Mutants (19 page)

A
CHONDROPLASIA
. M
ARY
A
SHBERRY
(d. 1856)
WITH THE SKULL OF HER STILLBORN INFANT, USA
.

We know this because 99 per cent of all cases of achondroplasia are caused by a mutation in which an amino acid (a glycine) at a particular location in the FGFR3 protein sequence (position 380) is replaced by another (an arginine). This mutation has the peculiar property of causing the FGFR3 molecule to become hyperactive. Nearly all of the mutations discussed in this book cause a deficiency in the quantity or efficacy of some protein, often by causing it to be completely absent. If the protein is a signalling molecule like FGF, the disorder that we see is due to an absence of some critical piece of information that the cells require. The achondroplasia mutation is, however, different in
that it occasionally causes the receptor to transmit a signal into the interior of the cell even if no FGF is bound to it. The effect is like a switch that spontaneously flips on when it should be off, and that transmits a blast of unwanted information to the cells of the growing limb.

If an excess of FGF signalling causes limbs to be unusually short, then the usual role of FGFs must be to act as a brake on the growth of the infant limb. They do this by limiting the rate at which the cells of the growth plate divide. The bones of achondroplastic children have growth plates that are only a fraction of the size they should be. They contain far fewer dividing chondrocytes than those of normal children, and fewer yet that swell and form cartilage.

Achondroplasia is a relatively mild disorder. However, a surplus of FGF signalling can, in the extreme, have terrible consequences. Among the many skeletons in Amsterdam’s Museum Vrolik is one that belonged to a male infant stillborn sometime in the early 1800s. When you look at the skeleton, now labelled M715, you can see quite clearly that there is something the matter with it. The child’s vertebrae, ribs and pelvis are all truncated, bowed or flattened, and the skull is enormously enlarged. In his great 1849 teratological treatise, Willem Vrolik depicts the child’s forehead as a large tuberose object. The stunted limbs and the large head are both characteristic of ‘thanatophoric dysplasia’ – death-bringing dysplasia. As the name suggests, it is fatal at birth.

Thanatophoric dysplasia is also caused by activating mutations in the FGFR3 gene, but of a far more destructive variety
than those responsible for achondroplasia. The havoc they wreak shows that FGFs control the growth not only of the limbs, but of some other parts of the skeleton as well, such as the skull. The mildly domed foreheads of many achondroplastic dwarfs remind us that their disorder is a weaker version of a lethal one. Should a foetus inherit two copies of the achondroplasia mutation (by virtue of having two achondroplastic parents), it too will die shortly after birth with all the symptoms of thanatophoric dysplasia.

FGF must be only one molecule among many that limit the growth of this or that part of the body. Every organ must have devices that tell it to stop growing, and many will be unique to particular organs. There is hardly a part of the body that is not stunted or overgrown in some genetic disorder or other. Some mutations cause children to be born with tongues that are too large for their mouths; others result in intestines that do not fit inside abdominal cavities. Even muscles have their own devices for regulating growth. Belgian blues, a breed of beef cattle, are remarkable for having about a third more muscle than normal cows; their flanks resemble the thighs of Olympic weightlifters. They lack a protein called myostatin (related, as it happens, to BMPs) that instructs muscles to stop their growth. Myostatin-defective mice have about two or three times the normal muscle mass, but this gain seems to be bought at the expense of growth elsewhere, since they also have smaller than normal internal organs. Myostatin-defective people surely also exist, but there seems to be no record of them. Perhaps extra muscles are not noticed or, if noticed, are not something worth worrying about.

RENEWAL

The pseudoachondroplasia gene encodes one part of the matrix that chondrocytes spin about themselves. But it is only a minor one. Indeed, mice in which the protein has been engineered out altogether seem to suffer no ill-effects at all. One has to wonder just what it’s doing there in the first place. Not so for the rest of the matrix. Most of the cartilage is made of collagen. Humans have about fifteen different types of collagens that make up about a quarter of the total protein in our bodies. Collagens are found in our connective tissue and skin. They are the stuff that holds our cells together. And they give bone much of its flexibility and strength.

Mutations that disable bone collagens cause a disorder called osteogenesis imperfecta. There are at least four forms of the disease, some of which are lethal in infancy. The most characteristic symptom of the disorder is the extreme fragility of its victim’s bones. For this reason it is often known as ‘glass bone disease’. The mutations have their devastating effects because of the hierarchical nature in which collagens are organised. Any given collagen protein is made up of three peptides – strings of amino acids – wrapped together in a triple helix. The triple helices are in turn grouped together in enormous fibrils that, woven together, make up the structure of connective tissue and cartilage. Each peptide is encoded by a different gene, but a single mutant gene can wreck any number of triple helices, and so any number of fibrils, and so any number of bones.

Osteogenesis imperfecta is the disorder that afflicted the
French painter Achille Empéraire (1829–98), who was himself painted by Cezanne, and the French jazz pianist Michel Petrucciani (1962–99). These artistic associations have lent the disorder, at least in France, a spurious romance (the ‘glass-bone man’ in Jean-Pierre Feunet’s film
Le fabuleux destin d’Amélie Poulain
springs to mind). The reality is more mundane. Children with osteogenesis imperfecta often suffer minor bone fractures of which their parents are quite unaware. When, after a more severe fracture, the children finally wind up in hospital, radiographs reveal a long history of broken and healed bones. Suspicions of child abuse often follow. In the United States, afflicted children have been taken into care by over-zealous social workers; some parents have even been jailed.

O
STEOGENESIS IMPERFECTA TYPE
II. S
TILLBORN INFANT
, A
MSTERDAM
.

Even once our growth plates are sealed and growth has stopped, there is no rest for the skeleton. The interiors of most adult bones are fully replaced every three or four years, while their outer peripheries, being harder, turn over about once every decade. This cycle of destruction and renewal is the product of an engagement between osteoblasts and other cells that continually wear the skeleton away, taking minute bites from its fabric and reducing it to its constituent parts, rather in the manner of so many chisels. These are the osteo
clasts
: giant cells that attach to fragments of bone and dissolve them using protein-chewing enzymes and hydrochloric acid. Bones may be built by osteoblasts, but they are carved by osteoclasts, for it is these cells that hew the ducts, channels and cavities through which nerves and blood vessels thread, and bone marrow percolates.

There are many ways to upset the balance between growth and destruction that is found in every bone. An excess of bone may be due to an excess of osteoblasts, but it can also be caused by a want of osteoclasts. Osteo
petrosis
, literally bones-like-rock, is an osteoclast disorder, the opposite of the far more familiar osteo
porosis
that is the bane of post-menopausal women. Having bones-like-rock can be lethal. There is a particularly harsh variety of the disorder that affects children and usually kills them before they turn twenty. Often they die of infections because bone accretes in the cavities where marrow is manufactured, marrow being one of the main sources of immune-system cells. Somewhat paradoxically, the bones of people with osteopetrosis also tend to fracture rather easily, the probable consequence of an architecture that has gone awry. And when fractures do
occur they are not easily repaired, for among the things that osteoclasts do is to smooth away the jagged edges of our bones should we break them.

Osteopetrosis, albeit of a fairly mild variety, is thought by some to be responsible for the shortness of Henri de Toulouse-Lautrec. This is just one of several retrospective diagnoses – achondroplasia and osteogenesis imperfecta among them – that have been attempted of the French painter. None is particularly convincing, but then bone disorders are so many, and their symptoms so various and subtle, that they are easily mistaken for one another, particularly when all we know of the patient comes from biography, a handful of photographs, and a selection of self-portraits, mostly caricatures. Yet the search for ‘Lautrec’s disease’ goes on. Part of his fascination, particularly for French physicians, comes from the fact that he was a scion of one of France’s most noble houses, the Comtes de Toulouse-Lautrec, a dynasty of rambunctious southern noblemen who had, at one time or another, ruled much of Rouergue, Provence and the Languedoc, sacked Jerusalem, dabbled in heresy, been excommunicated by the Pope (on ten separate occasions) and, in the thirteenth century, felt the military wrath of the French Crown. But more than this, the impulse to diagnose Henri Toulouse-Lautrec comes from the belief that this gifted painter made his deformity part of his art.

There may be something to this. As one walks through the Musée d’Orsay in Paris or else the museum at Albi, not too far from Toulouse itself, which is dedicated to his work, what strikes you are the nostrils. In painting after painting – of the dancer La Goulue, the actress Yvette Guilbert, the socialite May
Milton, or the many other anonymous Parisian
demi-mondaines
who inhabit Lautrec’s art – what we see are nostrils, gaping, dark and cavernous. It is hardly a flattering view, but perhaps it is one that would have come quite naturally to the artist, for he was rather short. By the time he was full grown, Lautrec was only 150 centimetres (four feet eleven inches) tall. Critics have also argued that Lautrec’s disorder had a more subtle effect on his art: a tendency after 1893 to truncate the limbs of his models so that only the heads and torsos remain in the frame, a device for excluding that part of his own anatomy that he would much rather forget: his legs.

Lautrec’s legs caused him much grief. He seems to have had a fairly healthy childhood, but by the time he was seven his mother had taken him to Lourdes, where she hoped to find a cure for some vaguely described limb problem. He was stiff and clumsy and prone to falls, and only went to school for one year, leaving when he proved too delicate for schoolyard roughhousing. By the age of ten he was complaining of constant severe pains in his legs and thighs, and at thirteen minor falls caused fractures in both femurs which, to judge from the length of time during which he supported himself with canes, took about six months to heal. He would use a cane nearly all his adult life; indeed, friends believed that he walked any distance only with reluctance and difficulty.

As he grew, Lautrec also underwent some unusual facial changes. A pretty infant, and a handsome boy, he later developed a pendulous lower lip, a tendency to drool, and a speech impediment rather like a growling lisp, and his teeth rotted
while he was still in his teens – traits which his parents, who were notably good-looking, did not share. He was self-conscious about his looks, wore a beard all his adult life, and never smiled for a camera. Many critics have argued that it was a sort of physical self-loathing that caused him to seek and portray all that was most vicious and harsh in his
milieu
. But then,
fin-de-siècle
Paris could be a vicious and harsh place. One night at Maxim’s, when Lautrec had sketched some lightning caricatures of his neighbours, one of them called to him as he hobbled away. ‘Monsieur,’ he said, gesturing to a pencil stub left on the table, ‘you have forgotten your cane.’ On another occasion, looking at one of the many portraits he had done of her, Yvette Guilbert remarked, ‘Really, Lautrec, you are a genius at deformity.’ He replied, ‘Why, of course I am.’