OI types and related gene/protein defects.
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.
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 . 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 . 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 .
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 . Interestingly, cartilage targeted overexpression of a ligand (FGF9) that activates FGFR3 also generated a dwarf mouse . 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 . 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 .
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 . 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 .
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/
(85–90% of OI cases)
|I/#166200||COL1A1||Collagen I||Collagen quantitative
|II/#166210||COL1A1 or COL1A2||Collagen I||Collagen qualitative/
|III/#259420||COL1A1 or COL1A2||Collagen I||Qualitative/structural
|IV/#166220||COL1A1 or COL1A2||Collagen I||Qualitative/structural
(10–15% of OI cases)
|AR—very rare||XII/#613849||SP7/OX||OSTERIX||Osteoblast differentiation||+++|
|OI type||Gene||Mutation||Phenotypic defect||Reference|
|I AD||COL1A1||c.757 C>T
p. R253 stop
|Haploinsufficiency (decreased amount of structurally normal collagen)|||
|II AD||COL1A2||c.1874 G>A
|Structurally abnormal collagen chains|||
|III AD||COL1A1||c.2461 G>A
|Structurally abnormal collagen chains|||
|IV AD||COL1A2||c.577 G>A
|Structurally abnormal collagen chains|||
|V AD||IFITM5||c.-14 C>T
|Functionally abnormal IFITM5 protein (gain of function)|||
|VI AR||SERPINF1||c.423delG + c.423delG
|Lack of PEDF protein|||
|VII AR||CRTAP||(c.118_133del16insTACCC)+ (c.118_133del16insTACCC)
|Severe impairment of prolyl 3-hydroxylation complex activity (collagen post translational modification)|||
|XI AR||FKBP10||c.1399+1G>A + c.1399+1G>A aberrant splicing||Lack of FKBP65 protein|||
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
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 . 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
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.
Most of the experimental data described in this chapter come from either
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 .
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 . 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.
Durand C, Rappold GA. Height matters – from monogenic disorders to normal variation. Nat Rev Endocrinol. 2013;9(3):171–7. doi: 10.1038/nrendo.2012.251
Rimoin DL. The chondrodystrophies. Adv Hum Genet. 1975;5:1–118.
Horton WA, Degnin CR. FGF in endochondral skeletal development. Trends Endocrinol Metab. 2009;20(7):341–8. doi: 10.1016/j.tem.2009.04.003. Epub 2009 Aug 27.
Foldynova-Trantirkova S, Wilcox WR, Krejci P. Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Hum Mutat. 2012;33(1):29–41. doi: 10.1002/humu.21636. Epub 2011 Nov 16.
Ornitz DM, Marie PJ. Fibroblast growth factor signaling in skeletal development and disease. Genes Dev. 2015;29(14):1463–86. doi: 10.1101/gad.266551.115
Colvin JS, Bohne BA, Harding GW, McEwen DG, Ornitz DM. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet. 1996;12(4):390–7.
Toydemir RM, Brassington AE, Bayrak-Toydemir P, Krakowiak PA, Jorde LB, Whitby FG, Longo N, Viskochil DH, Carey JC, Bamshad MJ. A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome. Am J Hum Genet. 2006;79(5):935–41. Epub 2006 Sep 26.
Laederich MB, Horton WA. FGFR3 targeting strategies for achondroplasia. Expert Rev Mol Med. 2012;14:e11. doi: 10.1017/erm.2012.4
Shinde DN, Elmer DP, Calabrese P, Boulanger J, Arnheim N, Tiemann-Boege I. New evidence for positive selection helps explain the paternal age effect observed in achondroplasia. Hum Mol Genet. 2013;22(20):4117–26. doi: 10.1093/hmg/ddt260. Epub 2013 Jun 4.
Wang Y, Spatz MK, Kannan K, Hayk H, Avivi A, Gorivodsky M, Pines M, Yayon A, Lonai P, Givol D. A mouse model for achondroplasia produced by targeting fibroblast factor receptor 3. Proc Natl Acad Sci U S A. 1999;96(8):4455–60.
Monsonego-Ornan E, Adar R, Feferman T, Segev O, Yayon A. The transmembrane mutation G380R in fibroblast growth factor receptor 3 uncouples ligand-mediated receptor activation from down-regulation. Mol Cell Biol. 2000;20(2):516–22.
Garofalo S, Kliger-Spatz M, Cooke JL, Wolstin O, Lunstrum GP, Moshkovitz SM, Horton WA, Yayon A. Skeletal dysplasia and defective chondrocyte differentiation by targeted overexpression of fibroblast growth factor 9 in transgenic mice. J Bone Miner Res. 1999;14(11):1909–15.
Murakami S, Balmes G, McKinney S, Zhang Z, Givol D, de Crombrugghe B. Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype. Genes Dev. 2004;18(3):290–305.
Webster MK, Donoghue DJ. Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia. EMBO J. 1996;15(3):520–7.
Klag KA, Horton WA. Advances in treatment of achondroplasia and osteoarthritis. Hum Mol Genet, 2016, 25(R1):R2–R8.doi:10.1093/hmg/ddv419
McKusick VA, Kelly TE, Dorst JP. Observations suggesting allelism of the achondroplasia and hypochondroplasia genes. J Med Genet. 1973;10(1):11–6.
Bellus GA, McIntosh I, Smith EA, Aylsworth AS, Kaitila I, Horton WA, Greenhaw GA, Hecht JT, Francomano CA. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet. 1995;10(3):357–9.
Tavormina PL, Shiang R, Thompson LM, Zhu YZ, Wilkin DJ, Lachman RS, Wilcox WR, Rimoin DL, Cohn DH, Wasmuth JJ. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet. 1995;9(3):321–8.
Lievens PM, Liboi E. The thanatophoric dysplasia type II mutation hampers complete maturation of fibroblast growth receptor 3 (FGFR3), which activates signal transducer and activator of transcription 1 (STAT1) from the endoplasmic reticulum. J Biol Chem. 2003;278(19):17344–9. Epub 2003 Mar 6.
Lievens PM, Mutinelli C, Baynes D, Liboi E. The kinase activity of the fibroblast growth factor receptor 3 with activation loop mutations affects receptor trafficking and signaling. J Biol Chem. 2004;279(41):43254–60. Epub 2004 Aug 2.
Tavormina PL, Bellus GA, Webster MK, Bamshad MJ, Fraley AE, McIntosh I, Szabo J, Jiang W, Jabs EW, Wilcox WR, Wasmuth JJ, Donoghue DJ, Thompson LM, Francomano CA. A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene. Am J Hum Genet. 1999;64(3):722–31.
Lievens PM, Roncador A, Liboi E. K644E/M FGFR3 mutants activate Erk1/2 from the endoplasmic reticulum through FRS2 alpha and PLC gamma-independent pathways. J Mol Biol. 2006;357(3):783–92. Epub 2006 Feb 3.
Posey KL, Alcorn JL, Hecht JT. Pseudoachondroplasia/COMP – translating from the bench to the bedside. Matrix Biol. 2014;37:167–73. doi: 10.1016/j.matbio.2014.05.006
Hecht JT, Montufar-Solis D, Decker G, Lawler J, Daniels K, Duke PJ. Retention of cartilage oligomeric matrix protein (COMP) and cell death in redifferentiated pseudoachondroplasia chondrocytes. Matrix Biol. 1998;17(8–9):625–33.
Svensson L, Aszódi A, Heinegård D, Hunziker EB, Reinholt FP, Fässler R, Oldberg A. Cartilage oligomeric matrix protein-deficient mice have normal skeletal development. Mol Cell Biol. 2002;22(12):4366–71.
Satoh H, Susaki M, Shukunami C, Iyama K, Negoro T, Hiraki Y. Functional analysis of diastrophic dysplasia sulfate transporter. Its involvement in growth regulation of chondrocytes mediated by sulfate proteoglycans. J Biol Chem. 1998;273(20):12307–15.
Rossi A, Superti-Furga A. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat. 2001;17(3):159–71.
Superti-Furga A, Hastbacka J, Wilcox WR, Cohn DH, van der Harten HJ, Rossi A, et al. Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene. Nat Genet. 1996;12(1):100–2.
Marini JC, Forlino A, Cabral WA, Barnes AM, San Antonio JD, Milgrom S, et al. Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum Mutat. 2007;28(3):209–21.
Morello R, Bertin TK, Chen Y, Hicks J, Tonachini L, Monticone M, et al. CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell. 2006;127(2):291–304.
Cabral WA, Chang W, Barnes AM, Weis M, Scott MA, Leikin S, et al. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet. 2007;39(3):359–65. Erratum in: Nat Genet. 2008;40(7):927.
Venturi G, Monti E, Dalle Carbonare L, Corradi M, Gandini A, Valenti MT, et al. A novel splicing mutation in FKBP10 causing osteogenesis imperfecta with a possible mineralization defect. Bone. 2012;50(1):343–9. doi: 10.1016/j.bone.2011.10.023
Marini JC, Reich A, Smith SM. Osteogenesis imperfecta due to mutations in non-collagenous genes: lessons in the biology of bone formation. Curr Opin Pediatr. 2014;26(4):500–7. doi: 10.1097/MOP.0000000000000117
Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. 1979;16(2):101–16.
Venturi G,Tedeschi E, Mottes M, Valli M, Camilot M, Viglio S, Antoniazzi F, Tatò L. Osteogenesis imperfecta: clinical, biochemical and molecular findings. Clin Genet. 2006 Aug;70(2):131–9. Erratum in Clin Genet. 2006 Nov;70(5):455.
Corradi M, Monti E, Venturi G, Gandini A, Mottes M, Antoniazzi F. The recurrent causal mutation for osteogenesis imperfecta type V occurs at a highly methylated CpG dinucleotide within the IFITM5 gene. Journal of Pediatric Genetics 3 (2014) 35–39 DOI 10.3233/PGE-14079
Venturi G, Gandini A, Monti E, Dalle Carbonare L, Corradi M, Vincenzi M, et al. Lack of expression of SERPINF1, the gene coding for pigment epithelium-derived factor, causes progressively deforming osteogenesis imperfecta with normal type I collagen. J Bone Miner Res. 2012;27(3):723–8. doi: 10.1002/jbmr.1480
Valli M, Barnes AM, Gallanti A, Cabral WA, Viglio S, Weis MA, et al. Deficiency of CRTAP in non-lethal recessive osteogenesis imperfect reduces collagen deposition into matrix. Clin Genet. 2012;82(5):453–9. doi: 10.1111/j.1399-0004.2011.01794
Christiansen HE, Schwarze U, Pyott SM, AlSwaid A, Al Balwi M, Alrasheed S, et al. Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta. Am J Hum Genet. 2010;86(3):389–98. doi: 10.1016/j.ajhg.2010.01.034
Alanay Y, Avaygan H, Camacho N, Utine GE, Boduroglu K, Aktas D, et al. Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am J Hum Genet. 2010;86(4):551–9. doi: 10.1016/j.ajhg.2010.02.022
Glorieux FH, Rauch F, Plotkin H, Ward L, Travers R, Roughley P, et al. Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res. 2000;15(9):1650–8.
Glorieux FH, Ward LM, Rauch F, Lalic L, Roughley PJ, Travers R. Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res. 2002;17(1):30–8.
Cho TJ, Lee KE, Lee SK, Song SJ, Kim KJ, Jeon D, et al. A single recurrent mutation in the 5'-UTR of IFITM5 causes osteogenesis imperfecta type V. Am J Hum Genet. 2012;91(2):343–8. doi: 10.1016/j.ajhg.2012.06.005
Homan EP, Rauch F, Grafe I, Lietman C, Doll JA, Dawson B, et al. Mutations in SERPINF1 cause osteogenesis imperfecta type VI. J Bone Miner Res. 2011;26(12):2798–803. doi: 10.1002/jbmr.487
Bogan R, Riddle RC, Li Z, Kumar S, Nandal A, Faugere MC, et al. A mouse model for human osteogenesis imperfecta type VI. J Bone Miner Res. 2013;28(7):1531–6. doi: 10.1002/jbmr.1892
Farber CR, Reich A, Barnes AM, Becerra P, Rauch F, Cabral WA, et al. A novel IFITM5 mutation in severe atypical osteogenesis imperfecta type VI impairs osteoblast production of pigment epithelium-derived factor. J Bone Miner Res. 2014;29(6):1402–11.
Lapunzina P, Aglan M, Temtamy S, Caparrós-Martín JA, Valencia M, Letón R, et al. Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta. Am J Hum Genet. 2010;87(1):110–4. doi: 10.1016/j.ajhg.2010.05.016
Laine CM, Joeng KS, Campeau PM, Kiviranta R, Tarkkonen K, Grover M, et al. WNT1 mutations in early onset osteoporosis and osteogenesis imperfecta. N Engl J Med. 2013;368(19):1809–16. doi: 10.1056/NEJMoa1215458
Plotkin H. Growth in osteogenesis imperfecta. GGH J. 2007;23(2):17–23. Available from: www.GGHjournal.com
Marini JC, Bordenick S, Heavner G, Rose S, Hintz R, Rosenfeld R, Chrousos GP. The growth hormone and somatomedin axis in short children with osteogenesis imperfecta. J Clin Endocrinol Metab. 1993;76(1):251–6.
Zeitlin L, Rauch F, Plotkin H, Glorieux FH. Height and weight development during four years of therapy with cyclical intravenous pamidronate in children and adolescents with osteogenesis imperfecta types I, III, and IV. Pediatrics. 2003;111(5 Pt 1):1030–6.
Thomas KR, Capecchi MR. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell. 1987;51(3):503–12.
Brodie SG, Deng CX. Mouse models orthologous to FGFR3-related skeletal dysplasia. Pediatr Pathol Mol Med. 2003;22(1):87–103.
Iwata T, Li CL, Deng CX, Francomano CA. Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice. Hum Mol Genet. 2001;10(12):1255–64.
Becker J, Semler O, Gilissen C, Li Y, Bolz HJ, Giunta C, et al. Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Am J Hum Genet. 2011;88(3):362–71. doi: 10.1016/j.ajhg.2011.01.015
Shaheen R, Alazami AM, Alshammari MJ, Faqeih E, Alhashmi N, Mousa N, et al. Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation. J Med Genet. 2012;49(10):630–5. doi: 10.1136/jmedgenet-2012-101142