107 As recently as 1900. The story of the Cleppies is told by the British geneticist Karl Pearson (1908) in one of the first studies of a ‘lobster-claw’ family. Most British historians, Macaulay among them, accept that the Wigtown martyrs existed, but some such as Irving (1862) have noted that there are no eyewitness accounts and doubts that the whole thing happened, the graves notwithstanding. The best account is Fraser (1877). Irving and Fraser also note that another legend has another officer, the Provost, saying to maid Wilson, ‘Hech, my hearty! tak anither drink,’ only to find himself evermore afflicted with an unappeasable thirst. The uncertain nature of the story is made even clearer by the reference to ‘Good King Charlie’ – Charles II – who at the time of the execution, 11 May 1685, had been dead for two months. Historians generally blame his successor, the Roman Catholic James II, for unleashing the army on the Scottish Lowlands. The etymology of ‘clep’ is also confusing. W.A. Craigie, in his Dictionary of the older Scottish tongue(1931), gives ‘clep’ as ‘call’, but Pearson’s story suggests that ‘clepped’ also means to have a limb deformity. The clepped families themselves are described by Pearson (1908), McMullen and Pearson (1913) and Lewis and Embleton (1908). Pearson’s papers are of particular historical interest for he uses them to advance the agenda of the biometricians against the Mendelians by showing that this apparently dominant gene does not segregate in Mendelian ratios. While his campaign against Mendelianism proved futile, he was partly right about this trait: it looks as though at least one ectrodactyly allele is over-represented in male progeny, an apparent case of meiotic drive, the only one known in a human pathology (Jarvik et al. 1994).
109 The fragments of myth. Euterpe Bazopoulou-Kyrkanidou (1997) argues persuasively that Hephaestus’ lameness was usually represented as club-feet. Aterman (1999) proposes that Hephaestus’ deformity is related to the achondroplasia of the Egyptian deity Ptah – on which more in Chapter V – and, later, to arsenic neuritis, an acquired disease associated with smiths. These points of view are not necessarily inconsistent as the iconography clearly evolved over time. For the origins of the story of the Ostrich-Footed Wadoma see Gelfland et al. (1974); Roberts (1974); articles resurrecting the myth (e.g. Barrett and McCann 1980) and genetic investigations (Farrell 1984, Viljoen and Beighton 1984). Limb defects are second only to congenital heart defects in frequency (Bamshad et al. 1999).
111 One of the strange things about limbs. Pearson (1908) and Lewis and Embleton (1908) recount the manual dexterity of ‘lobster-claw’ families. See Hermann Unthan’s (1935) memoirs for an edifying account of armlessness. The goat is described by Slijper (1942).
113 What induces a limb-bud to grow out into space? The original description of the apical ectodermal ridge (or AER) and its experimental removal is described by Saunders (1948). Acheiropody (200500) is described by Freire-Maia (1975, 1981).
115 The apical ectodermal ridge is the sculptor of the limb. ‘Lobster-Claw syndrome’ and ‘ectrodactyly’ are both now less commonly used than ‘split-hand-split-foot-malformation’ syndrome (SHFM). The disorder occurs in 1 in 18,000 newborns; inheritance is usually dominant. There are at least three distinct SHFM loci in humans: SHFM1 at 7q21.3-q22.1 (183600); SHFM2 at Xq26 (313350), SHFM3 at 10q24 (600095), and we can add a fourth, ectrodactyly, ectodermal dysplasia and cleft lip syndrome (EEC) at 3q27 (129900) (Celli et al. 1999). There are many other related syndromes besides. Celli et al. (1999) identify the EEC gene as p63, a close relative of the tumor suppressor gene, P53; Yang et al. (1999) and Mills et al. (1999) study its function in mice. Another ectrodactyly gene in mice, Dactylplasia, encodes an F-box/WD40 family protein thought to be involved in protein destruction, and although the human homologue of this gene maps near to SHFM3, it has not yet been shown to be causually involved (Crackower et al. 1998; Sidow et al. 1999). The same is true for two distal-less related genes, DLX5 and DLX6, thought to be responsible for SHFM1 (Merlo et al. 2002). Both P63 and Dactylplasia are involved in the maintenance of the AER; among their many other skin defects, p63-homozyous mice have no limbs at all.
116 Action at a distance in the embryo. Developmental biologists will notice that the account given here, which focuses on the AER’s role in promoting the growth of the limb-bud, is not that given in textbooks. There is no mention of how the AER patters the proximo-distal axis of the limb-bud via the ‘Progress-Zone clock’ (Wolpert 1971). This is because a pair of recent papers (Sun et al. 2002; Dudley et al. 2002) have convincingly shown that the Progress-Zone clock model is wrong. This is fascinating, but a bit upsetting, since it seems to throw the question of proximo-distal patterning open again. Niswander et al. (1993) describe how beads soaked in FGF can replace the apical ectodermal ridge. Sun et al. (2002) also give the most recent account of what is now a plethora of engineered FGF mutations in mice which have shed light on how they work.
116 Ridge FGFs not only keep mesodermal cells proliferating. The role of FGFs in regulating cell death is shown by Dudley et al. (2002). See Zou and Niswander (1996) for the role of cell death in eliminating inter-digital webbing in chickens but not ducks. Webbing in humans, more precisely syndactyly, is sometimes the result of an excess of FGF signalling caused by gain-of-function mutations in the FGF receptor, FGFR2, as in Apert syndrome (101200; 176943) (Wilkie et al. 1995).
118 This account of the making of our limbs. The role of thalidomide in phocomelia was first reported by McBride (1961) and Lenz (1962). Phocomelia appears in Roberts’s syndrome (268300) and SC Phocomelia syndrome A (269000), which may be the same disorder and are known as ‘pseudothalidomide’ syndromes; the genetic basis of neither is known. Goya’s sketch of a phocomelic infant is in the Louvre; Vrolik (1844–49) depicts Pepin; a brief account of his life is given in Gould and Pyle (1897) p.263.
120 How does thalidomide have its devastating effects? Stephens et al. (2000) reviews some of the voluminous literature on thalidomide. He firmly discounts recent sensationalistic claims that thalidomide-induced phocomelics (who are now in their late thirties) are giving birth to phocomelic children – which, if true, would imply the existence of some form of Lamarkian inheritance. In principle, however, thalidomide might be a general mutagen causing high frequencies of all sorts of genetic disorders in second-generation infants. Exhaustive studies have failed to show that this is so. Until recently, the best account of the action of thalidomide on limb formation was given by Tabin (1998). His explanation, which he convincingly defended against others (Neubert et al. 1999; Tabin 1999), rested on the idea that thalidomide causes a disassociation between proliferation and proximal-distal specification of limb-buds. In other words, it was couched in terms of the ‘Progress Zone’ model of limb specification. With the demise of that model (Sun et al. 2002; Dudley et al. 2002) the specificity of thalidomide becomes a little more difficult to explain but still probably depends on the abnormal inhibition of proliferation in particular populations of bone-precursors. It is striking that FGF8-conditional limb mutants in mice have phocomelia (Lewandoski et al. 2000; Moon and Capecchi 2000).
121 Metric, with its base 10 units. Until recently it was held that all modern vertebrates (living or not) have no more than five digits (Shubin et al. 1997). True, some creatures such as pandas and moles appeared to have six, but they could be dismissed as not being true fingers, but rather modified wrist bones (the radial sesamoid in pandas and falciform bone in moles). Polydactyly can, however, evolve in flippers such as the paddles of the icthyosaur, Opthalmosaurus, which appear to conceal eight digits (Hinchliffe and Johnson 1980 p.56), and those of the vaquita dolphin, which have six (Ortega-Ortiz and Villa-Ramirez 2000). Alberch (1986) discusses polydactylous dogs; Lloyd (1986) does so for cats; and Wright (1935) for guinea pigs. Galis (2001) reviews the question of why, despite the frequency of polydactylous mutations, so few species exist with more than five digits per limb. Polydactly in humans (603596) and many other entries). Frequencies and kinds of Polydactyly from Flatt (1994); in the Ruhe family (Glass 1947); in the Scipion family (M
anoiloff 1931).
122 If the apical ectodermal ridge. For the discovery of the zone of polarising activity see Saunders and Gasseling (1968); for its interpretation see Tickle et al. (1975). Sonic hedgehog (600725) was first identified as the gene encoding the morphogen by Riddle et al. (1993). Since then, some (Yang et al. 1997) have argued that it is not the morphogen since it does not form a gradient in the limb. More recent evidence suggests that it does (Zeng et al. 2001).
126 This catalogue of mutations. Many polydactyly genes have been identified in mice and humans, and many are transcription factors. For example, mutations in GH3 (165240), a zinc-finger transcription factor, cause Greig’s cephalopolysyndactyly (175700), Pallister-Hall syndrome (146150) and postaxial polydactyly (174200; 174700). See Manouvrier-Hanu et al. (1999) for a brief review of others. On-line Mendelian Inheritance in Man (August 2002) lists ninety-seven disorders with polydactyly in the clinical synopsis. How many of these are genuinely different is an interesting question, but the suggestion is certainly that more than ten genes are involved in correctly determining Shh activity. The Shh regulatory mutation causes extra thumbs and index fingers, more broadly, preaxial polydactyly (190605; 174500). The genetics are complicated. Zguricas et al. (1999) mapped the mutations, deletions and translocations to 7q36, close to the Shh gene. Clark et al. (2001) showed that these mutations deleted a portion of Lmbri (605522), a gene near sonic hedgehog, and inferred that Lmbri was causal. Lettice et al. (2002), whose interpretation I follow here, provide evidence that 7q36 Polydactyly mutations are due to deletions of sonic hedgehog cis-acting regulatory elements that lie within a Lmbri intron rather than Lmbri itself. Achieropody (200500), which also maps to 7q36, has a similarly complex history. Achieropody mutations also delete Lmbri and, again, this gene was thought to be causal (Ianakiev et al. 2001; Clark et al. 2001), but is also probably due to a Shh regulatory mutation – though the jury is still out (Lettice et al. 2002). Certainly, the similarity of acheiropody to the pawless limbs of Shh-null mice is striking (Chiang et al. 1996; Chiang et al. 2001).
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 h
istory 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).
Mutants Page 29