Description:
ACHONDROPLASIA; ACH
FIBROBLAST GROWTH FACTOR RECEPTOR 3; FGFR3
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Repository
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NIGMS Human Genetic Cell Repository
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| Subcollection |
Heritable Diseases |
| Class |
Disorders of Connective Tissue, Muscle, and Bone |
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Cell Type
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Fibroblast
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Transformant
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Untransformed
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Race
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White
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Family Member
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1
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Relation to Proband
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proband
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Confirmation
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Molecular characterization after cell line submission to CCR
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Species
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Homo sapiens
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Common Name
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Human
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Remarks
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| Passage Frozen |
5 |
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| IDENTIFICATION OF SPECIES OF ORIGIN |
Species of Origin Confirmed by Nucleoside Phosphorylase, Glucose-6-Phosphate Dehydrogenase, and Lactate Dehydrogenase Isoenzyme Electrophoresis |
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| GENE MAPPING & DOSAGE STUDIES - Y CHROMOSOME |
PCR analysis of DNA from this cell culture gave a negative result with a primer for Yq11, DYS227. |
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| Gene |
FGFR3 |
| Chromosomal Location |
4p16.3 |
| Allelic Variant 1 |
134934.0001; ACHONDROPLASIA; ACH |
| Identified Mutation |
GLY380ARG, 1138G>A; In achondroplasia, codon 380 in the FGFR3 gene is changed from GGG to AGG or CGG (Shiang et al., 1994). Codon 379 is TAC (tyr). Rousseau et al. (1994) found the gly380-to-arg mutation in all 23 cases of achondroplasia studied (17 sporadic and 6 familial). Twenty-two of the 23 probands had the G-to-A transition; only 1 had the G-to-C transversion (134934.0002). See also Ikegawa et al. (1995).
Nucleotide 1138 of the FGFR3 gene may be one of the most mutable bases in the human genome. Wilkie (1997) commented that it seems unlikely to be coincidental that the 3 highest germline point mutation rates described in the human (elevated approximately 1000-fold over background) all concern FGFRs: G380R in FGFR3, P250R also in FGFR3 (134934.0014), and S252W in FGFR2 (176943.0010). These 3 mutations result in achondroplasia, Muenke nonsyndromic coronal craniosynostosis, and Apert syndrome, respectively. Increased paternal age associated with achondroplasia and Apert syndrome has long been known, and an exclusively paternal origin of mutation was shown in studies of 57 Apert syndrome patients by Moloney et al. (1996) and in 10 achondroplasia patients by Szabo et al. (1996).
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| Gene |
FGFR3 |
| Chromosomal Location |
4p16.3 |
| Allelic Variant 2 |
134934.0001; ACHONDROPLASIA; ACH |
| Identified Mutation |
GLY380ARG, 1138G>A; In achondroplasia, codon 380 in the FGFR3 gene is changed from GGG to AGG or CGG (Shiang et al., 1994). Codon 379 is TAC (tyr). Rousseau et al. (1994) found the gly380-to-arg mutation in all 23 cases of achondroplasia studied (17 sporadic and 6 familial). Twenty-two of the 23 probands had the G-to-A transition; only 1 had the G-to-C transversion (134934.0002). See also Ikegawa et al. (1995).
Nucleotide 1138 of the FGFR3 gene may be one of the most mutable bases in the human genome. Wilkie (1997) commented that it seems unlikely to be coincidental that the 3 highest germline point mutation rates described in the human (elevated approximately 1000-fold over background) all concern FGFRs: G380R in FGFR3, P250R also in FGFR3 (134934.0014), and S252W in FGFR2 (176943.0010). These 3 mutations result in achondroplasia, Muenke nonsyndromic coronal craniosynostosis, and Apert syndrome, respectively. Increased paternal age associated with achondroplasia and Apert syndrome has long been known, and an exclusively paternal origin of mutation was shown in studies of 57 Apert syndrome patients by Moloney et al. (1996) and in 10 achondroplasia patients by Szabo et al. (1996).
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| Remarks |
Clinically affected; marked rhizomelic shortening with characteristic trident hands; upper/lower segment ratio is 1.67; shorter femora, tibias, fibulas, and ribs than in heterozygous achondroplasia; both parents have achondroplasia; donor subject is homozygous for a G>A transition at nucleotide 1138 of the FGFR3 gene resulting in the substitution of arginine for glycine at codon 380 [Gly380Arg (G380R)] |
| Moura S, Hartl I, Brumovska V, Calabrese PP, Yasari A, Striedner Y, Bishara M, Mair T, Ebner T, Schütz GJ, Sevcsik E, Tiemann-Boege I, Exploring FGFR3 Mutations in the Male Germline: Implications for Clonal Germline Expansions and Paternal Age-Related Dysplasias Genome biology and evolution16: 2024 |
| PubMed ID: 38411226 |
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| Striedner Y, Arbeithuber B, Moura S, Nowak E, Reinhardt R, Muresan L, Salazar R, Ebner T, Tiemann-Boege I, Exploring the Micro-Mosaic Landscape of Genes15: 2024 |
| PubMed ID: 38397181 |
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| Tiemann-Boege I, Navidi W, Grewal R, Cohn D, Eskenazi B, Wyrobek AJ, Arnheim N, The observed human sperm mutation frequency cannot explain the achondroplasia
paternal age effect. Proc Natl Acad Sci U S A99(23):14952-7 2002 |
| PubMed ID: 12397172 |
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| Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, Winokur ST, Wasmuth JJ, Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell78:335-42 1994 |
| PubMed ID: 7913883 |
| Passage Frozen |
5 |
| Split Ratio |
1:3 |
| Temperature |
37 C |
| Percent CO2 |
5% |
| Medium |
Eagle's Minimum Essential Medium with Earle's salts and non-essential amino acids with 2mM L-glutamine or equivalent |
| Serum |
15% fetal bovine serum Not inactivated |
| Substrate |
None specified |
| Subcultivation Method |
trypsin-EDTA |
| Supplement |
- |
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