A Novel Homozygous Mutation in FGFR3 Causes Tall Stature, Severe Lateral Tibial Deviation, Scoliosis, Hearing Impairment, Camptodactyly, and Arachnodactyly

Makrythanasis, Periklis; Temtamy, Samia; Aglan, Mona; Otaify, Ghada A.; Hamamy, Hanan; Antonarakis, Stylianos E.

doi:10.1002/humu.22597

Cited by 70 publications

(55 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This mutation inactivates the kinase domain and likely confers dominant-negative activity to the receptor. A homozygous mutation in the FGFR3 tyrosine kinase domain (T546K) has also been identified in two siblings with CATSHL from consanguineous parents (Makrythanasis et al 2014). Interestingly, a similar recessive mutation in FGFR3(V700E) in sheep results in spider lamb syndrome, characterized by long limbs, kyphoscoliosis, malformed ribs and sternebrae, Roman noses, lack of body fat, and muscular atrophy (Beever et al 2006).…”

Section: Chondrodysplasia Syndromesmentioning

confidence: 99%

Fibroblast growth factor signaling in skeletal development and disease

2015

View full text Add to dashboard Cite

Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored.

show abstract

Section: Chondrodysplasia Syndromesmentioning

confidence: 99%

Fibroblast growth factor signaling in skeletal development and disease

2015

View full text Add to dashboard Cite

show abstract

“…A recent report has identified an activating FGFR3 mutation in a family with autosomal dominant proportionate short stature 60 . Conversely, heterozygous 61 and homozygous 62 inactivating mutations in FGFR3 have been reported in individuals with tall stature. At the growth plate, FGF signaling through FGFR3 leads to activation of several pathways including the MAPK and JAK/STAT pathways and negatively regulates growth by decreasing proliferation in the proliferative zone, decreasing matrix production, accelerating the onset of hypertrophic differentiation, and decreasing the size of the hypertrophic chondrocytes 53,63–65 .…”

Section: Introductionmentioning

confidence: 99%

Short and tall stature: a new paradigm emerges

et al. 2015

View full text Add to dashboard Cite

In the past, the growth hormone (GH) – insulin-like growth factor-I (IGF-I) axis was thought to be the central system regulating childhood growth and therefore responsible for short stature and tall stature. However, recent findings have revealed that the GH-IGF-I axis is just one of many regulatory systems that control chondrogenesis in the growth plate, the biological process that drives height gain. Consequently, normal growth in children depends not only on GH and IGF-I but on multiple hormones, paracrine factors, extracellular matrix molecules, and intracellular proteins that regulate growth plate chondrocytes. Mutations in genes encoding many of these local proteins cause short stature or tall stature. Similarly genome-wide association studies have revealed that the normal variation in height appears to be due largely to genes outside the GH-IGF-I axis that affect growth at the growth plate through a wide variety of mechanisms. These findings point to a new conceptual framework for understanding short and tall stature, which is centered not on two particular hormones but rather on the growth plate, the structure responsible for height gain.

show abstract

“…Loss of function of FGFR3, either globally or specifically in chondrocytes, leads to skeletal overgrowth in mice, sheep and humans (Beever et al, 2006;Colvin et al, 1996;Deng et al, 1996;Makrythanasis et al, 2014;Ornitz and Marie, 2015;Toydemir et al, 2006;Zhou et al, 2015). The inhibitory activity of FGFR3 on growth plate chondrocytes explains the pathogenic consequences of gain-of-function mutations in FGFR3 in suppressing pre-pubertal skeletal growth in achondroplasia and related chondrodysplastic disorders (Laederich and Horton, 2012;Naski et al, 1998Naski et al, , 1996.…”

Section: Introductionmentioning

confidence: 99%

FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth

Karuppaiah

Lim

et al. 2016

Development

View full text Add to dashboard Cite

Fibroblast growth factor (FGF) signaling is important for skeletal development; however, cell-specific functions, redundancy and feedback mechanisms regulating bone growth are poorly understood. FGF receptors 1 and 2 (Fgfr1 and Fgfr2) are both expressed in the osteoprogenitor lineage. Double conditional knockout mice, in which both receptors were inactivated using an osteoprogenitor-specific Cre driver, appeared normal at birth; however, these mice showed severe postnatal growth defects that include an ∼50% reduction in body weight and bone mass, and impaired longitudinal bone growth. Histological analysis showed reduced cortical and trabecular bone, suggesting cellautonomous functions of FGF signaling during postnatal bone formation. Surprisingly, the double conditional knockout mice also showed growth plate defects and an arrest in chondrocyte proliferation. We provide genetic evidence of a non-cell-autonomous feedback pathway regulating Fgf9, Fgf18 and Pthlh expression, which led to increased expression and signaling of Fgfr3 in growth plate chondrocytes and suppression of chondrocyte proliferation. These observations show that FGF signaling in the osteoprogenitor lineage is obligately coupled to chondrocyte proliferation and the regulation of longitudinal bone growth.

show abstract

A Novel Homozygous Mutation in FGFR3 Causes Tall Stature, Severe Lateral Tibial Deviation, Scoliosis, Hearing Impairment, Camptodactyly, and Arachnodactyly

Cited by 70 publications

References 8 publications

Fibroblast growth factor signaling in skeletal development and disease

Fibroblast growth factor signaling in skeletal development and disease

Short and tall stature: a new paradigm emerges

FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth

Contact Info

Product

Resources

About