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Rare mutations of FGFR2 causing apert syndrome: identification of the first partial gene deletion, and an Alu element insertion from a new subfamily.
Hum Mutat. 2009 Feb; 30(2):204-11.HM

Abstract

Apert syndrome (AS) is a severe disorder, characterized by craniosynostosis and complex syndactyly of the hands and feet. Two heterozygous gain-of-function substitutions (Ser252Trp and Pro253Arg) in exon IIIa of fibroblast growth factor receptor 2 (FGFR2) are responsible for >98% of cases. Here we describe two novel mutations in FGFR2 in the two patients in whom a mutation had not previously been found in our cohort of 227 AS cases. The first is a 1.93-kb deletion, removing exon IIIc and substantial portions of the flanking introns. This is the first large FGFR2 deletion described in any individual with craniosynostosis. The other mutation is a 5' truncated Alu insertion into exon IIIc. This is the third Alu insertion identified in AS; all have occurred within an interval of only 104 bp, representing an enrichment of over a million-fold compared to the background genomic rate. We show that the inserted Alu element belongs to a small subfamily, not previously known to be mobile, which we term Alu Yk13. Both the deletion and insertion are likely to act by a similar gain-of-function mechanism in which disruption of exon IIIc leads to illegitimate mesenchymal expression of an FGFR2 spliceform containing the alternatively spliced exon IIIb. All the AS-associated Alu insertions have arisen in the paternal germline; we propose that their enrichment in FGFR2 is driven by positive selection of the mutant spermatogonial progenitors, a mechanism analogous to that explaining why the canonical AS nucleotide substitutions also reach exceptionally high levels in sperm.

Authors+Show Affiliations

Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.No 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

Language

eng

PubMed ID

18726952

Citation

Bochukova, Elena G., et al. "Rare Mutations of FGFR2 Causing Apert Syndrome: Identification of the First Partial Gene Deletion, and an Alu Element Insertion From a New Subfamily." Human Mutation, vol. 30, no. 2, 2009, pp. 204-11.
Bochukova EG, Roscioli T, Hedges DJ, et al. Rare mutations of FGFR2 causing apert syndrome: identification of the first partial gene deletion, and an Alu element insertion from a new subfamily. Hum Mutat. 2009;30(2):204-11.
Bochukova, E. G., Roscioli, T., Hedges, D. J., Taylor, I. B., Johnson, D., David, D. J., Deininger, P. L., & Wilkie, A. O. (2009). Rare mutations of FGFR2 causing apert syndrome: identification of the first partial gene deletion, and an Alu element insertion from a new subfamily. Human Mutation, 30(2), 204-11. https://doi.org/10.1002/humu.20825
Bochukova EG, et al. Rare Mutations of FGFR2 Causing Apert Syndrome: Identification of the First Partial Gene Deletion, and an Alu Element Insertion From a New Subfamily. Hum Mutat. 2009;30(2):204-11. PubMed PMID: 18726952.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rare mutations of FGFR2 causing apert syndrome: identification of the first partial gene deletion, and an Alu element insertion from a new subfamily. AU - Bochukova,Elena G, AU - Roscioli,Tony, AU - Hedges,Dale J, AU - Taylor,Indira B, AU - Johnson,David, AU - David,David J, AU - Deininger,Prescott L, AU - Wilkie,Andrew O M, PY - 2008/8/30/pubmed PY - 2009/4/11/medline PY - 2008/8/30/entrez SP - 204 EP - 11 JF - Human mutation JO - Hum Mutat VL - 30 IS - 2 N2 - Apert syndrome (AS) is a severe disorder, characterized by craniosynostosis and complex syndactyly of the hands and feet. Two heterozygous gain-of-function substitutions (Ser252Trp and Pro253Arg) in exon IIIa of fibroblast growth factor receptor 2 (FGFR2) are responsible for >98% of cases. Here we describe two novel mutations in FGFR2 in the two patients in whom a mutation had not previously been found in our cohort of 227 AS cases. The first is a 1.93-kb deletion, removing exon IIIc and substantial portions of the flanking introns. This is the first large FGFR2 deletion described in any individual with craniosynostosis. The other mutation is a 5' truncated Alu insertion into exon IIIc. This is the third Alu insertion identified in AS; all have occurred within an interval of only 104 bp, representing an enrichment of over a million-fold compared to the background genomic rate. We show that the inserted Alu element belongs to a small subfamily, not previously known to be mobile, which we term Alu Yk13. Both the deletion and insertion are likely to act by a similar gain-of-function mechanism in which disruption of exon IIIc leads to illegitimate mesenchymal expression of an FGFR2 spliceform containing the alternatively spliced exon IIIb. All the AS-associated Alu insertions have arisen in the paternal germline; we propose that their enrichment in FGFR2 is driven by positive selection of the mutant spermatogonial progenitors, a mechanism analogous to that explaining why the canonical AS nucleotide substitutions also reach exceptionally high levels in sperm. SN - 1098-1004 UR - https://www.unboundmedicine.com/medline/citation/18726952/Rare_mutations_of_FGFR2_causing_apert_syndrome:_identification_of_the_first_partial_gene_deletion_and_an_Alu_element_insertion_from_a_new_subfamily_ L2 - https://doi.org/10.1002/humu.20825 DB - PRIME DP - Unbound Medicine ER -