MUTANTS genetic variation in human development Lecture 14 Fall 2006 Bennington College

1. MUTANTSgenetic variation in human developmentLecture 14 Fall 2006Bennington College

2. higian Melanocyte melanocytes synthesize pigment called melanin eumelanin - black, dk. brown phaeomelanin - red, lt. brown, yellow

3. 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.

6. phaeomelanin produces red hair phaeomelanin is mutagenic and toxic in addition to being less protective against UV light UV light is mutagenic

8. 65% increased risk!!!!!! 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

9. 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)

15. 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

16. Epidermis, Glands, and Cutaneous appendages The same “epidermal stem cell” has the ability to become epidermis, hair (or scales and feathers), or sebaceous glands.

18. 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…

19. 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

20. 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.

21. 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.

22. 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…

23. 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

24. 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)

25. 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

26. Petrus Gonsalvus circa 1582 artist unknown (but likely German)

27. Tognina, daughter of Petrus painted by Lavinia Fontana (1552-1614)

28. Arrigo Gonsalvus, son of Petrus Arrigo Peloso, Pietro Matto e Amon Nano Agostino Carracci, 1598

29. Shwe-Maong failure of teeth to develop puberty delayed until age 20 John Crawfurd, 1829

30. Maphoon, daughter of Shwe-Maong also late/missing teeth

31. Fedor Jeftichew, (1868-1904) (Theodoro Petrov) aka “Jo-Jo the Dog-Faced Boy”

32. 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

33. 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

34. 66-yr old woman with history of breast cancer

35. Supernumerary breast

36. Conde et al., Pseudomamma on the foot: An unusual presentation of supernumerary breast tissue. Dermatology Online Journal12(4): 7, 2006.