidermis
What enzyme controls the shade of eumelanin (black, brown)?
tyrosinase-related protein 1
Where is the defect in melanogenesis with Chediak-Higashi syndrome?
melanosome biogenesis
Besides the epidermis and hair follicle, where else are melanocytes located?
ducts of sebaceous and sweat glands, superficial dermis, uvea of eye, cardiovascular system, cochlea (stria vascularis), CNS, adipose tissue
What processes can up-regulate MITF (microphthalmia-associated transcription factor)?
1) Binding of c-kit with steel factor (stem cell factor) –> leads to activation of cAMP pathway; 2) Binding of MC1R (melanocortin 1 receptor) by alpha-MSH and ACTH (eumelanin) and ASP (agonist stimulating protein = agouti) - pheomelanin
Clinical features of oculocutaneous albinism
white hair coat, blue irides, nystagmus, photophobia
What are the two microtubule proteins that transport melanosomes along the melanocyte dendrite?
dynein (retrograde motion) and kinesins (anterograde)
Which is produced when alpha-MSH or ACTH binds to MC1R: eumelanin or pheomelanin?
eumelanin
Where are melanocyte stem cells located?
epidermis, dermis (mouse), glands, “bulge” of hair follicle, Schwann cell precursors along nerves
Does alpha-MSH stimulate or inhibit melanogenesis?
stimulate
What are the three most important enzymes involved in melanin synthesis?
phenylalanine hydroxylase, tyrosine hydroxylase-1, tyrosinase
What is the mode of inheritance of the Merle Phenotype? In what gene is the mutation?
Autosomal dominant mutation in SILV (PMEL17) = silver protein/premelanosome protein 17
Which comes first with uveodermatologic syndrome: ocular or dermatologic signs?
ocular
T/F: Phenylalanine is an essential amino acid.
TRUE
Which contains higher sulfur content: eumelanin or pheomelanin?
pheomelanin
Where are follicular melanocytes located?
outer root sheath and hair matrix of hair follicles
In vitiligo, what cell type is targeted?
melanocytes – keratinocytes are normal!
In what breed of horse has lavendar foal syndrome been reported?
Egyptian Arabians
What shape are the melanosomes of pheomelanin?
spherical
A mutation in AP3B1, which encodes the beta-subunit of the AP-3 complex that delivers the enzymes to developing melanosomes, results in what clinical disease in dogs?
Gray Collie Syndrome
Does histamine stimulate or inhibit melanogenesis?
stimulate
Describe the changes present in melanogenesis of cats with seal-points
Have a temperature-sensitive tyrosinase – only active on cooler areas of the body (ear tips, face, feet, tail) –> those are the only areas with pigment
A mutation in the coat color gene at D locus results in what disease?
color dilution
What is the role of endothelin-3 in melanogenesis?
involved in melanoblast migration from dermis to basal layer of epidermis; produced by ectodermal cells –> binds to endothelin receptor B on melanoblasts; essential for survival, proliferation, and migration of melanoblasts as well as normal formation of enteric nerves
Does IL-6 stimulate or inhibit melanogenesis?
inhibit
What is the role of endothelin-1 in melanogenesis?
activates tyrosinase, increases MC1R, increases TRP-1; stimulates melanocyte proliferation, increases dendrite formation; increased thymin dimer repair
Why is it not recommended to breed two Overo spotted paint horses?
can result in lethal white foal syndrome – Waardenburg syndrome type IV
What element is an important cofactor of tyrosinase?
copper
Functions of melanocytes
1) Cosmetic appearance, 2) Protection against ionizing radiation - can absrob a wide spectrum ov UV and visible light wavelengths; 3) Scavenger of Cytotoxic free radicals and intermediates; 4) Secretion of pro-inflammatory cytokines: IL-8, IL-1alpha, TNF-alpha; 5) Inhibition of keratinocyte proliferation; 6) Calcium homeostasis
What shape are the melanosomes of eumelanin?
elliptical
What special stains are needed to visualize melanocytes on histopathology?
DOPA oxidase reaction, Fontana-Masson stain, Schmorl’s method; immunohistochemistry: vimentin, S-100 protein
T/F: Animals with Waardenburg Syndrome lack melanocytes in hypopigmented areas.
True - defect is due to a failure in migration and development of melanoblasts
Which is produced with high levels of tyrosinase: eumelanin or pheomelanin?
eumelanin
Mutations in what genes have been reported with digital squamous cell carcinoma in Black Standard Poodles?
Kit Ligand (SCF), MC1R
What changes in coat color can be seen with phenylalanine deficiency? Why?
Decreased melanin synthesis, most common color change is red-brown hair coat instead of black
What abnormality would be present in a trichogram of an animal with Chediak-Higashi syndrome? Why?
large, irregular clumps of melanin in the hair shaft; due to defect in formation of melanosome => results in irregular dispersion and irregular size to the melanosome
Conditions with white coat color in animals occurring with congenital sensorineural deafness and/or hypopigmented iridies are similar to what disease in humans?
Waardenberg syndrome type-2
T/F: Tyrosine is an essential amino acid.
False - can be synthesized from Phenylalanine
