Genotype phenotype correlation in achondroplasia and hypochondroplasia

Matsui, Yoshito; Yasui, Natsuo; Kimura, Takeshi; Tsumaki, Noriyuki; Kawabata, Hidehiko; Ochi, Takahiro

doi:10.1302/0301-620x.80b6.9277

Cited by 38 publications

(16 citation statements)

References 23 publications

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“…The abnormalities seen in HCH are less severe overall than those seen in ACH and HCH patients have less dysmorphic facial features (Matsui et al. 1998). Most cases can be readily distinguished clinically and radiographically.…”

Section: Discussionmentioning

confidence: 99%

FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry

Xue

Sun

Mekikian

et al. 2014

Molec Gen & Gen Med

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Fibroblast growth factor receptor 3 (FGFR3) is the only gene known to cause achondroplasia (ACH), hypochondroplasia (HCH), and thanatophoric dysplasia types I and II (TD I and TD II). A second, as yet unidentified, gene also causes HCH. In this study, we used sequencing analysis to determine the frequency of FGFR3 mutations for each phenotype in 324 cases from the International Skeletal Dysplasia Registry (ISDR). Our data suggest that there is a considerable overlap of genotype and phenotype between ACH and HCH. Thus, it is important to test for mutations found in either disorder when ACH or HCH is suspected. Only two of 29 cases with HCH did not have an identified mutation in FGFR3, much less than previously reported. We recommend testing other mutations in FGFR3, instead of just the common HCH mutation, p.Asn540Lys. The mutation frequency for TD I and TD II in the largest series of cases to date are also reported. This study provides valuable information on FGFR3 mutation frequency of four skeletal dysplasias for clinical diagnostic laboratories and clinicians.

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Section: Discussionmentioning

confidence: 99%

FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry

Xue

Sun

Mekikian

et al. 2014

Molec Gen & Gen Med

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“…In patients with HCP, the skeletal features are less severe than in patients with ACP (1,2). Therefore, the diagnosis of HCP is often difficult, and some affected patients may be evaluated as idiopathic short stature.…”

Section: Discussionmentioning

confidence: 92%

“…In patients with N540K mutations, adult height ranges from 138 cm to 155 cm in men and from 128 cm to 145 cm in women (13,14). The use of recombinant growth hormone (rGH) therapy for HCP has been evaluated by several centers in trials (2,14,15,16,17,18). In most of these trials, a statistically significant increase in predicted growth rate was reported.…”

Section: Discussionmentioning

confidence: 99%

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Hypochondroplasia in a Child With 1620c>G (Asn540lys) Mutation in FGFR3

Korkmaz

Hazan²,

Dizdarer³

et al. 2012

Jcrpe

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Hypochondroplasia (HCP) is an autosomal dominant skeletal dysplasia characterized by short extremities, short stature and lumbar lordosis, usually exhibiting a phenotype similar to but milder than achondroplasia (ACP). Fibroblast growth factor receptor 3 gene (FGFR3) mutations in the germline are well-known causes of skeletal syndromes. FGFR3 is a negative regulator of bone growth and all mutations in FGFR3 are gain-of-function mutations that lead to skeletal dysplasias. We report a child who presented with short stature, a relatively long trunk, short legs, short arm span, radiographic evidence of HCP and mild mental retardation. Genetic analysis revealed a heterozygous 1620C>G (Asn540Lys) mutation in FGFR3. To our knowledge, ours is the first case report of HCP with a heterozygous 1620C>G (Asn540Lys) mutation in Turkey.Conflict of interest:None declared.

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“…Other less frequent mutations are also identified in FGFR3 but are mainly associated with hypochondroplasia and thanatophoric dysplasia type I and II [19]. Therefore, in comparison to other genetic diseases, ACH is a genetically and phenotypically homogenous disorder where very few rather than hundreds of mutations are responsible [20, 21]. In this study a non-consanguineous Pakistani family involving two affected generations, was clinically and genetically characterized for skeletal dysplasia.…”

Section: Introductionmentioning

confidence: 99%

Identification and in silico characterization of p.G380R substitution in FGFR3, associated with achondroplasia in a non-consanguineous Pakistani family

Ajmal

Mir

Shoaib³

et al. 2017

Diagn Pathol

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BackgroundThe dimerization efficiency of FGFR3 transmembrane domain plays a critical role in the formation of a normal skeleton through the negative regulation of bone development. Recently, gain-of-function mutations in the transmembrane domain of FGFR3 has been described associated with an aberrant negative regulation, leading to the development of achondroplasia-group disorders, including achondroplasia (ACH), hypochondroplasia (HCH) and thanatophoric dysplasia (TD). Here, we describe a non-consanguineous Pakistani family with achondroplasia to explain hereditary basis of the disease.MethodsPCR-based linkage analysis using microsatellite markers was employed to localize the disease gene. Gene specific intronic primers were used to amplify the genomic DNA from all affected as well as phenotypically healthy individuals. Amplified PCR products were then subjected to Sanger sequencing and RFLP analysis to identify a potentially pathogenic mutation. The impact of identified mutation on FGFR3 protein’s structure and stability was highlighted through different bioinformatics tools.ResultsGenetic screening of the family revealed a previously reported heterozygous c.1138 G > A (p.G380R) mutation in the coding exon 8 of FGFR3 gene. Identified genetic variation was confirmed in all affected individuals while healthy individuals and controls were found genotypically normal. The results were further validated by RFLP analysis as c.1138 G > A substitution generates a unique recognition site for SfcI endonuclease. Following SfcI digestion, the electrophoretic pattern of three bands/DNA fragments for each patient is indicative of heterozygous status of the disease allele. In silico studies of the mutant FGFR3 protein predicted to adversely affect the stability of FGFR3 protein.ConclusionsMutation in the transmembrane domain may adversely affect the dimerization efficiency and overall stability of the FGFR3, leading to a constitutively active protein. As a result, an uncontrolled intracellular signaling or negative bone growth regulation leads to achondroplasia. Our findings support the fact that p.G380R is a common mutation among diverse population of the world and like other countries, can be used as a molecular diagnosis marker for achondroplasia in Pakistan.Electronic supplementary materialThe online version of this article (doi:10.1186/s13000-017-0642-3) contains supplementary material, which is available to authorized users.

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Genotype phenotype correlation in achondroplasia and hypochondroplasia

Cited by 38 publications

References 23 publications

FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry

FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry

Hypochondroplasia in a Child With 1620c>G (Asn540lys) Mutation in FGFR3

Identification and in silico characterization of p.G380R substitution in FGFR3, associated with achondroplasia in a non-consanguineous Pakistani family

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