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Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome.
Eur J Hum Genet. 2006 Mar; 14(3):289-98.EJ

Abstract

Crouzon Syndrome (CS), Pfeiffer syndrome (PS) and the phenotypically related Jackson-Weiss (JW) variant are three craniosynostotic conditions caused by heterozygous mutations in Fibroblast Growth Factor Receptor (FGFR) genes. Screening a large cohort of 84 patients with clinical features of CS, PS or JW by direct sequencing of genomic DNA, enabled FGFR1, 2 or 3 mutation detection in 79 cases. Mutations preferentially occurred in exons 8 and 10 of FGFR2 encoding the third Ig loop of the receptor. Among the 74 FGFR2 mutations that we identified, four were novel including three missense substitutions causing CS and a 2 bp deletion creating a premature stop codon and producing JW phenotype. Five FGFR2 mutations were found in one of the two tyrosine kinase subdomains and one in the Ig I loop. Interestingly, two FGFR2 mutations creating cysteine residues (W290C and Y340C) caused severe forms of PS while conversion of the same residues into another amino-acid (W290G/R, Y340H) resulted in Crouzon phenotype exclusively. Our data provide conclusive evidence that the mutational spectrum of FGFR2 mutations in CS and PS is wider than originally thought. Genotype-phenotype analyses based on our cohort and previous studies further indicate that in spite of some overlap, PS and CS are preferentially accounted for by two distinct sets of FGFR2 mutations. A limited number of recurrent amino-acid changes (W290C, Y340C, C342R and S351C) is commonly associated with the most severe Pfeiffer phenotypes of poor prognosis.

Authors+Show Affiliations

1INSERM U 393, Hôpital Necker-Enfants malades, Paris, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16418739

Citation

Lajeunie, Elisabeth, et al. "Mutation Screening in Patients With Syndromic Craniosynostoses Indicates That a Limited Number of Recurrent FGFR2 Mutations Accounts for Severe Forms of Pfeiffer Syndrome." European Journal of Human Genetics : EJHG, vol. 14, no. 3, 2006, pp. 289-98.
Lajeunie E, Heuertz S, El Ghouzzi V, et al. Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome. Eur J Hum Genet. 2006;14(3):289-98.
Lajeunie, E., Heuertz, S., El Ghouzzi, V., Martinovic, J., Renier, D., Le Merrer, M., & Bonaventure, J. (2006). Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome. European Journal of Human Genetics : EJHG, 14(3), 289-98.
Lajeunie E, et al. Mutation Screening in Patients With Syndromic Craniosynostoses Indicates That a Limited Number of Recurrent FGFR2 Mutations Accounts for Severe Forms of Pfeiffer Syndrome. Eur J Hum Genet. 2006;14(3):289-98. PubMed PMID: 16418739.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome. AU - Lajeunie,Elisabeth, AU - Heuertz,Solange, AU - El Ghouzzi,Vincent, AU - Martinovic,Jelena, AU - Renier,Dominique, AU - Le Merrer,Martine, AU - Bonaventure,Jacky, PY - 2006/1/19/pubmed PY - 2006/5/26/medline PY - 2006/1/19/entrez SP - 289 EP - 98 JF - European journal of human genetics : EJHG JO - Eur J Hum Genet VL - 14 IS - 3 N2 - Crouzon Syndrome (CS), Pfeiffer syndrome (PS) and the phenotypically related Jackson-Weiss (JW) variant are three craniosynostotic conditions caused by heterozygous mutations in Fibroblast Growth Factor Receptor (FGFR) genes. Screening a large cohort of 84 patients with clinical features of CS, PS or JW by direct sequencing of genomic DNA, enabled FGFR1, 2 or 3 mutation detection in 79 cases. Mutations preferentially occurred in exons 8 and 10 of FGFR2 encoding the third Ig loop of the receptor. Among the 74 FGFR2 mutations that we identified, four were novel including three missense substitutions causing CS and a 2 bp deletion creating a premature stop codon and producing JW phenotype. Five FGFR2 mutations were found in one of the two tyrosine kinase subdomains and one in the Ig I loop. Interestingly, two FGFR2 mutations creating cysteine residues (W290C and Y340C) caused severe forms of PS while conversion of the same residues into another amino-acid (W290G/R, Y340H) resulted in Crouzon phenotype exclusively. Our data provide conclusive evidence that the mutational spectrum of FGFR2 mutations in CS and PS is wider than originally thought. Genotype-phenotype analyses based on our cohort and previous studies further indicate that in spite of some overlap, PS and CS are preferentially accounted for by two distinct sets of FGFR2 mutations. A limited number of recurrent amino-acid changes (W290C, Y340C, C342R and S351C) is commonly associated with the most severe Pfeiffer phenotypes of poor prognosis. SN - 1018-4813 UR - https://www.unboundmedicine.com/medline/citation/16418739/Mutation_screening_in_patients_with_syndromic_craniosynostoses_indicates_that_a_limited_number_of_recurrent_FGFR2_mutations_accounts_for_severe_forms_of_Pfeiffer_syndrome_ L2 - http://www.diseaseinfosearch.org/result/5702 DB - PRIME DP - Unbound Medicine ER -