CHAPTER V: FLESH OF MY FLESH, BONE OF MY BONE
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).