Mutants (43 page)

127
Around day 32 after conception.
For the gross development of the human limb see Hinchliffe and Johnson (1980) p.75 and Ferretti and Tickle (1997). The condensations are described by Shubin and Alberch (1986). For a Hoxa13 mutation in man causing hand-foot-genital syndrome, (
142959; 140000
) see Mortlock and Innes (1997). Mouse models: Fromental-Ramain et al. (1996) and Mortlock et al. (1996). For a Hoxan mutation causing radioulnar systosis (
142958; 605432
) see Thompson and Nguyen (2000); Hoxd13 (gain of function) (
142989
), Muragaki et al. (1996); Hoxd cluster deletion, Del Campo et al. (1999). For the most comprehensive attempt at determining what the Hox genes are doing in the limb see Zákány et al. (1997), who report the effects of knocking out a variety of Hoxa and Hoxd genes in combination.

128
Limbs are not the only appendages.
For Hox mutations that cause both limb and genital defects in humans see the preceeding note and Kondo et al. (1997). Penis size and foot length (Siminoski and Bain, 1993). For the roles of FGFs and sonic hedgehog in genitals see Perriton et al. (2002) and Haraguchi et al. (2000).

131
The result is rather puzzling.
On the homology of lobe-finned fish fins to tetrapod limbs see Shubin et al. (1997) for a review. Sordino et al. (1995) describe Hox gene expression patterns in zebrafish compared to tetrapods. Cohn and Bright (2000) review zebrafish fin development. Dollé et al. (1993) report the Hox d13 knockout in mice; Zákány et al. (1997) argue for the successive accretion of Hox genes in evolution. The first edition of Darwin’s
The variation of animals and vegetables under domestication
was published in 1868; Gegenbauer’s critique in 1880. The Darwin quote is from the second (1882) edition of
The variation
pp.457–8 where he retreats. Coates and Clack (1990) describe
Acanthostega’
s limbs.

CHAPTER V: FLESH OF MY FLESH, BONE OF MY BONE 137

137
Around 1896, a Chinese sailor named.
Arnold and his descendants are
described by Jackson (1951) and Ramesar et al. (1996). Their disorder was cleidocranial dyplasia (
119600
) caused by a dominant haploinsufficient mutation in the osteoblast transcription factor CBFA1 gene (
600211
). See Komori et al. (1997), Mundlos et al. (1997) and Mundlos (1999) for the identification of the mutation, its function in mice, and a review of the disorder. One of the minor puzzles of this disorder is the absence of apparent homozygous infants in South Africa. With so many carriers living in a small community, two carriers must surely have occasionally married. If the mutation works in humans as it does in mice (and there is every indication it does), one quarter of the children from such a marriage would be completely boneless and stillborn (and half would be partly boneless and one quarter would be normal).

138
Perhaps because they are the last of our remains to dissipate.
For a more general review of bone growth see Olsen et al. (2000). For a review of the bone morphogenetic proteins see Cohen (2002). The emphasis placed here on the role of BMPs in making condensations is a little controversial; the evidence from mouse mutations tends to support a role for BMPs in patterning rather than osteoblast and chondrocyte differentiation or condensation formation (Wagner and Karsenty 2001). I suspect that this is due to redundancy among BMPs.

140
By one of those quirks of genetic history.
Sclerosteosis (
269500
) is caused by recessive mutations in sclerostin, a secreted protein (
605740
). Until recently it was thought that the South African families (who are all Afrikaaners), a family in Bahia, Brazil, and Dutch families with a similar disorder called Van Buchem’s disease or hyperostosis corticalis generalisata (
239100
) were all related, however remotely. However, the Afrikaaner, Bahia and Dutch families have now all been shown to carry different mutations in or near the SOST gene, so they cannot be related, and the presence of a similar disorder in all three populations is merely a coincidence (Brunkow et al. 2001; Balemans et al. 2001). The fused-finger disorder is proximal symphalangism syndrome (
185800
) caused by dominant haploinsufficient mutations in noggin (
602991
) (Gong et al. 1999). For null noggin mutations in mice see Brunet et al. (1998).

141
The disorder is known as.
Fibrodysplasia ossificans progressiva or FOP (
135100
), caused by dominant mutations in an unknown gene. In 2001, a French group reported noggin mutations in FOP patients (Sémonin et al. 2001), but this could not be replicated (Cohen 2002). For Harry Eastlack’s clinical history see Worden (2002) pp.185–6. For a nice essay about FOP, the people afflicted by it, and the search for its cure, see Maeder (1998).

144
A newly born infant has.
Baker (1974) notes that the brain case of most adults is about 5 millimetres; of Australids it can be 10 millimetres; Kohn (1995) briefly discusses the head-beating ritual.

144
What makes bones grow to the size that they do?
For an account of Victor Twitty’s experiments see Twitty and Schwind (1931) and Twitty (1966).
These experiments were carried out in the laboratory of the great developmental biologist Ross Harrison at Yale who initiated them (Harrison 1924). See Brockes (1998) for a review of salamander limb regeneration.

147
The man whose name.
For a biography of Mengele see Posner and Ware (1986).

148
Among those spared.
The account is partly based on Elizabeth Ovitz’s memoir (Moskovitz 1987) which is also the source of quotations. A careful study of the family and their experience at Auschwitz-Birkenau (Koren and Negev 2003) has, however, shown numerous inaccuracies in the memoir. Detailed accounts of the medical experiments on human subjects carried out in the Third Reich can be found in Lifton (1986).

154
Pseudoachondroplasia – the disorder that afflicted.
Pseudoachondroplasia (
177170
) is caused by dominant gain-of-function mutations in the cartilage oligomeric matrix protein gene (
600310
) (Briggs and Chapman 2002). The diagnosis of the Ovitzes as having this disorder rather than achondroplasia (as is often stated) is given in Koren and Negev (2003) and is consistent with their attractive facial features.

154
Achondroplasia is caused.
Achondroplasia (
100800
) is caused by dominant gain-of-function mutations in the fibroblast growth factor receptor 3 gene (
134934
) Rousseau et al. (1994); Bonaventure et al. (1996). For a history of the iconography of dwarfism see Dasen (1993; 1994) and Aterman (1999).

156
If an excess of FGF signalling.
For the role that FGFs play in limb growth see Naski et al. (1996; 1998) and Chen et al. (2001). Colvin et al. (1996) study the FGFR3 knockout mouse; De Luca and Baron (1999) review FGFR3 function.

156
Achondroplasia is a relatively mild disorder.
Thanatophoric dysplasia (
187600
) is caused by severe dominant gain-of-function mutations in FGFR3 (Rousseau et al. 1995; Tavormina et al. 1995). Oostra et al. (1998b) describes the Vrolik skeletal dysplasia specimens.

157
FGF must be only one molecule among many.
The authoritative review of overgrowth syndromes is Cohen (1989). Myostatin (
601788
) McPherron et al. (1997) for the mouse mutation; McPherron and Lee (1997) for cattle. The original myostatin mutation occurred naturally on a Flemish farm and so Belgian Blue meat is made ubiquitously into hamburger. Had the same animal been engineered by Monsanto it would have been surely rejected by a public ever suspicious of ‘genetically modified foods’.

158
Mutations that disable bone collagens.
There are several types of osteogenesis imperfecta. The most common type that is not lethal at birth is osteogenesis imperfecta type 1 (
166200
) caused by dominant hapoloinsufficient or gain-of-function mutations in the collagen 1A2 or collagen 1A1 genes (120150; 120160) (Olsen et al. 2000).

160
Even once our growth plates.
See Blair (1998) and Günther and Schinke (2000) for reviews on osteoclast function and specification.

160
There are many ways to upset the balance.
Malignant autosomal recessive osteopetrosis (
259700
) is caused by recessive mutations in genes that encode part of the vacuolar proton pump need for hydrochloric acid transport (Kornak et al. 2000).

161
The shortness of Henri de Toulouse-Lautrec.
The biographical material and anecdotes come largely from Frey’s (1994) authoritative biography. See Lazner et al. (1999) for the relationship between osteopetrosis and osteoporosis. Maroteaux and Lamy (1965) diagnosed Lautrec with pycknodysos-tosis and review older diagnoses; see Frey (1995 a; b) and Maroteaux (1995) for the exchange concerning his malady. Pycnodysostosis (
265800
) is caused by recessive mutations in the Cathepsin K gene (
601105
) (Gelb et al. 1996).

CHAPTER VI: THE WAR WITH THE CRANES

169
From the walls of the Prado.
For the iconography of dwarfing see Tietze-Conrat (1957) and Emery (1996). Tanner (1981) pp.120–1 discusses Geoffroy and Buffon on dwarfs.

170
Were all the court dwarfs unhappy.
See Boruwlaski’s memoirs (1792) and Heron (1986) for a modern account of his life.

175
At the base of our brains.
See Laycock and Wise (1996) for the regulation of growth by the hypothalamus-pituitary pathway. Primary growth-hormone deficiency (
262400
) is caused by recessive mutations in the growth-hormone gene (
139250
). There is an enormous literature on this group of syndromes; see López-Bermejo et al. (2000) for a brief review.

176
Joseph Boruwlaski has all the signatures.
The Ecuadorean dwarfs have Laron- or growth-hormone resistance syndrome (
262500
) caused by recessive mutations in the growth-hormone receptor gene (
600946
); see Rosenfeld et al. (1994) and Rosenbloom and Guevara-Aguirre (1998).

177
In 1782 Joseph Boruwlaski met.
Frankcom and Musgrave (1976) write about Patrick Cotter; Bondeson (1997) about Charles Byrne; Thompson (1930, 1996) tells of both men as well as other famous eighteenth-century giants.

179
Charles Byrne had a pituitary tumor.
See Keith (1911) for original diagnosis.

179
An old photograph shows a triptych of skeletons.
See Schnitzer (1888) (Emin Pasha’s given name) for an account of how he obtained the skeletons. See Schweinfurth (1878) for an account of meeting Akadimoo. The Homeric quote is from
The Iliad
(1950 trans. E.V. Rieu, Penguin Books, Harmondsworth, UK). Tyson (1699, 1966); Schweinfurth (1878); de Quatrefages (1895); Cavalli-Sforza (1986) all give accounts of Greek and Roman writings on pygmies, but the authoritative work on pygmies in antiquity is Dasen (1993). See Addison (1721) for his verses on pygmies.

182
Addison’s poem.
See Tyson (1699,1966) for his dissection of a ‘pygmie’; de Quatrefages (1895) says that the word ‘Aka’ can be found inscribed on the frescos of a fifth-century Egyptian tomb beneath a depiction of a dancing
pygmy; Cavalli-Sforza (1986) repeats the story. This would be remarkable if true, but sadly Véronique Dasen assures me it is not.

183
The French anthropologist Armand de Quatrefages.
See Schebesta (1952) and Weber (1995–99) for the history of the negritos; Diamond (1991) discusses theories about pygmy smallness. For the most recent study on the genetic relationships of Andaman Island negritos see Thangaraj et al. (2003).

185
The diagnosis of achondroplasia.
The Attic vase is just one of many examples of Greek pygmy iconography given by Dasen (1993). Gates (1961) asserted thatpygmies have achondroplasia.

185
That pygmy proportions.
The genetics of pygmy smallness are obscure, but the evidence seems to exclude a single locus with substantial dominance. See Shea and Bailey (1986), Shea and Gomez (1988) and Shea (1989) for an analysis of pygmy proportions.

187
The geographers, entranced by their acquisition.
The history of Chair-Allah and Thibaut is given in de Quatrefages (1895) and Schweinfurth (1878); their growth curve is given in Cavalli-Sforza (1986) p.366.

188
A newborn infant grows.
See Tanner (1990) p.12 for the pubertal growth spurt and Tanner (1981) pp.104–5 for the history of its study; see Bogin (1999) for pubertal spurts in other primates.

189
The pubertal spurt is driven.
There is some disagreement as to whether pygmies show low IGF-1 serum titres or whether they have a less effective IGF-1 receptor relative to taller people. In any event, what we know about short stature in pygmies is based on endocrinological studies (Merimee et al. 1981; 1987; Geffner et al. 1995). The following note also bears on the interpretation of these data.

189
The proof of this is the mini-mouse.
The account of the relationship between IGF and GH given here differs from the ‘somatomedin hypothesis’ given in most textbooks. Recent experiments have suggested that: (1) IGF-I’S primary role is as a paracrine (short-range) growth factor rather than an exocrine hormone; (2) that liver IGF-1 is responsible for most serum IGF, and that it contributes little to post-natal growth; (3) that IGF-1’s effects on growth are therefore to a considerable degree – though not entirely – inde pendent of GH’s. See Le Roith et al. (2001) for a review of these matters, and Lupu et al. (2001) for an account of the GHR; IGF-1 double knockout mouse.