Asn540Lys mutation in fibroblast growth factor receptor 3 and phenotype in hypochondroplasia

Grigelioniené, G.; Eklöf, O.; Laurencikas, E.; Ollars, B.; Hertel, NT; Dumanski, Jan P.; Hagenäs, L.

doi:10.1080/713794579

Cited by 15 publications

(20 citation statements)

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“…Point mutations and deletions of the short stature homeobox containing gene (SHOX) have been described in DCO and idiopathic short stature with mild rhizomelic body disproportion (Belin et al 1998;Ogata 1999;Rao et al 1997;Shears et al 1998), while 40-70% of the HCH cases have the Asn540Lys mutation in the fibroblast growth factor receptor 3 (FGFR3) gene (Bellus et al 1995;Prinos et al 1995;Prinster et al 1998;Ramaswami et al 1998). It has been suggested that HCH individuals without the Asn540Lys substitution in the FGFR3 gene are less disproportionate (Ramaswami et al 1998;Grigelioniene et al 2000), indicating that these cases might have a phenotype resembling idiopathic short stature or mild cases of DCO without Madelung deformity.…”

Section: Giedre Grigelioniene · Ole Eklöf · Sten Anders Ivarsson · Otmentioning

confidence: 98%

“…Five probands with DCO (three familial and two sporadic cases, all Caucasians and of Swedish origin) and 18 probands with HCH (11 familial and 7 sporadic cases, all Caucasians, 15 of Swedish and two of South European origin) were included in the study. The HCH probands were previously found to be negative for the known HCH-associated FGFR3 mutations (Grigelioniene et al 2000). The inclusion criteria were disproportionate short stature and clinically and radiologically confirmed HCH (Hall and Spranger 1979) or DCO (Langer 1965).…”

Section: Patientsmentioning

confidence: 99%

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Mutations in short stature homeobox containing gene (SHOX) in dyschondrosteosis but not in hypochondroplasia

et al. 2000

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Dyschondrosteosis (DCO) and hypochondroplasia (HCH) are common skeletal dysplasias characterized by disproportionate short stature. The diagnosis of these conditions might be difficult to establish especially in early childhood. Point mutations and deletions of the short stature homeobox containing gene (SHOX) are detected in DCO and idiopathic short stature with some rhizomelic body disproportion, whereas mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are found in 40-70% of HCH cases. In this study, we performed mutational analysis of the coding region of the SHOX gene in five DCO and 18 HCH patients, all of whom tested negative for the known HCH-associated FGFR3 mutations. The polymorphic CA-repeat analysis, direct sequencing and Southern blotting were used for detection of deletions and point mutations. The auxological and radiological phenotype of these patients was carefully determined. Three novel mutations in DCO patients were found: (1) a deletion of one base (de1272G) (according to GenBank accession nos. Y11536, Y11535), resulting in a premature stop codon at position 75 of the amino acid sequence; (2) the transversion C485G resulting in the substitution Leu132Val; and (3) the transversion G549T causing an Arg153Leu substitution. These substitutions segregate with the DCO phenotype and affect evolutionarily conserved homeodomain residues, based on a comparison of homeobox containing proteins in 13 species. Moreover, these changes were not found in 80 unrelated, unaffected individuals. This strongly suggests that these mutations are pathogenic. The phenotype of our patients with DCO and HCH varied from mild to severe shortness and body disproportion. These results further support clinical and genetic heterogeneity of dyschondrosteosis and hypochondroplasia.

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Section: Giedre Grigelioniene · Ole Eklöf · Sten Anders Ivarsson · Otmentioning

confidence: 98%

Section: Patientsmentioning

confidence: 99%

Mutations in short stature homeobox containing gene (SHOX) in dyschondrosteosis but not in hypochondroplasia

et al. 2000

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“…24). Two recurrent mutations in exon 13, 1620C → A and 1620C → G, result in Asn540Lys and account for about 50% to 70% of all cases of hypochondroplasia [Bellus et al, 1995b, 1996, 2000; Prinster et al, 1998; Ramaswami et al, 1998; Grigelioniene et al, 2000]. A Crouzon syndrome mutation in the first kinase domain occurs at the equivalent residue on FGFR2 (Kan et al, 2002).…”

Section: Fgfs/fgfrs Fgfr3 Skeletal Dysplasias Craniosynostosis Andmentioning

confidence: 99%

The new bone biology: Pathologic, molecular, and clinical correlates

Cohen

2006

American J of Med Genetics Pt A

285

197

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Bone and cartilage and their disorders are addressed under the following headings: functions of bone; normal and abnormal bone remodeling; osteopetrosis and osteoporosis; epithelial-mesenchymal interaction, condensation and differentiation; osteoblasts, markers of bone formation, osteoclasts, components of bone, and pathology of bone; chondroblasts, markers of cartilage formation, secondary cartilage, components of cartilage, and pathology of cartilage; intramembranous and endochondral bone formation; RUNX genes and cleidocranial dysplasia (CCD); osterix; histone deacetylase 4 and Runx2; Ligand to receptor activator of NFkappaB (RANKL), RANK, osteoprotegerin, and osteoimmunology; WNT signaling, LRP5 mutations, and beta-catenin; the role of leptin in bone remodeling; collagens, collagenopathies, and osteogenesis imperfecta; FGFs/FGFRs, FGFR3 skeletal dysplasias, craniosynostosis, and other disorders; short limb chondrodysplasias; molecular control of the growth plate in endochondral bone formation and genetic disorders of IHH and PTHR1; ANKH, craniometaphyseal dysplasia, and chondrocalcinosis; transforming growth factor beta, Camurati-Engelmann disease (CED), and Marfan syndrome, types I and II; an ACVR1 mutation and fibrodysplasia ossificans progressiva; MSX1 and MSX2: biology, mutations, and associated disorders; G protein, activation of adenylyl cyclase, GNAS1 mutations, McCune-Albright syndrome, fibrous dysplasia, and Albright hereditary osteodystrophy; FLNA and associated disorders; and morphological development of teeth and their genetic mutations.

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“…Although the recurrent p.N540K mutation in the tyrosine kinase domain accounts for about 70% of all reported patients [Rousseau et al, 1996b; Stenson et al, 2003], six other pathogenic amino acid substitutions in the FGFR3 gene have been identified in HCH patients: p.N540T p.N540S, p.I538V, p.N328I, p.K650N, and p.K650Q [Deutz‐Terlouw et al, 1998; Prinster et al, 1998; Bellus et al, 2000; Grigelioniene et al, 2000; Mortier et al, 2000; Winterpacht et al, 2000]. Patients with p.N540K mutation presented with a more severe phenotype compared to those with other FGFR3 mutations or unlinked to 4p16.3 [Rousseau et al, 1996b; Prinster et al, 1998; Grigelioniene et al, 2000]. The implication of several factors that include differentiations in the intracellular processing of other than p.N540K mutant FGFR3 molecules or additional modifying genes unlinked to 4p16.3 may play a role in determining the final phenotype [Karadimas et al, 2006].…”

Section: Introductionmentioning

confidence: 99%

FGFR3 related skeletal dysplasias diagnosed prenatally by ultrasonography and molecular analysis: Presentation of 17 cases

Hatzaki¹,

Sifakis

Apostolopoulou³

et al. 2011

American J of Med Genetics Pt A

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Fibroblast Growth Factor Receptor 3 (FGFR3) related skeletal dysplasias are caused by mutations in the FGFR3 gene that result in increased activation of the receptors causing alterations in the process of endochondral ossification in all long bones, and include achondroplasia, hypochondroplasia, thanatophoric dysplasia, and SADDAN. Reports of prenatal diagnosis of FGFR3 related skeletal dysplasias are not rare; however, the correlation between 2nd trimester ultrasonographic findings and underlying molecular defect in these cases is relatively poor. There is a need for specific ultrasound (U/S) predictors than can distinguish lethal from non-lethal cases and aid an earlier prenatal diagnosis. Here we present one familial and 16 sporadic cases with FGFR3 related skeletal dysplasia, and we evaluate biometric parameters and U/S findings consistent with the diagnosis of skeletal dysplasia. U/S scan performed even at the 18th week of gestation can indicate a decreased rate of development of the femora (femur length (FL) <5th centile), while the mean gestational age at diagnosis is still around the 26th week. The utility of other biometric parameters and ratios is discussed (foot length, BPD, HC, FL/foot, and FL/AC). Prenatal cytogenetic and molecular genetic analyses were performed. A final diagnosis was reached by molecular analysis. In two cases of discontinued pregnancy, fetal autopsy led to a phenotypic diagnosis and confirmed the prenatal prediction of lethality. We conclude that the combination of U/S and molecular genetic approach is helpful for establishing an accurate diagnosis of FGFR3-related skeletal dysplasias in utero and subsequently for appropriate genetic counselling and perinatal management.

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Asn540Lys mutation in fibroblast growth factor receptor 3 and phenotype in hypochondroplasia

Abstract: Individuals with hypochondroplasia heterozygous for the Asn540Lys substitution are significantly more disproportionate than individuals without this mutation. Our study further confirms the clinical and genetic heterogeneity of hypochondroplasia.

Cited by 15 publications

References 0 publications

Mutations in short stature homeobox containing gene (SHOX) in dyschondrosteosis but not in hypochondroplasia

Mutations in short stature homeobox containing gene (SHOX) in dyschondrosteosis but not in hypochondroplasia

The new bone biology: Pathologic, molecular, and clinical correlates

FGFR3 related skeletal dysplasias diagnosed prenatally by ultrasonography and molecular analysis: Presentation of 17 cases

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