MUTANTS
genetic variation in human development
Lecture 14
Fall 2006
Bennington College
melanocytes synthesize pigment
called melanin
eumelanin - black, dk. brown
phaeomelanin - red, lt. brown, yellow
higian
Melanocyte
OCA2 - tyrosinase positive, mutated P protein
Mutations in MC1R
(melanocyte stimulating hormone receptor)
in combination with mutated P protein
produces red-haired albinism
When MC1R receives melanocyte-stimulating factor (from pituitary),
it produces eumelanin (black/brown). If inactive, phaeomelanin
(red/yellow) is produced.
phaeomelanin produces red hair
phaeomelanin is mutagenic and toxic in addition
to being less protective against UV light
UV light is mutagenic
Certain polymorphisms in MC1R predispose heavily toward melanoma
recent data points not to the fair-skinned redheads, but those
with medium or olive complexion as being most at risk.
greatest risk found in women who had one RHC allele (red hair color ;
especially linked to Arg151Cys mutation) and one NRHC (non-red hair color) allele
65% increased risk!!!!!!
Pituitary gland secretes melanocyte-stimulating factor (MSH)
Some people with adrenalectomies develop progressively darker skin
(loss of regulation of pituitary secretion of MSH by the adrenal gland)
Piebaldism is linked to genes that affect
neural crest cell migration
Autosomal dominant
c-kit protooncogene - cell surface receptor for the STEEL
embryonic growth factor
mutations lead to defects in melanocyte differentiation and
resultant loss of those supposed-to-be pigment-producing cells
SLUG transcription factor - critical for the proper development
of neural crest cells
Epidermis, Glands, and Cutaneous appendages
The same “epidermal stem cell” has the
ability to become epidermis, hair (or
scales and feathers), or sebaceous
glands.
During development, the aggregation of cells in the epidermal
basal layer signals an impending hair follicle
This begins at around 3 months of gestation and is
directed by the underlying dermis.
An embryo develops 5 million hair follicles!
but not all at the same time…starts at the eyebrows, then head
and face…then neck, throat, torso…then hips and shoulders…
finally arms and legs…
The interaction of the dermis and epidermis
dictate the fate of the overlying epidermal cells
The epidermis must have a way to say “NO” to
the dermal signals (or we would be one giant
hair follicle)
BMP4 is the likely epidermal inhibitor:
BMP4-soaked bead placed on a chicken embryo’s skin
results in a featherless patch
FGF is the likely dermal instigator:
FGF-soaked bead placed on a chicken embryo’s skin
results in excess (and erratic) feathers
Hair factoids
* On average, each person's head carries about 100,000 hair follicles.
Some people have as many as 150,000.
* On a baby's head, there are about 1,100 follicles per square centimeter
(this is more follicles/cm2 than monkeys or cats!!!)
* By the age of 25, this number has fallen to about 600, but the number
depends on the individual.
* Between the ages of 30 and 50, the number drops further, to 250-300.
There is only a slight further fall with age.
* Each follicle grows about 20 new hairs in a lifetime.
Each new hair grows for several years, and can reach over a meter in length.
* Each hair falls out eventually and is replaced by a new one.
Three types of hair:
Lanugo hair
This is the hair that develops on an unborn baby.
It begins to grow about three months after the baby's
conception.
The hairs are fine and soft, and they grow all over the
baby's body.
They all grow at the same rate, so the hairs are the same
length.
Some prematurely born babies are still covered with these
downy hairs. Normally they are shed about four weeks
before the baby is due to be born.
Three types of hair:
Vellus hairs
Short hairs, only a centimeter or two long
Contain little or no pigment
The follicles that produce them do not have sebaceous glands
At puberty, vellus hairs in armpits, on chest and face (mostly in men),
and pubic regions give way to the next hair type…
Three types of hair:
Terminal hairs
The long hairs that grow on the head (and in many people on the body, arms and
legs too)
They are produced by follicles with sebaceous glands
When people are “going bald”, the hairs in these follicles gradually become thinner
and shorter until they resemble vellus hairs
Hypertrichosis - excessive growth of hair (terminal,
vellus, or lanugo) in an adrogen-independent manner
Only 50 reported cases since the late 1800’s
estimates as low as 1:1000 million
Can be congenital (inherited) or acquired
Some types appear autosomal dominant, some appear X-linked dominant
No specific genes linked to this disorder (yet)
In 1556 12-year old Petrus Gonsalvus
arrived in France at the King’s request
(some sources say he was born in 1556)
His unusual appearance led to him being
treated well and given an education
Was married to a “non-hairy” Dutchwoman
at the behest of the Duchess of Parma
3 of their 4 children had hypertrichosis
Petrus Gonsalvus
circa 1582
artist unknown
(but likely German)
Tognina, daughter of Petrus
painted by Lavinia Fontana (1552-1614)
Arrigo Gonsalvus, son of Petrus
Arrigo Peloso, Pietro Matto e Amon Nano
Agostino Carracci, 1598
Shwe-Maong
failure of teeth to
develop
puberty delayed
until age 20
John Crawfurd, 1829
Maphoon, daughter of Shwe-Maong
also late/missing teeth
Fedor Jeftichew, (1868-1904)
(Theodoro Petrov)
aka “Jo-Jo the Dog-Faced Boy”
Acquired Hypertrichosis Lanuginosa
any number of drugs (corticosteroids, cyclosporine, diazoxide,
interferon, minoxidil, phenytoin, streptomycin, zidovudine)
head injury/cerebral disturbance
malnutrition/anorexia (especially exclusion of carbohydrates)
juvenile hypothyroidism (helped by thyroxine replacement)
AIDS (immunological dysregulation)
internal malignancy of some kind
68-yr old woman presented with 30 kg weight loss and sudden hair growth
hair was of the lanugo variety
hormones and bloodwork all normal except for an
elevated level of a carcinoembryonic antigen
found rectal adenocarcinoma
66-yr old woman with history of breast cancer
Supernumerary
breast
Conde et al., Pseudomamma on the foot: An unusual presentation of supernumerary
breast tissue. Dermatology Online Journal 12(4): 7, 2006.