Disease relevance of Thanatophoric Dysplasia

• Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia [1].
• One such disorder, thanatophoric dysplasia, the most common form of sporadic, lethal dwarfism, is associated frequently with cysteine substitutions (G370C, S371C, and Y373C) in the extracellular juxtamembrane region of the receptor [2].
• Mutation of Lys650-->Glu in the activation loop of the FGFR3 kinase domain causes the lethal human skeletal disorder thanatophoric dysplasia type II (TDII) and is also found in patients with multiple myeloma, bladder and cervical carcinomas [3].
• The gel electrophoretic pattern of COMP was studied in thanatophoric dysplasia, diastrophic dysplasia, homozygous achondroplasia, fibrochondrogenesis, hypochondrogenesis, Goldblatt syndrome, and Kniest dysplasia [4].
• Specific final diagnoses included thanatophoric dysplasia (8), osteogenesis imperfecta (6), Roberts syndrome (2), achondroplasia (3), Ellis-van Creveld syndrome (1), metaphyseal dysplasia (1), spondyloepiphyseal dysplasia (1), distal arthrogryposis (1), caudal regression (1), and glycogen storage disorder (1) [5].

High impact information on Thanatophoric Dysplasia

• The abnormal phenotypes of the Hspg2-/- skeleton are similar to those of thanatophoric dysplasia (TD) type I, which is caused by activating mutations in FGFR3 (refs 7, 8, 9), and to those of Fgfr3 gain-of-function mice [6].
• In contrast, only FGFR3 mutations have been reported in dwarfing conditions--achondroplasia, thanatophoric dysplasia, and hypochondroplasia [7].
• Mutations in the FGFR3 gene also result in hypochondroplasia, the lethal thanatophoric dysplasias, the recently described SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) dysplasia, and two craniosynostosis disorders: Muenke coronal craniosynostosis and Crouzon syndrome with acanthosis nigricans [8].
• Some t(4;14) patients have activating mutations of FGFR3, of which a minority are K650E (thanatophoric dysplasia type II [TDII]) [9].
• Similarly, activating FGF receptor 3 mutations impair growth in achondroplasia and thanatophoric dysplasia [10].

Chemical compound and disease context of Thanatophoric Dysplasia

• Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1) [11].
• The K650E substitution in the fibroblast growth factor receptor 3 (FGFR3) causes constitutive tyrosine kinase activity of the receptor and is associated to the lethal skeletal disorder, thanatophoric dysplasia type II (TDII) [12].

Biological context of Thanatophoric Dysplasia

• We have identified a novel fibroblast growth factor receptor 3 (FGFR3) missense mutation in four unrelated individuals with skeletal dysplasia that approaches the severity observed in thanatophoric dysplasia type I (TD1) [13].
• We speculate that short telomere length and low telomerase activity may be important for chondrocyte differentiation in rhizomeric shortening of the limbs in thanatophoric dysplasia [14].
• The FGFR3 Lys650Met mutation results in severe disturbances in endochondral bone growth that approach and overlap those observed in thanatophoric dysplasia, type I. However, this mutation is most often compatible with survival into adulthood [15].
• Second trimester molecular diagnosis of a stop codon FGFR3 mutation in a type I thanatophoric dysplasia fetus following abnormal ultrasound findings [16].
• BACKGROUND: The point mutations of fibroblast growth factor receptor 3 (FGFR3) are associated with autosomal dominant human skeletal disorders such as thanatophoric dysplasia (TD) [17].

Anatomical context of Thanatophoric Dysplasia

• Abnormal FGFR 3 expression in cartilage of thanatophoric dysplasia fetuses [18].
• METHODS: The mutant FGFR3 genes causing ACH and thanatophoric dysplasia (TD), which is a more severe neonatal lethal form, were introduced into a chondrogenic cell line, ATDC5 [19].

Gene context of Thanatophoric Dysplasia

• Here we compared the ubiquitylation of either wild type or a K508A 'kinase-dead' mutant of fibroblast growth factor receptor 3 (FGFR3) with that of its naturally occurring overactive mutants, G380R as in achondroplasia, or K650E involved in thanatophoric dysplasia [20].
• We present 13 cases of thanatophoric dysplasia collected in the Spanish Collaborative Study of Congenital Malformations from a total population of 517,970 births [21].
• The heterogeneous group of platyspondylic lethal skeletal dysplasias (PLSD) originally included thanatophoric dysplasias (TD1/2: MIM 187600, 187100) as the most common forms of this condition, as well as TD variants San Diego type (PLSD-SD: MIM 270230) and Torrance-Luton type (PLSD-TL: MIM 151210) [22].

References