OI types and related gene/protein defects.
Abstract
Restricted growth (RG) or dwarfism is a varied phenotype ascribable to many different causes, most of which are genetic. Conditions associated with disproportionate short stature (DSS) are usually caused by de novo dominant mutations in genes coding for proteins involved in cartilage/bone development. Rarer conditions, which may occur in inbred families, show an autosomal recessive inheritance. Causative mutations, consequent to cellular dysfunctions, genotype-to-phenotype correlations in RG conditions such as achondroplasia, hypochondroplasia, thanatophoric dysplasia, severe achondroplasia with delay in development and acanthosis nigricans, pseudoachondroplasia, multiple epiphyseal dysplasia, diastrophic dysplasia, achondrogenesis, and osteogenesis imperfecta, are discussed in this chapter.
Keywords
- dwarfism
- cartilage
- bone
- chondrocyte
- osteoblast
1. Introduction
Human height is a genetically complex phenotype. In recent years, several genome-wide association studies (GWAS) have collectively identified hundreds of common variants with a putative effect on determining adult height [1]. The variability between individuals has a normal distribution; extremes in height are often caused by monogenic mutations in genes involved in growth control. Gain in height in children is determined by the rate of endochondral ossification, i.e. the rate of proliferation of chondrocytes at the growth plate, a thin layer of cartilage that is found in most bones, other than skull and facial bones. Newly generated cartilage tissue is remodeled into bone tissue; as new bone is progressively created at the growth plate, bones grow longer and children grow taller. At puberty increasing levels of estrogen, in both females and males, lead to increased apoptosis of chondrocytes in the growth plate; growth slows down and later stops when the entire cartilage has become replaced by bone, leaving only a thin epiphyseal scar. Systemic factors such as growth and thyroid hormones provide important signals for the regulation of cartilage/bone growth by modulating expression of locally produced factors, such as tissue-specific transcription factors (e.g. short stature homeobox-containing factor, SHOX), multiple fibroblast growth factors (FGFs), bone morphogenetic proteins (BMPs), secreted signaling factors such as Wnts, and many others. Cartilage extracellular matrix components, secreted by chondrocytes, also play a crucial role in regulating growth plate activity. Dysfunctions in any of the multiple players in this complex process may cause genetic growth disorders. Gene mutations affecting various stages of the bone formation process, e.g. osteoblast differentiation, bone extracellular matrix deposition and mineralization, may as well result in substantial growth deficiency, a hallmark feature of osteogenesis imperfecta, a molecularly heterogeneous group of connective tissue disorders.
In this chapter, we will describe some paradigmatic conditions of restricted growth from the cell biologist’s perspective. We will first consider various
2. Cartilage disorders associated with impaired height
Chondrodysplasias causing dwarfism comprise a group of skeletal disorders associated with improper regulation of cartilage growth during endochondral ossification (see Figure 1 for a simplified sketch of the process). Although this notion had been widely accepted for a long time, the idea that morphological assessment of the growth plate could be used to distinguish among the different disorders was successfully proposed only in the 1970s [2]. This brought to the concept of "chondrodysplasia families" formulated in the 1980s and the hypothesis that chondrodysplasias that look similar could be pathogenetically related. But it was only in the 1990s, with the advent of molecular genetics identifying the mutated genes associated with different chondrodysplasias, that in many instances chondrodysplasia family disorders turned out to be caused by mutations within the same gene, indeed [3].
2.1. FGFR signaling defects
Dwarf-associated chondrodysplasias are caused by genetic alterations in the
FGFR3 is highly expressed in both proliferating and prehypertrophic chondrocytes where it normally limits their growth rate (Figure 1). At the molecular level, the FGFR3-Gly380Arg mutant showed ligand-independent activation and a specific defect in receptor down-regulation resulting in prolonged signaling activity [11]. Interestingly, cartilage targeted overexpression of a ligand (FGF9) that activates FGFR3 also generated a dwarf mouse [12]. These evidences established that FGFR3 signaling negatively regulates bone growth. Among the signaling effectors downstream to FGFR3 activation, STAT and MAPK signals have been the most studied in relation to skeletal development (a scheme of major FGFR3 signaling pathways is presented in Figure 3). FGFR3 is thought to inhibit chondrocyte proliferation through the cyclin-dependent kinase inhibitor p21 (WAF1/CIP1), where the latter controls chondrocyte proliferation and terminal differentiation through the recruitment of p38 and ERK effectors [8, 13]. Biochemically, replacement of glycine 380 with arginine causes ligand-independent activation of FGFR3, which increases the constitutive level of phosphotyrosine on FGFR3 [14]. The consequent unregulated signal transduction through FGFR3 impacts growth plate function and therefore long bone development. Several approaches to reduce FGFR3 signaling by blocking receptor activation or inhibiting downstream signals have been proposed. The most promising utilizes an analog of C-type natriuretic peptide (CNP), which antagonizes the mitogen-activated protein (MAP) kinase pathway downstream of the FGFR3 receptor [15].
2.2. COMP defects
Thrombospondin-5, better known as cartilage oligomeric protein (
2.3. Sulfate transporter defects
A group of chondrodysplasias showing moderate to lethal phenotypes have been associated with mutations in SLC26A2 gene, which codes for a sulfate-chloride transmembrane exchanger, DTSTD. This protein is predominantly present in chondrocytes, and it ensures proper sulfation of proteoglycans, essential components of the cartilage extracellular matrix. The highly organized structure of cartilage ECM is of crucial importance for the endochondral ossification process. Furthermore, sulfated proteoglycans are important for transmission of FGF signaling [26]. In humans, as well as in animal models, impaired sulfation of proteoglycans due to DTDST gene defects causes a continuous phenotypic spectrum of skeletal dysplasia. The clinical phenotype is modulated by the degree of residual protein activity, as shown in Figure 5. All conditions are recessively inherited; heterozygous carriers appear to be asymptomatic [27].
Missense mutations such as R279W cause an amino acid substitution (arginine to tryptophan), which alters but does not abolish the sulfate transporter activity. This is a recurrent mutation found in the Finnish population as well as in other Europeans; at the homozygous state, it results in
3. Bone disorders featuring short stature: osteogenesis imperfecta
3.1. Defects in collagen
Type I collagen is a heterotrimer made of two α1(I) and one α2(I) chains. It is synthesized as a procollagen molecule, with N-terminal and C-terminal globular domains flanking the helical domain. N-terminal and C-terminal propeptides are removed after secretion by specific proteases in the extracellular matrix. After processing, the collagen helices are capable of spontaneous assembly into fibrils, to be further stabilized by crosslinks. The helical domain is characterized by uninterrupted G-X-Y triplets since just the small glycine side chain fits the internal helical space. The most common genetic defects in dominant OI are missense mutations causing glycine substitutions within the helical domain and consequently structural defects in collagen heterotrimers. Gly substitutions delay helical folding and, in this way, promote post-translational overmodifications. Misfolded chains disturb intracellular metabolism, delay collagen secretion, and affect extracellular matrix deposition and mineralization. Phenotypic consequences vary depending on the nature of substituting amino acid, helical position, and chain type. In the α1(I) chain, substitutions with charged or branched side chains disrupt helix stability and are mostly lethal. In the α2(I) chain, substitutions are mainly non-lethal. Heterozygous COL1A1 loss-of-function mutations result in synthesis of reduced amount (about 50%) of structurally normal collagen and cause the mildest form of
3.2. Defects in collagen post-translational modifications
Procollagen undergoes several post-translational modifications, most of which occur in the endoplasmic reticulum. Such modifications are required for its correct folding, secretion, and extracellular matrix assembly. A complex of three proteins in a 1:1:1 ratio (CRTAP, P3H1, CyPB) called the 3-hydroxylation complex post-translationally modifies selected prolines in type I collagen chains in osteoblasts and type II collagen chains in chondrocytes. Deficiency of any of the three partners of the 3-hydroxylation complex, caused by loss-of-function mutations in both alleles of the corresponding gene, results in clinically distinct forms of moderate to lethal recessive OI (types VII, VIII, and IX, respectively, see Table 1). Common features are very low BMD, rhizomelia, bone fragility, and moderate to very severe growth deficiency. These recessive forms of OI are much rarer than the dominant forms (they account for 2–5% of OI cases detected in North America and Europe) and occur prevalently in inbred families.
Mode of Inheritance | OI type/ OMIM # |
Defective gene |
Defective protein |
Cellular disturbance | Short stature* |
---|---|---|---|---|---|
(85–90% of OI cases) |
I/#166200 | COL1A1 | Collagen I | Collagen quantitative defect |
No |
II/#166210 | COL1A1 or COL1A2 | Collagen I | Collagen qualitative/ structural defect |
Lethal | |
III/#259420 | COL1A1 or COL1A2 | Collagen I | Qualitative/structural defect |
+++ | |
IV/#166220 | COL1A1 or COL1A2 | Collagen I | Qualitative/structural defect |
+ | |
V/#610967 | IFITM5 | BRIL | Bone matrix mineralization |
+ | |
(10–15% of OI cases) |
VI/#613982 | SERPINF1 | PEDF | Bone matrix mineralization |
++ |
VII/#610682 | CRTAP | CRTAP | Collagen hydroxylation |
++ | |
VIII/#610915 | LEPRE1 | P3H1 | Collagen hydroxylation |
+++ | |
IX/#259440 | PPIB | CyPB | Collagen hydroxylation |
+/++ | |
X/#613848 | SERPINH1 | HSP47 | Collagen chaperoning | +++ | |
XI/#610968 | FKBP10 | FKBP65 | Collagen chaperoning | + | |
AR—very rare | XII/#613849 | SP7/OX | OSTERIX | Osteoblast differentiation | +++ |
XIII/#614856 | BMP1 | PICP endopeptidase |
Abnormal procollagen I C-terminal propeptide processing |
+++ | |
XIV/#615066 | TMEM38B | TRIC-B | Intracellular [Ca] modulation |
+ | |
XV/#615220 | WNT1 | WNT1 | Wnt signaling pathway (bone formation) |
++ | |
XVI/#616229 | CREB3L1 | OASIS | Bone formation | +++ |
OI type | Gene | Mutation | Phenotypic defect | Reference |
---|---|---|---|---|
I AD | COL1A1 | c.757 C>T p. R253 stop |
Haploinsufficiency (decreased amount of structurally normal collagen) | [35] |
II AD | COL1A2 | c.1874 G>A p.G625 D |
Structurally abnormal collagen chains | [35] |
III AD | COL1A1 | c.2461 G>A p.G821 S |
Structurally abnormal collagen chains | [35] |
IV AD | COL1A2 | c.577 G>A p.G193 S |
Structurally abnormal collagen chains | [35] |
V AD | IFITM5 | c.-14 C>T p. +MALQP |
Functionally abnormal IFITM5 protein (gain of function) | [36] |
VI AR | SERPINF1 | c.423delG + c.423delG p.I142Sfs*9 |
Lack of PEDF protein | [37] |
VII AR | CRTAP | (c.118_133del16insTACCC)+ (c.118_133del16insTACCC) p.Q40Yfs*117 |
Severe impairment of prolyl 3-hydroxylation complex activity (collagen post translational modification) | [38] |
XI AR | FKBP10 | c.1399+1G>A + c.1399+1G>A aberrant splicing | Lack of FKBP65 protein | [32] |
3.3. Defects in collagen folding and secretion
Folding of post-translationally modified α chains is assisted by ER-resident collagen-specific chaperones. Absence or dysfunction of two collagen chaperones, HSP47 and FKBP65, due to mutations in both alleles of the corresponding genes (SERPINH1 and FKBP10, respectively) have been reported to cause very rare recessive OI. A single patient has been reported so far with HSP47 deficiency and a severe
3.4. Defects in bone mineralization
Autosomal-dominant
3.5. Defects in osteoblast development
Mutations in two genes involved in osteoblast differentiation have been recently associated with recessive
Schematic and simplified representation of the differentiation steps from bone marrow mesenchymal stem cell to mature osteoblast. The transcription factors with an inductive effect (RUNX2, OSTERIX) are indicated in red as well as the osteoblast-specific proteins PEDF and BRIL, as cited in the text. The WNT signaling pathway plays a crucial role in osteoblast differentiation, proliferation, and bone matrix formation/mineralization. Defects, due to mutations in the corresponding genes, in any of the proteins shown in the figure, are responsible for various types of osteogenesis imperfecta (see the text for details).
3.6. Restricted growth in OI
Short stature is the most prevalent secondary feature of OI [49]. Only in the mildest form, OI type I, affected individuals have minimal bone deformities and normal stature. In all other types of OI, mild/moderate (+/++) to very severe (+++) growth deficiency is to be found (see Table 1). Short stature in OI is not caused by premature closure of growth plates; it can be the consequence of compromised extracellular matrix structure and mineralization, which impact on bone properties, leading to repeated long bones fractures, deformities, and bowing. Severely affected patients may be short because of vertebral compression fractures, severe scoliosis, lower limb deformities, and disruption of growth plates. However, growth can also be delayed in the absence of these abnormalities. The mean standing height of patients with OI is lower than that of their unaffected first-degree family members, regardless of severity. Truncal height is reduced, and head size increased in one-third of the patients with moderate or severe OI.
During childhood, there appears to be no difference between the standing heights of girls and boys, but women have lower height
3.7. Conclusions
The intent of this chapter was to give a molecular and cellular overview of selected conditions associated with impaired height, focusing on growth plate misregulation, cartilage extracellular matrix dysfunctions, osteoblast differentiation, and mineralization process impairments.
4. Methods
Most of the experimental data described in this chapter come from either
4.1. In vitro cell cultures
Cell culture studies on mutated FGFR3 were mostly performed in chondrosarcoma RCS cells from rat, ATDC5 from mouse, or in heterologous cell lines as Hek293 or PC12. Single-codon substitutions were introduced into the cDNA encoding FGFR3 by site-directed mutagenesis, and the plasmids carrying different mutant molecules were transfected into cultured cells to allow protein expression. To address questions related to the biochemistry of mutant FGFR3 molecules, which is assessing the degree of receptor activation, FGFR3 proteins were isolated from cell lysates by immunoprecipitation techniques and analyzed by Western blot using specific antibodies directed to phosphorylated tyrosine. Intracellular receptor localization was visualized by immunofluorescence [22].
Studies in the field of O.I. are mostly based on cultivation of fibroblasts obtained (upon informed consent) from patients’ skin biopsies. Fibroblasts are grown in DMEM medium supplemented with 10% fetal bovine serum (FBS), 2 mM l-glutamine, and antibiotics (penicillin and streptomycin) at standard concentration. Proteins, DNA, and mRNA are extracted and purified from cells for subsequent analyses. Detailed description of methods can be found in Refs [31, 38].
4.2. Animal models
Transgenic mice described in the chapter were generated by targeting the specific genes of interest in murine embryonic stem cells with the homologous recombination technique, originally described by Thomas AND Capecchi [52]. Several mouse models orthologous to human skeletal dysplasia have been generated where gene expression was targeted to chondrocytes. The list includes ACH, TDI, TDII, and SADDAN [53, 54]). Histochemical analyses were performed on tissues isolated from proximal tibial growth plate tissue, generally prepared from 1-week-old mice.
4.3. Gene sequencing
The search of causative mutations described in the text was performed by sequencing exons and exon/intron boundaries of the candidate genes. Typically, single exons are amplified by PCR using appropriate primers and then subjected to automated sequencing according to standard protocols. When analysis of known established disease genes failed to identify the causative mutations, whole exome sequencing strategies were employed in order to identify novel loci [55, 56].
4.4. Growth plate histology
For analyses on human samples, tibial and/or femoral cartilage fragments were obtained from medically aborted fetuses upon informed parental consent. Pregnancies were legally terminated after ultrasonographic and X-ray detection of severe dwarfism.
4.5. Bone histology
Biopsies obtained from iliac crest (upon informed consent) are fixed in 70% ethanol and embedded undecalcified in methylmethacrylate resin. Bone sections are cut by microtome, stained by Goldner’s stain, and mounted on microscope slides.
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