A Novel Skeletal Dysplasia with Developmental Delay and Acanthosis Nigricans Is Caused by a Lys650Met Mutation in the Fibroblast Growth Factor Receptor.

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A Novel Skeletal Dysplasia with Developmental Delay and Acanthosis Nigricans Is Caused by a Lys650Met Mutation in the Fibroblast Growth Factor Receptor 3 Gene Patricia L. Tavormina, Gary A. Bellus, Melanie K. Webster, Michael J. Bamshad, Alexander E. Fraley, Iain McIntosh, Jinny Szabo, Wen Jiang, Ethylin W. Jabs, William R. Wilcox, John J. Wasmuth, Daniel J. Donoghue, Leslie M. Thompson, Clair A. Francomano The American Journal of Human Genetics Volume 64, Issue 3, Pages 722-731 (March 1999) DOI: 10.1086/302275 Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 1 An affected individual is heterozygous for a sporadic mutation disrupting a unique BbsI restriction site in FGFR3 exon 15. PCR amplification of FGFR3 exon 15 was performed on DNA isolated from fibroblasts and lymphoblast cell lines derived from patient 1 and from lymphoblast cell lines derived from both her parents. Products were digested with the restriction enzyme BbsI, analyzed on 2% agarose gels, and visualized by ethidium bromide staining. BbsI digests essentially all the 334-bp amplicon derived from the four parental FGFR3 alleles but does not digest one allele of the amplicon derived from the patient's DNA. L = patient lymphoblast cell line; F = patient fibroblast cell line. The American Journal of Human Genetics 1999 64, 722-731DOI: (10.1086/302275) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 2 Mutation disrupting the BbsI site—an A→T transversion at position 1949, predicting a Lys650Met substitution. The FGFR3 PCR amplicon from patient 1 and one of her parents (control) was sequenced with fluorescent dideoxynucleotides. The sequence of the antisense strand is shown, and the nucleotide change in the patient's DNA is indicated. The predicted amino acid substitution in the sense strand (lysine to methionine) is shown below, and the BbsI recognition sequence is underlined. The American Journal of Human Genetics 1999 64, 722-731DOI: (10.1086/302275) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 3 Clinical and radiographic features of a patient with an FGFR3 Lys650Met mutation. A, Patient 1: age 4 years. B, Patient 1: age 1 year. The lateral skull is shown. Note severe midface hypoplasia. C, Patient 1: age 1 d. The lower extremities are shown. Note severe shortening of the long bones as well as femoral and tibial bowing. D, Patient 1: age 1 d. The lateral spine is shown. Note moderately severe platyspondyly. The American Journal of Human Genetics 1999 64, 722-731DOI: (10.1086/302275) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 4 FGFR3 Lys650Met results in strong activation of kinase activity. NIH 3T3 cells were transfected with 10 μg of each expression construct, as described in the Material and Methods section, and immunoprecipitated with FGFR3 antibody. Kinase assays were performed on the immune complexes with γ[32P]-labeled ATP, and the products were analyzed by electrophoresis on a 7.5% SDS-PAGE gel followed by transfer to nitrocellulose and exposure to x-ray film. The phosphorylated FGFR3 protein is indicated by the arrow. Background FGFR3 activity of untransfected NIH 3T3 cells is shown in the lane labeled “mock.” The identity of the lower-molecular weight–labeled product is not currently known. To control for the amount of receptor loaded, duplicate filters prepared as above were incubated with anti-FGFR3 antiserum and horseradish peroxidase–conjugated goat antirabbit IgG and visualized by enhanced chemiluminescence, as described in Material and Methods. The American Journal of Human Genetics 1999 64, 722-731DOI: (10.1086/302275) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 5 FGFR3 mutations associated with human genetic disorders. A schematic diagram of the FGFR3 protein is presented and the locations of the known human missense mutations are indicated. Immunoglobulin-like loops in the extracellular domain are labeled I–III. Standard single-letter amino acid abbreviations are used to indicate the location and nature of the mutations associated with each human disorder. The nucleotide and amino acid sequence of part of the kinase activation loop is shown, and the locations of the nucleotide substitutions in TD2 and SADDAN are indicated. The nucleotide and amino acid substitutions in SADDAN are underlined. ACH = achondroplasia; CAN = Crouzon syndrome with acanthosis nigricans; NSC = nonsyndromic craniosynostosis; HCH = hypochondroplasia; TM = transmembrane domain; TK-1 = proximal tyrosine kinase domain (ATP binding); and TK-2 = distal tyrosine kinase domain (substrate binding and catalytic). References for the mutations listed are given in the Introduction. The American Journal of Human Genetics 1999 64, 722-731DOI: (10.1086/302275) Copyright © 1999 The American Society of Human Genetics Terms and Conditions