Genotype-Phenotype Correlation for Nucleotide Substitutions in the IgII-IgIII Linker of FGFR2

• Published in: Human molecular genetics Vol. 6; no. 1; pp. 137 - 143
• Main Authors: Oldridge, Michael, Lunt, Peter W., Zackai, Elaine H., McDonald-McGinn, Donna M., Muenke, Maximilian, Moloney, Dominique M., Twigg, Stephen R. F., Heath, John K., Howard, Timothy D., Hoganson, George, Gagnon, Deborah M., Jabs, Ethylin Wang, Wilkie, Andrew O. M.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.01.1997
• Subjects: Adult; Biological and medical sciences; Child; Craniosynostoses - genetics; Craniosynostoses - metabolism; Dipeptides - genetics; Diseases of the osteoarticular system; Female; Foot Deformities, Congenital - diagnostic imaging; Foot Deformities, Congenital - genetics; Genotype; Hand Deformities, Congenital - genetics; Humans; Immunoglobulins; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Nucleotides; Pedigree; Phenotype; Proline; Radiography; Receptor Protein-Tyrosine Kinases - genetics; Receptor, Fibroblast Growth Factor, Type 2; Receptors, Fibroblast Growth Factor - genetics; Serine; Human; Fibroblast growth factor; Correlation; Diseases of the osteoarticular system; Genotype; Genetic disease; Pfeiffer syndrome; Phenotype; Apert syndrome; Crouzon disease; Gene; Malformation; Genetics; Mutation; Face; Biological receptor
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/6.1.137

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 immuno-globulin-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 non-canonical 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.