Tuesday, January 31, 2012

Why do people with marfan syndrome grow taller?

The most famous individual with Marfan's Syndrome is the late Vincent Schiavelli who was a towering 6'6".  Marfan's Syndrome is associated with tall stature and marfan's syndrome deals with connective tissue.  The connective tissue gene COL2A1 likely playing a large role in height.  Why do people with Marfan's Syndrome grow taller and can we use this information to grow taller ourselves?

Microenvironmental regulation by fibrillin-1.

"Fibrillin-1 is a ubiquitous extracellular matrix molecule that sequesters latent growth factor complexes.  Fibrillin-1 provides extracellular control of growth factor signaling. Mutations in FBN1 are mainly responsible for the Marfan syndrome (MFS), recognized by its pleiotropic clinical features including tall stature and arachnodactyly, aortic dilatation and dissection, and ectopia lentis. Each of the many different mutations in FBN1 known to cause MFS must lead to similar clinical features through common mechanisms, proceeding principally through the activation of TGFβ signaling[LSJL upregulates TGF-Beta expression]. Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice. WMS mice confirm that this mutation does not cause MFS. The mutation deletes three domains in fibrillin-1, abolishing a binding site utilized by ADAMTSLIKE-2, -3, -6, and papilin. Our results place these ADAMTSLIKE proteins in a molecular pathway involving fibrillin-1 and ADAMTS-10. Investigations of microfibril ultrastructure in WMS humans and mice demonstrate that modulation of the fibrillin microfibril scaffold can influence local tissue microenvironments and link fibrillin-1 function to skin homeostasis and the regulation of dermal collagen production. Hence, pathogenetic mechanisms caused by dysregulated WMS microenvironments diverge from Marfan pathogenetic mechanisms, which lead to broad activation of TGFβ signaling in multiple tissues[WMS causes short stature rather than tall stature and WMS messes where TGF-Beta signaling occurs(more in the skin and less in the cartilage for example) thereby linking TGF-Beta signaling to one of the reasons that people with Marfan's Syndrome grow taller]. We conclude that local tissue-specific microenvironments, affected in WMS, are maintained by a fibrillin-1 microfibril scaffold, modulated by ADAMTSLIKE proteins in concert with ADAMTS enzymes."

"More than a thousand different mutations in FBN1, the gene for fibrillin-1, are known to cause MFS, suggesting that the same general pathogenetic mechanisms are initiated by each of these distinct mutations."<-So many mutations in FBN1 are likely to cause tall stature Marfan's Syndrome but relatively few are likely to cause short stature.

"fibrillin-1 targets and sequesters the large latent Transforming Growth Factor β (TGFβ) complex as well as multiple Bone Morphogenetic Proteins (BMPs) and Growth and Differentiation Factor-5 (GDF-5)"<-all of these proteins have been associated with height growth.

According to "A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression.",  knockout of FBN1 can be lethal and no evidence of larger stature was shown.  Thus, Fibrillin-1 is likely not a purely inhibitive compound on height growth and specific mutations must occur to increase height growth(numerous combinations of mutations work however).


"While most of the known mutations in fibrillin-1 cause Marfan syndrome, a number of other mutations lead to clinical features unrelated to Marfan syndrome. Pathogenesis of Marfan syndrome is currently thought to be driven by mechanisms due to haploinsufficiency of wild-type fibrillin-1[haploinsufficiency means a partial knockout of the gene]. However, haploinsufficiency-driven mechanisms cannot explain the distinct phenotypes found in other fibrillinopathies. To test the hypothesis that mutations in fibrillin-1 cause disorders through primary effects on microfibril structure[if marfan's syndrom primarily acts on microfibers than perhaps microfibrils play a role in height growth], two different mutations were generated in Fbn1 in mice. One mutation leads to a truncated fibrillin-1 molecule that is tagged with green fluorescent protein, allowing visualization of mutant fibrillin-1 incorporated into microfibrils. In heterozygosity, these mutant mice demonstrate progressive fragmentation of the aortic elastic lamellae and also display fragmentation of microfibrils in other tissues. Fibrillin-2 epitopes are also progressively revealed in these mice, suggesting that fibrillin-2 immunoreactivity can serve as a marker for microfibril degradation. In contrast, a second mutation (in-frame deletion of the first hybrid domain) in fibrillin-1 results in stable microfibrils, demonstrating that fibrillin-1 molecules are not required to be in perfect register for microfibril structure and function and that the first hybrid domain is dispensable for microfibril assembly. Taken together, these results suggest that perturbation of microfibril structure may underlie one of the major features of the Marfan syndrome: fragmentation of aortic elastic lamellae."

"Overexpression of mutant human FBN1 showed incorporation of the human fibrillin-1 into microfibril structures, using human specific fibrillin-1 antibodies, but no apparent effects of the mutant human fibrillin-1 were found on microfibril structure or function in these transgenic mice"<-So merely having higher levels of fibrillin-1 doesn't do anything.

"In one line, fibrillin-1 is truncated[so the gene does not attain it's proper form] and tagged with enhanced green fluorescent protein (eGFP), allowing us to conclusively demonstrate that mutant fibrillin-1 is incorporated into microfibrils. In heterozygosity, these mice develop features of Marfan syndrome and, in homozygosity, do not survive past the early postnatal period. In a second line of mutant mice, exon 7 is deleted, resulting in the in-frame deletion of the first hybrid domain in fibrillin-1. To our surprise, these mice survived normally, even in homozygosity, and manifested no apparent defects in microfibril structure or function"<-So when you have non-functional fibrillin-1 incorporated into microbrils then you get the tall stature of Marfan's syndrome.    However, if you just have lower levels of fibrillin-1, no change is noted at all.  So perhaps when non-functional fibrillin-1 is incorporated into microfibrils it serves some purpose that makes you grow taller.

"Although wild-type fibroblasts assembled abundant fibrillin-1 fibrils, heterozygous GT-8 fibroblasts assembled fewer fibrillin-1 fibrils[mice with some of the fibrillin-1 fibrils non-functional and some functional], and homozygous GT-8 fibroblasts failed to assemble a fibrillin-1 fibril matrix[all the fibrillin-1 fibrils were non-functional]. eGFP-tagged and -truncated fibrillin-1 was assembled into fibrils by heterozygous GT-8 fibroblasts but not by homozygous GT-8 fibroblasts"<-So the mice with marfan's syndrome(and taller stature) assumed fewer fibrillin-1 fibrils.  Thus, fibrillin-1 fibrils may play an inhibitory role on height but you need some quantity of fibrillin-1 fibrils to grow taller and live.  Fewer microfibrils may be more elastic thus allowing for more height growth.

It's possible that the malfunction of the fibroblasts due to the incorporation of truncated fibrillin-1 fibrils interferes with TGF-Beta signaling which results in height growth.

In the first study, we saw that also disorders in FBN1 can cause short stature.  With the malfunctioning microfibril hypothesis in the last study, we can theorize that perhaps a specific truncation of fibrillin-1 results in short stature

What we can conclude is that microfibrils may play a role in height growth and that having less of them in the growth plate or possibly even the bone may be beneficial for height.  Therefore, we might want to come up with ways to reduce the number of microfibrils(we need some though).

Immunolocalisation of fibrillin microfibrils in the calf metacarpal and vertebral growth plate.

"Overgrowth of limbs and spinal deformities are typical clinical manifestations of Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA){both diseases cause overgrowth}, caused by mutations of the genes encoding fibrillin-1 (FBN1) and fibrillin-2 (FBN2), respectively. FBN1 mutations are also associated with acromicric (AD) and geleophysic dysplasias (GD), and with Weill-Marchesani syndrome (WMS), which is characterised by short stature.Here we investigated the organisation of fibrillin microfibrils in the growth plate of the long bone and vertebra immunohistochemically. Fibrillin-1 was dual-immunostained with elastin, with fibrillin-2 or with collagen X.  Fibrillin microfibrils are distributed throughout all regions of the growth plate, and that fibrillin-1 and fibrillin-2 were differentially organised. Fibrillin-1 was more abundant in the extracellular matrix of the resting and proliferative zones of the growth plate than in the hypertrophic zone. More fibrillin-2 was found in the calcified region than in the other regions. No elastin fibres were observed in either the proliferative or hypertrophic zones. This study indicates that, as fibrillin microfibrils are involved in growth factor binding and may play a mechanical role, they could be directly involved in regulating bone growth."

"Fibrillin microfibrils are associated with the elastic fibre network, which in general consists of an elastin core surrounded by a network of fibrillin microfibrils. An extensive elastic network is distributed in the ECM of many tissues"

"the network of microfibrils could play a functional role in the long bone and spinal growth. Microfibrils, as part of the elastic fibre system, are commonly thought to play a mechanical role"

2 comments:

  1. im going to read this one a couple times to wrap my head around it, many to terms and growth factors i never heard of before,

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  2. Travis MiragliottaJanuary 31, 2012 at 7:11 PM

    Tyler, in one of your earlier posts this year you stated that being in a pool lowers hydrostatic pressure. Does the pressure bounce back to normal when you come out? Would you recommend swimming because it does increase GH secretion? You also stated that LSJL is optimized in 3 minute intervals for loading. Does this mean I should up my load time from 1 minute to 3 on each epiphysis?

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