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Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2.
Hum Mol Genet. 1997 Jan; 6(1):137-43.HM

Abstract

Dominantly acting, allelic mutations of the fibroblast growth factor receptor 2 (FGFR2) gene have been described in five craniosynostosis syndromes. In Apert syndrome, characterised by syndactyly of the hands and feet, recurrent mutations of a serine-proline dipeptide (either Ser252Trp or Pro253Arg) in the linker between the IgII and IgIII extracellular immunoglobulin-like domains, have been documented in more than 160 unrelated individuals. We have identified three novel mutations of this dipeptide, associated with distinct phenotypes. A C-->T mutation that predicts a Ser252Leu substitution, ascertained in a boy with mild Crouzon syndrome (craniosynostosis with normal limbs) is also present in three clinically normal members of his family. A CG-->TT mutation that predicts a Ser252Phe substitution results in a phenotype consistent with Apert syndrome. Finally, a CGC-->TCT mutation that predicts a double amino acid substitution (Ser252Phe and Pro253Ser) causes a Pfeiffer syndrome variant with mild craniosynostosis, broad thumbs and big toes, fixed extension of several digits, and only minimal cutaneous syndactyly. The observation that the Ser252Phe mutation causes Apert syndrome, whereas the other single or double substitutions are associated with milder or normal phenotypes, highlights the exquisitely specific molecular pathogenesis of the limb and craniofacial abnormalities associated with Apert syndrome. Ser252Phe is the first noncanonical mutation to be identified in this disorder, its rarity being explained by the requirement for two residues of the serine codon to be mutated. The description of independent, complex nucleotide substitutions involving identical nucleotides is unprecedented, and we speculate that this may result from functional selection of FGFR mutations in sperm.

Authors+Show Affiliations

Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9002682

Citation

Oldridge, M, et al. "Genotype-phenotype Correlation for Nucleotide Substitutions in the IgII-IgIII Linker of FGFR2." Human Molecular Genetics, vol. 6, no. 1, 1997, pp. 137-43.
Oldridge M, Lunt PW, Zackai EH, et al. Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2. Hum Mol Genet. 1997;6(1):137-43.
Oldridge, M., Lunt, P. W., Zackai, E. H., McDonald-McGinn, D. M., Muenke, M., Moloney, D. M., Twigg, S. R., Heath, J. K., Howard, T. D., Hoganson, G., Gagnon, D. M., Jabs, E. W., & Wilkie, A. O. (1997). Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2. Human Molecular Genetics, 6(1), 137-43.
Oldridge M, et al. Genotype-phenotype Correlation for Nucleotide Substitutions in the IgII-IgIII Linker of FGFR2. Hum Mol Genet. 1997;6(1):137-43. PubMed PMID: 9002682.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2. AU - Oldridge,M, AU - Lunt,P W, AU - Zackai,E H, AU - McDonald-McGinn,D M, AU - Muenke,M, AU - Moloney,D M, AU - Twigg,S R, AU - Heath,J K, AU - Howard,T D, AU - Hoganson,G, AU - Gagnon,D M, AU - Jabs,E W, AU - Wilkie,A O, PY - 1997/1/1/pubmed PY - 1997/1/1/medline PY - 1997/1/1/entrez SP - 137 EP - 43 JF - Human molecular genetics JO - Hum Mol Genet VL - 6 IS - 1 N2 - Dominantly acting, allelic mutations of the fibroblast growth factor receptor 2 (FGFR2) gene have been described in five craniosynostosis syndromes. In Apert syndrome, characterised by syndactyly of the hands and feet, recurrent mutations of a serine-proline dipeptide (either Ser252Trp or Pro253Arg) in the linker between the IgII and IgIII extracellular immunoglobulin-like domains, have been documented in more than 160 unrelated individuals. We have identified three novel mutations of this dipeptide, associated with distinct phenotypes. A C-->T mutation that predicts a Ser252Leu substitution, ascertained in a boy with mild Crouzon syndrome (craniosynostosis with normal limbs) is also present in three clinically normal members of his family. A CG-->TT mutation that predicts a Ser252Phe substitution results in a phenotype consistent with Apert syndrome. Finally, a CGC-->TCT mutation that predicts a double amino acid substitution (Ser252Phe and Pro253Ser) causes a Pfeiffer syndrome variant with mild craniosynostosis, broad thumbs and big toes, fixed extension of several digits, and only minimal cutaneous syndactyly. The observation that the Ser252Phe mutation causes Apert syndrome, whereas the other single or double substitutions are associated with milder or normal phenotypes, highlights the exquisitely specific molecular pathogenesis of the limb and craniofacial abnormalities associated with Apert syndrome. Ser252Phe is the first noncanonical mutation to be identified in this disorder, its rarity being explained by the requirement for two residues of the serine codon to be mutated. The description of independent, complex nucleotide substitutions involving identical nucleotides is unprecedented, and we speculate that this may result from functional selection of FGFR mutations in sperm. SN - 0964-6906 UR - https://www.unboundmedicine.com/medline/citation/9002682/Genotype_phenotype_correlation_for_nucleotide_substitutions_in_the_IgII_IgIII_linker_of_FGFR2_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/6.1.137 DB - PRIME DP - Unbound Medicine ER -