MUTANTSgenetic variation in human development

Lecture 14

Fall 2006Bennington College

higian

Melanocyte

melanocytes synthesize pigmentcalled melanin

eumelanin - black, dk. brown

phaeomelanin - red, lt. brown, yellow

OCA2 - tyrosinase positive, mutated P protein

Mutations in MC1R(melanocyte stimulating hormone receptor)in combination with mutated P proteinproduces red-haired albinism

When MC1R receives melanocyte-stimulating factor (from pituitary),it produces eumelanin (black/brown). If inactive, phaeomelanin(red/yellow) is produced.

phaeomelanin is mutagenic and toxic in addition to being less protective against UV light

phaeomelanin produces red hair

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 affectneural crest cell migration

c-kit protooncogene - cell surface receptor for the STEEL embryonic growth factor

Autosomal dominant

mutations lead to defects in melanocyte differentiation andresultant loss of those supposed-to-be pigment-producing cells

SLUG transcription factor - critical for the proper developmentof 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 isdirected by the underlying dermis.

An embryo develops 5 million hair follicles!

but not all at the same time…starts at the eyebrows, then headand face…then neck, throat, torso…then hips and shoulders…finally arms and legs…

The interaction of the dermis and epidermisdictate the fate of the overlying epidermal cells

The epidermis must have a way to say “NO” tothe 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 skinresults in a featherless patch

FGF is the likely dermal instigator:

FGF-soaked bead placed on a chicken embryo’s skinresults in excess (and erratic) feathers

* 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.

Hair factoids

Three types of hair:

Lanugo hairThis 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

Can be congenital (inherited) or acquired

No specific genes linked to this disorder (yet)

Some types appear autosomal dominant, some appear X-linked dominant

estimates as low as 1:1000 million

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 beingtreated well and given an education

Was married to a “non-hairy” Dutchwomanat the behest of the Duchess of Parma

3 of their 4 children had hypertrichosis

Petrus Gonsalvuscirca 1582

artist unknown(but likely German)

Tognina, daughter of Petrus

painted by Lavinia Fontana (1552-1614)

Arrigo Peloso, Pietro Matto e Amon Nano

Agostino Carracci, 1598

Arrigo Gonsalvus, son of Petrus

John Crawfurd, 1829

Shwe-Maong

failure of teeth to develop

puberty delayed until age 20

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.